Retracted: Anticancer Activity of Phloretin Against Human Gastric Cancer Cell Lines Involves Apoptosis, Cell Cycle Arrest, and Inhibition of Cell Invasion and JNK Signalling Pathway.

This publication has been retracted by the Editor due to concerns regarding the originality of the figure images. Reference: Min Xu, Weiguang Gu, Zhou Shen, Fang Wang. Anticancer Activity of Phloretin Against Human Gastric Cancer Cell Lines Involves Apoptosis, Cell Cycle Arrest, and Inhibition of Cell Invasion and JNK Signalling Pathway. Med Sci Monit, 2018; 24: 6551-6558. DOI: 10.12659/MSM.910542.

Anticancer Activity of Phloretin Against Human Gastric Cancer Cell Lines Involves Apoptosis, Cell Cycle Arrest, and Inhibition of Cell Invasion and JNK Signalling Pathway.

BACKGROUND Gastric cancer is one of most commonly diagnosed cancers and causes significant mortality worldwide. In this study, the antiproliferative and anticancer effects of Phloretin were evaluated against gastric cancer cell lines. MATERIAL AND METHODS MTT assay was used to assess the proliferation rate of gastric cancer cells. DAPI and annexin V/PI were used for detection of apoptotic cell death. Cell invasion was investigated by Transwell assays and the expression of the proteins was estimated by immunoblotting. RESULTS The results revealed that Phloretin exerts anticancer effects on all the gastric cancer cell lines used in this study. However, the anticancer effects were more significant (p<0.05) on the AGS cell line. Further, the effect of Phloretin on the viability of normal GES-1 cells was minimal. Apoptosis assays showed that Phloretin triggers apoptotic cell death in AGS gastric cancer cells. Phloretin could also cause the arrest of the AGS gastric cancer cells in the G2/M phase of the cell cycle and suppress their ability to migrate. Western blotting analysis revealed that Phloretin significantly decreased the expression of p-JNK and p-38. However, comparatively lower effects were observed on the expression of JNK and P38. CONCLUSIONS We showed that Phloretin is an important molecule for the treatment of gastric cancer.

A phase I study of nedaplatin, pemetrexed and thoracic intensity-modulated radiotherapy for inoperable stage III lung adenocarcinoma.

BACKGROUND: Concurrent chemotherapy and radiation is the standard treatment for unresectable stage III Lung adenocarcinoma. However, no optimal concurrent chemotherapeutic regimen has been described. This study aimed to assess concurrent pemetrexed, nedaplatin and thoracic intensity-modulated radiotherapy followed by consolidation pemetrexed/nedaplatin for unresectable Stage IIIA/B lung adenocarcinoma. METHODS: Patients with unresectable stage III lung adenocarcinoma received thoracic intensity-modulated radiotherapy at 60-64 Gy in 30-32 fractions, concurrently with two cycles of 500 mg/m2 pemetrexed, with nedaplatin doses escalating from 60 mg/m2 (level 1) to 70 mg/m2 (level 2) and 80 mg/m2 (level 3). Consolidation consisted of three pemetrexed/nedaplatin (500 mg/m2, 60 mg/m2) cycles every 3 weeks after concurrent therapy. The primary objective of the safety was to determine the maximum-tolerated dose (MTD). The secondary endpoints included response rate, PFS and OS. RESULTS: Fifteen patients were enrolled, including 3, 6 and 6 individuals in the first, second, and third dose levels, respectively. Three cases of dose-limiting toxicities (grade 3 hepatitis, pneumonitis, and grade 4 thrombocytopenia), including one and two patients at levels 2 and 3, respectively, were observed and resulted in discontinued/delayed treatment. Response rates were 86.7 % (95 % confidence interval [CI], 64.2-97.8 %) and 64.3 % (95 % CI, 38.3-85.4 %) at chemoradiation and treatment completions, respectively. Median OS was 30.0 months (95 % CI, 16.4-43.6 months); 2-year OS was 44.0 % (95 % CI, 18.7-69.2 %). Median PFS was 12.0 months (95 % CI, 6.9-17.0 months), and the 2-year PFS 27.0 % (95 % CI, 4.7-49.3 %). CONCLUSIONS: Full dose 500 mg/m2 of pemetrexed and nedaplatin 70 mg/m2 could be used safely with thoracic intensity-modulated radiotherapy for inoperable stage III lung adenocarcinoma. Further evaluation of stage III lung adenocarcinoma management is warranted. TRIAL REGISTRATION: This study was retrospectively registered at Chinese Clinical Trial Registry ( ChiCTR-OPN-16008316 , April 2016).

Ruthenium Complexes Induce HepG2 Human Hepatocellular Carcinoma Cell Apoptosis and Inhibit Cell Migration and Invasion through Regulation of the Nrf2 Pathway.

Ruthenium (Ru) complexes are currently the focus of substantial interest because of their potential application as chemotherapeutic agents with broad anticancer activities. This study investigated the in vitro and in vivo anticancer activities and mechanisms of two Ru complexes-2,3,7,8,12,13,17,18-Octaethyl-21H,23H-porphine Ru(II) carbonyl (Ru1) and 5,10,15,20-Tetraphenyl-21H,23H-porphine Ru(II) carbonyl (Ru2)-against human hepatocellular carcinoma (HCC) cells. These Ru complexes effectively inhibited the cellular growth of three human hepatocellular carcinoma (HCC) cells, with IC50 values ranging from 2.7-7.3 µM. In contrast, the complexes exhibited lower toxicity towards L02 human liver normal cells with IC50 values of 20.4 and 24.8 µM, respectively. Moreover, Ru2 significantly inhibited HepG2 cell migration and invasion, and these effects were dose-dependent. The mechanistic studies demonstrated that Ru2 induced HCC cell apoptosis, as evidenced by DNA fragmentation and nuclear condensation, which was predominately triggered via caspase family member activation. Furthermore, HCC cell treatment significantly decreased the expression levels of Nrf2 and its downstream effectors, NAD(P)H: quinone oxidoreductase 1 (NQO1) and heme oxygenase 1 (HO1). Ru2 also exhibited potent in vivo anticancer efficacy in a tumor-bearing nude mouse model, as demonstrated by a time- and dose-dependent inhibition on tumor growth. The results demonstrate the therapeutic potential of Ru complexes against HCC via Nrf2 pathway regulation.

Enzyme/pH Dual-Responsive Engineered Nanoparticles for Improved Tumor Immuno-Chemotherapy.

Combining immune checkpoint blockade (ICB) therapy with chemotherapy can enhance the efficacy of ICB and expand its indications. However, the limited tumor specificity of chemotherapy drugs results in severe adverse reactions. Additionally, the low tissue penetration and immune-related adverse events associated with monoclonal antibodies restrict their widespread application. To address challenges faced by traditional combination therapies, we design a dual-responsive engineered nanoparticle based on ferritin (denoted as CMFn@OXA), achieving tumor-targeted delivery and controlled release of the anti-PD-L1 peptide CLP002 and oxaliplatin (OXA). Our results demonstrate that CMFn@OXA not only exhibits tumor-specific accumulation but also responds to matrix metalloproteinase-2/9 (MMP-2/9), facilitating the controlled release of CLP002 to block PD-1/PD-L1 interaction. Simultaneously, it ensures the precise delivery of the OXA to tumor cells and its subsequent release within the acidic environment of lysosomes, thereby fostering a synergistic therapeutic effect. Compared to traditional combination therapies, CMFn@OXA demonstrates superior performance in inhibiting tumor growth, extending the survival of tumor-bearing mice, and exhibiting excellent biocompatibility. Collectively, our results highlight CMFn@OXA as a novel and promising strategy in the field of cancer immunotherapy.

MDSC-targeting gold nanoparticles enhance PD-1 tumor immunotherapy by inhibiting NLRP3 inflammasomes.

Myeloid-derived suppressor cells (MDSCs) play a crucial role in the immune escape mechanisms that limit the efficacy of immunotherapeutic strategies. In the tumor microenvironment, NLRP3 inflammasome-driven Interleukin-1ß (IL-1ß) production serves to dampen antitumor immune responses, promoting tumor growth, progression, and immunosuppression. In this study, we revealed that gold nanoparticles (Au NPs) with a size of 30 nm disrupted NLRP3 inflammasome, but not other inflammasomes, in bone marrow-derived macrophages through abrogating NLRP3-NEK7 interactions mediated by reactive oxygen species (ROS). Density functional theory (DFT) calculations provided insights into the mechanism underlying the exceptional ROS scavenging capabilities of Au NPs. Additionally, when coupled with H6, a small peptide targeting MDSCs, Au NPs demonstrated the capacity to effectively reduce IL-1ß levels and diminish the MDSCs population in tumor microenvironment, leading to enhanced T cell activation and increased immunotherapeutic efficacy in mouse tumor models that are sensitive and resistant to PD-1 inhibition. Our findings unraveled a novel approach wherein peptide-modified Au NPs relieved the suppressive impact of the tumor microenvironment by inhibiting MDSCs-mediated IL-1ß release, which is the first time reported the employing a nanostrategy at modulating MDSCs to reverse the immunosuppressive microenvironment and may hold promise as a potential therapeutic agent for cancer immunotherapy.

Apatinib successfully administered in malignant tumour patients with severe hypotension: a case series, literature review, and considerations for treatment.

The most notable side-effect of apatinib, a novel antiangiogenic agent for the treatment of cancer, is hypertension, but there are few published studies regarding the use of apatinib to treat patients with cancer and severe hypotension. Here, the cases of three patients with tumours and severe hypotension are described: case 1, a 73-year-old male patient with lung squamous cell carcinoma who initially received radiotherapy and chemotherapy, and developed pneumonia and severe hypotension after 6 months; case 2, a 56-year-old male patient with nasopharyngeal carcinoma who was treated with chemotherapy and presented with fever and persistent hypotension; and case 3, a 77-year-old male patient with oesophageal cancer who was admitted with deglutition difficulty and severe hypotension. Apatinib was added to the treatment regimen of all three patients for antitumor therapy. Pneumonia, tumour progression, and severe hypotension improved noticeably in all patients within 1 month after receiving apatinib. Apatinib was associated with a positive effect on blood pressure stability, in synergy with other means of therapy, and the patients achieved satisfactory short-term clinical results. The role of apatinib in treating patients with cancer and hypotension merits further investigation.

DNA damage response and repair gene mutations are associated with tumor mutational burden and outcomes to platinum-based chemotherapy/immunotherapy in advanced NSCLC patients.

BACKGROUND: DNA damage response and repair (DDR) genes are crucial for maintaining the integrity of the genome. This study aims to explore the correlation of DDR gene mutations with TMB, clinical characteristics, and outcomes to platinum-based chemotherapy and platinum-based chemotherapy/immunotherapy in non-small cell lung cancer (NSCLC) without EGFR and ALK alterations. METHODS: Tumor tissue from 49 patients with stage III or IV NSCLC who were without EGFR and ALK alterations were analyzed using targeted next-generation sequencing (NGS). Among them, 13 patients received first-line platinum-based chemotherapy, 32 patients received first-line platinum-based chemotherapy/immunotherapy. RESULTS: In these NSCLC patients without EGFR and ALK alterations, the frequently mutated genes included TP53, KMT2D and KRAS, the most frequently mutated DDR gene was FANCG, DDR gene mutations were detected in 20 patients. The mutation frequency of homologous recombination (HR) pathway was significantly higher in lung squamous cell carcinoma (LUSC) than that in lung adenocarcinoma (LUAD) (30.8% vs. 5.7%). Among DDR positive patients, a lower percentage exhibited metastasis. Patients with DDR gene mutations, cell-cycle checkpoint pathway mutations, and BER pathway mutations had significantly higher TMB compared to those without corresponding mutations. In the patients receiving platinum-based chemotherapy/immunotherapy, the disease control rate was significantly lower in the DDR-positive group compared with that in the DDR-negative group (55.6% vs. 100.0%). Among LUAD patients receiving platinum-based chemotherapy/immunotherapy, we observed a worse overall survival (OS) in DDR-positive group, as well as poorer progression-free survival(PFS)and OS in BER-positive and FANCG mutated group. CONCLUSIONS: DDR gene mutations are associated with tumor metastasis, TMB, and outcomes to platinum-based chemotherapy/immunotherapy in advanced NSCLC patients.

Monitoring of gastrointestinal carcinoma via molecular residual disease with circulating tumor DNA using a tumor-informed assay.

BACKGROUND: Circulating tumor DNA (ctDNA)-based minimal residual disease (MRD) detection, which can identify disease relapse ahead of radiological imaging, has shown promising performance. The objective of this study was to develop and validate OriMIRACLE S (Minimal Residual Circulating Nucleic Acid Longitudinal Detection in Solid Tumor), a highly sensitive and specific tumor-informed assay for MRD detection. METHODS: Tumor-specific somatic single nucleotide variants (SNVs) were identified via whole exome sequencing of tumor tissue and matched germline DNA. Clonal SNVs were selected using the OriSelector algorithm for patient-specific, multiplex PCR-based NGS assays in MRD detection. Plasma-free DNA from patients with gastrointestinal tumors prior to and following an operation, and during monitoring, were ultradeep sequenced. RESULTS: The detection of three positive sites was sufficient to achieve nearly 100% overall sample level sensitivity and specificity and was determined by calculating binomial probability based on customized panels containing 21 to 30 variants. A total of 127 patients with gastrointestinal tumors were enrolled in our study. Preoperatively, MRD was positive in 18 of 26 patients (69.23%). Following surgery, MRD was positive in 24 of 82 patients (29.27%). The positivity rate for MRD was 33.33% (n = 18) for gastric adenocarcinoma and 32.26% (n = 62) for colorectal cancer. Twenty (20) of 59 patients (34.48%) experienced a change in MRD status over the monitoring period. Patients 8 and 31 responded to 3 cycles of systemic therapy, after which levels for all ctDNA dropped below the detection limit. Patient 53 was an example of using MRD to predict tumor metastasis. Patient 55 showed a weak response to treatments first and respond to new systemic therapy after tumor progression. CONCLUSION: Our study identified a sensitive and specific clinical detection method for low frequency ctDNA, and explored the detection performance of this technology in gastrointestinal tumors.

EGFR-TKI Combined with Pemetrexed versus EGFR-TKI Monotherapy in Advanced EGFR-mutated NSCLC: A Prospective, Randomized, Exploratory Study.

PURPOSE: We aimed to evaluate whether the addition of pemetrexed is effective in improving progression-free survival (PFS) in epidermal growth factor receptor (EGFR)-mutated patients with or without concomitant alterations. Materials and Methods: This multicenter clinical trial was conducted in China from June 15, 2018, to May 31, 2019. A total of 92 non-small cell lung cancer (NSCLC) patients harboring EGFR-sensitive mutations were included and divided into concomitant and non-concomitant groups. Patients in each group were randomly treated with EGFR-tyrosine kinase inhibitor (TKI) monotherapy or EGFR-TKI combined with pemetrexed in a ratio of 1:1. PFS was recorded as the primary endpoint. RESULTS: The overall median PFS of this cohort was 10.1 months. There were no significant differences in PFS between patients with and without concomitant and between patients received TKI monotherapy and TKI combined with pemetrexed (p=0.210 and p=0.085, respectively). Stratification analysis indicated that patients received TKI monotherapy had a significantly longer PFS in non-concomitant group than that in concomitant group (p=0.002). In concomitant group, patients received TKI combined with pemetrexed had a significantly longer PFS than patients received TKI monotherapy (p=0.013). Molecular dynamic analysis showed rapidly emerging EGFR T790M in patients received TKI monotherapy. EGFR mutation abundance decreased in patients received TKI combined chemotherapy, which supports better efficacy for a TKI combined chemotherapy as compared to TKI monotherapy. A good correlation between therapeutic efficacy and a change in circulating tumor DNA (ctDNA) status was found in 66% of patients, supporting the guiding role of ctDNA minimal residual disease (MRD) in NSCLC treatment. CONCLUSION: EGFR-TKI monotherapy is applicable to EGFR-sensitive patients without concomitant alterations, while a TKI combined chemotherapy is applicable to EGFR-sensitive patients with concomitant alterations. CtDNA MRD may be a potential biomarker for predicting therapeutic efficacy.

Elevated pretreatment neutrophil-to-lymphocyte ratio indicate low survival rate in apatinib-treated patients with non-small cell lung cancer: A STROBE-compliant article.

This study aimed to analyze the predictive value of the neutrophil-to-lymphocyte ratio (NLR) to better clarify which patients with advanced non-small cell lung cancer (NSCLC) would benefit most from apatinib after multiline treatment for drug resistance. This observational cohort study involved patients with advanced NSCLC who were treated with apatinib between May 2016 to May 2018. The participants in this study had previously been treated with at least two treatment regimens. Multivariate logistic regression and Cox proportional risk models were used to evaluate the overall survival (OS) and progression-free survival (PFS) of the pretreatment NLR. A total of 125 patients were reviewed. The median age was 64 years (range, 33-92); and 32.8% of the patients were female. Only 0.8% of the patients had an Eastern Cooperative Oncology Group Performance Status (ECOG-PS) score ≥ 2. In multivariate analysis, pretreatment NLR ≥ 5 had an independent correlation with inferior OS (median 2.07 vs 3.40 months; HR 1.493, 95% CI 1.022-2.182; P = .038) and inferior PFS (median 1.83 vs 2.76 months; HR 1.478, 95% CI 1.015-2.153; P = .042). Elevated pretreatment NLR is associated with shorter OS and PFS in patients with advanced NSCLC treated with apatinib after multiline treatment for drug resistance.

Case report: EGFR-mutant lung adenocarcinoma with the TP53 and RB1 mutations showed resistance to TKI therapy.

Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) are a standard treatment for patients with advanced non-small-cell lung cancer (NSCLC) harboring classic EGFR mutations. However, resistance to TKIs remains a major clinical challenge. The transformation from adenocarcinoma to small-cell lung cancer (SCLC) is a rare resistance mechanism to EGFR-TKIs. In this article, we report on 2 lung adenocarcinoma patients with EGFR mutations who developed EGFR-TKI resistance. In case one, the patient was initially diagnosed as lung adenocarcinoma with EGFR L858R, RB1 R445*, and TP53 Y205C mutations. EGFR-TKI failed to bring satisfactory curative effect with the emergence of EGFR T790M mutation and MET amplification and finally passed away. In case two, the patient was diagnosed with lung cancer harboring EGFR L747 and TP53 R342* mutations, and EGFR-TKIs brought a progression-free survival for nine months. However, EGFR-TKI resistance was acquired, and adenocarcinoma transformed into a complex of neuroendocrine carcinoma, SCLC, and lung adenocarcinoma, with the emergence of the EGFR L747, TP53 R342*, and RB1 mutations. Follow-up treatments failed to prevent tumor progression, and the patient died These 2 cases expand our understanding of EGFR-TKI resistance, SCLC transformation, and highlight the importance of histopathology and molecular characteristics for therapeutic strategies for transformed SCLC patients.

Low Infiltration of CD8+ PD-L1+ T Cells and M2 Macrophages Predicts Improved Clinical Outcomes After Immune Checkpoint Inhibitor Therapy in Non-Small Cell Lung Carcinoma.

BACKGROUND: Many clinical studies have shown that patients with non-small cell lung carcinoma (NSCLC) can benefit from immune checkpoint inhibitor (ICI) therapy; however, PD-L1 and tumor mutation burden (TMB), which are recommended by the NCCN guidelines, are still insufficient in predicting the response to and prognosis of immunotherapy. Given the widespread use of ICIs, it is important to find biomarkers that can predict immunotherapy outcomes in NSCLC patients, and the exploration of additional effective biomarkers for ICI therapy is urgently needed. METHODS: A total of 33 stage II-IV NSCLC patients were included in this study. We analyzed immune markers in biopsy and surgical tissue resected from these patients before treatment with ICIs. We examined the infiltration of immune cells and expression of PD-L1 in immune cells using fluorescent multiplex immunohistochemistry (mIHC) stained with CD8/CD68/CD163/PD-L1 antibodies. RESULTS: In this cohort, we observed that the levels of CD8+ T cells, CD8+PD-L1+ T cells, and CD68+CD163+ M2 macrophages in the total region were independent prognostic factors for progression-free survival (PFS) in NSCLC patients treated with ICIs (HR=0.04, P=0.013; HR=17.70, P=0.026; and HR=17.88, P=0.011, respectively). High infiltration of CD8+ T cells and low infiltration of CD8+PD-L1+ T cells throughout the region were correlated with prolonged PFS (P=0.016 and P=0.02, respectively). No statistically significant difference was observed for CD68+CD163+ M2 macrophages. The joint parameters CD8+ high/CD8+PD-L1+ low, CD8+ high/CD68+CD163+ low and CD8+PD-L1+ low/CD68+CD163+ low predicted better PFS than other joint parameters (P<0.01, P<0.01, and P<0.001, respectively), and they also demonstrated stronger stratification than single biomarkers. The response rate of patients with high infiltration of CD8+ T cells was significantly higher than that of those with low infiltration (P<0.01), and the joint parameters CD8+/CD8+PD-L1+ and CD8+/CD68+CD163+ also demonstrated stronger stratification than single biomarkers. CONCLUSIONS: This retrospective study identified the predictive value of CD8+PD-L1+ T cells, CD8+ T cells, and CD68+CD163+ M2 macrophages in NSCLC patients who received ICIs. Interestingly, our results indicate that the evaluation of joint parameters has certain significance in guiding ICI treatment in NSCLC patients.

Efficacy and safety of apatinib as third- or further-line therapy for patients with advanced NSCLC: a retrospective study.

BACKGROUND: Apatinib, an oral small-molecule angiogenesis inhibitor, selectively inhibits vascular endothelial growth factor receptor 2 (VEGFR-2), which inhibits vascular endothelial growth factor (VEGF) stimulated endothelial cell migration and proliferation and decreases tumour growth and metastasis. Recently, the efficacy of multi-target angiogenic drugs has been demonstrated for many cancers, including non-small-cell lung cancer (NSCLC). The aim of this retrospective study was to evaluate the clinical efficacy of apatinib in patients with advanced NSCLC. PATIENTS AND METHODS: We conducted a retrospective analysis of 70 patients with advanced NSCLC who received second-line and later treatment from November 2015 to July 2017 with poor results. Out of the 70 patients, 36 patients received apatinib treatment after second-line or later treatment, whereas 34 patients in the control group did not receive further treatment. The patients were treated with oral apatinib 500 mg once a day every day for 4 weeks per cycle. Treatment was continued in responding and stable patients until disease progression or intolerable toxicity. The objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and side effects of the drug were recorded and reviewed. RESULTS: ORR, DCR, PFS, and OS were evaluated in 36 patients receiving apatinib and 34 patients in the control group. The ORR and DCR in patients receiving apatinib therapy were 22.2% and 77.8%, respectively. The median PFS and OS in the treatment group were 5.6 and 9.6 months, respectively. The median OS in the apatinib group was significantly longer than that in the control group (9.6 versus 3.8 months; p < 0.0001). In contrast, there were no differences in adverse reactions between the patients in the treatment and control groups. CONCLUSION: Apatinib showed favourable efficacy and safety and can thus be used as a treatment option for patients with advanced NSCLC.

PI3K-AKT-mTOR pathway alterations in advanced NSCLC patients after progression on EGFR-TKI and clinical response to EGFR-TKI plus everolimus combination therapy.

BACKGROUND: Several mechanisms including abnormal activation of PI3K-AKT-mTOR pathway have been proved to generate acquired resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in non-small cell lung cancer (NSCLC). In this study, we investigated the genomic characteristics of PI3K pathway activated in NSCLC patients after progression on EGFR-TKIs and whether both targeting EGFR and PI3K pathway could overcome resistance. METHODS: A total of 605 NSCLC cases with a history of EGFR TKI treatment were reviewed, in which 324 patients harboring EGFR mutations were confirmed progression on at least one EGFR TKI and finally enrolled. Tumor tissues or blood samples were collected at the onset of TKI progression for next generation sequencing (NGS). Six EGFR mutant patients with co-occurring mutations in PI3K pathway were retrospectively collected to assess the effect of EGFR TKI plus everolimus, a mTOR inhibitor. RESULTS: Forty-nine (14.9%) patients resistant to EGFR TKIs have at least one genetic variation in PI3K pathway. PIK3CA, PTEN and AKT1 variations were detected in 31 (9.5%), 18 (5.5%) and 3 (0.9%) of patients, respectively. No significant differences were observed in distribution of PI3K pathway alterations among patients with different EGFR mutations (EGFR exon19 deletion mutations/EGFR L858R/uncommon EGFR mutations) and among patients resistant to different EGFR TKIs. For patients treated with everolimus and EGFR-TKI, five (5/6, 83.3%) achieved stable disease (SD) and one (1/6, 16.7%) didn't receive disease control. The median progression-free survival (PFS) was 2.1 months (95% confidence interval, 1.35-4.3 months, range, 0.9-4.4 months). The most common adverse events were dental ulcer (6/6), rash (1/6). CONCLUSIONS: Our study revealed that PI3K pathway was activated in at least 14.9% in EGFR-TKI resistant patients. EGFR-TKIs plus everolimus showed limited antitumor activity in EGFR mutant NSCLC patients with PI3K pathway aberrations.

Molecular gene mutation profiles, TMB and the impact of prognosis in Caucasians and east Asian patients with lung adenocarcinoma.

BACKGROUND: The difference in molecular gene mutation profile, tumor mutational burden (TMB) and their prognostic effects in lung adenocarcinoma between different ethnic groups are still unknown. A retrospective analysis was used to investigate the differences in lung adenocarcinoma driver gene mutations, TMB, and their impact on prognosis across different ethnic groups. METHODS: The incidence of epidermal growth factor receptor (EGFR) mutations and follow-up data of 647 Chinese lung adenocarcinoma patients were compared with the data from 522 Caucasian patients in The Cancer Genome Atlas (TCGA) database. Moreover, a comprehensive analysis was performed to compare the differences in gene mutation frequency, signaling pathway variation, and TMB using the whole-exome sequencing (WES) data of Chinese patients with that of Caucasian patients. RESULTS: A comparison of tumor signaling pathways and gene mutation profiles between Caucasians and Chinese revealed ethnic variations in the incidence of mutations in TGF-ß and RTK-RAS signaling pathways, with P values of 0.012 and 0.016, respectively. In the Caucasian population, the mutations in 5 signaling pathways and 18 genes were all significantly correlated with TMB, whereas in the Chinese population, only mutations in the Notch pathway and 6 genes were found to be associated with TMB-high. EGFR mutations showed a better prognosis in Chinese patients with lung adenocarcinoma, while the opposite was found in Caucasians patients. CONCLUSIONS: Variations in the incidence of mutations in signaling pathways involved in lung adenocarcinoma and the correlation of the signaling pathways with TMB may exist across different ethnic groups.

Comprehensive genomic profiling of small cell lung cancer in Chinese patients and the implications for therapeutic potential.

BACKGROUND: Small cell lung cancer (SCLC) is one of the deadliest malignancies and accounts for nearly 15% of lung cancers. Previous study had revealed the genomic characterization of SCLC in Western patients. However, little is known about that in Chinese SCLC patients. METHODS: Formalin-fixed paraffin-embedded tumor tissues and matched blood samples from 122 Chinese SCLC patients were collected for next generation sequencing to detect 450 cancer-related genes. All pathological diagnoses were confirmed by independent pathologists. RESULTS: The most frequently altered genes were TP53 (93.4%), RB1 (78.7%), LRP1B (18.9%), KMT2D (15.6%), FAT1 (11.5%), KMT2C (11.5%), SPTA1 (11.5%), STK24 (11.5%), FAM135B (10.7%), and NOTCH1 (10.7%). The gene fusion/rearrangement detection rate was 16.4%, and mostly occurred in chromosomes 7 and 17. The rate of co-occurring mutations of TP53 and RB1 in these Chinese SCLC patients was 74.6%, and lower than the reported Western patients (90.9%, P = 0.007). The most common gene mutations (83.6%) were found in cell cycle signaling pathway in Chinese SCLC patients. Mutation of Wnt and Notch signaling pathways in the Chinese cohort were lower than Western cohort (P = 0.0013 and 0.0068). A significant association was found between high tumor mutation burden and mutations involved in FAT1, TP53, SPTA1, KEAP1, KMT2D, MAGI2, NOTCH2, NOTCH3, FLT1, KDM6A, and FAT4. CONCLUSIONS: In this study, we characterized the genomic alterations profile of Chinese SCLC patients. Compared with westerners, the genetic alterations of Chinese SCLC patients presented different patterns. Our data might provide useful information in targeted therapy and drug development for Chinese SCLC patients.

Comprehensive molecular profiling of extrahepatic cholangiocarcinoma in Chinese population and potential targets for clinical practice.

BACKGROUND: Cholangiocarcinoma (CCA) is a diverse group of malignancies arising from the intra- or extrahepatic biliary epithelium and characterized by its late diagnosis and fatal outcome. Extrahepatic cholangiocarcinoma (ECC) accounts for 90% of CCA. However, little is known about the comprehensive genomic alterations of ECC in Chinese population for providing clinical managements especially targeted therapy. METHODS: Comprehensive genomic profiling (CGP) was performed with next generation sequencing panel on paraffin-embedded tumor from a cohort of 80 Chinese ECC patients. RESULTS: The most frequently altered genes were TP53 (68%), KRAS (46%), SMAD4 (22%), ARID1A (20%) and CDKN2A (19%). Mutual exclusivity was observed between multiple genes including ARID1A:TP53, KRAS:LRP1B and NF2:TP53. Genetic alterations with potential therapeutic implications were identified in 43% of patients. The top three actionable alterations include CDKN2A (n=11), BRAF (n=5) and ERBB2 (n=4). Potentially actionable alterations were mainly enriched in the G1-S transition, homologous recombination repair, MAPK/ERK pathway. CONCLUSIONS: This is the largest data set of ECC cases providing a comprehensive view on genetic alterations in Chinese population which differs significantly from a US cohort, and indicates the potential clinical implications for targeted therapies.

Overexpression of miR-758 inhibited proliferation, migration, invasion, and promoted apoptosis of non-small cell lung cancer cells by negatively regulating HMGB.

Non-small cell lung cancer (NSCLC) is one of the most fatal types of cancer with significant mortality and morbidity worldwide. MicroRNAs (miRs) have been confirmed to have positive functions in NSCLC. In the present study, we try to explore the role of miR-758 in proliferation, migration, invasion, and apoptosis of NSCLC cells by regulating high-mobility group box (HMGB) 3 (HMGB3.) NSCLC and adjacent tissues were collected. Reverse transcription quantitative PCR (RT-qPCR) was employed to detect expression of miR-758 and HMGB3 in NSCLC and adjacent tissues, in BEAS-2B cells and NSCLC cell lines. The targetted relationship between miR-758 and HMGB3 was identified by dual luciferase reporter gene assay. The effects of miR-758 on proliferation, migration, invasion, cell cycle, and apoptosis of A549 cells. MiR-758 expression was lower in NSCLC tissues, which was opposite to HMGB3 expression. The results also demonstrated that miR-758 can target HMGB3. The cells transfected with miR-758 mimic had decreased HMGB3 expression, proliferation, migration, and invasion, with more arrested cells in G1 phase and increased apoptosis. Our results supported that the overexpression of miR-758 inhibits proliferation, migration, and invasion, and promotes apoptosis of NSCLC cells by negative regulating HMGB2. The present study may provide a novel target for NSCLC treatment.

Chemotherapy with or without pemetrexed as second-line regimens for advanced non-small-cell lung cancer patients who have progressed after first-line EGFR TKIs: a systematic review and meta-analysis.

PURPOSE: The development of acquired resistance to the first-line epidermal growth factor-tyrosine kinase inhibitor (EGFR-TKI) treatment in non-small-cell lung cancer (NSCLC) is inevitable, and most of these patients needed second-line chemotherapy. Furthermore, the optimum chemotherapeutic regimen is unclear. The aim of this meta-analysis was to evaluate the chemotherapeutic regimens "with-pemetrexed" versus "non-pemetrexed" in advanced NSCLC patients who had progressed after first-line EGFR-TKIs. MATERIALS AND METHODS: We searched PubMed, Embase, Cochrane Library, and the Web of science for relevant clinical trials. Outcomes analyzed were response rate (RR), disease control rate (DCR), 1-year survival rate (1-year SR), progression-free survival (PFS), and overall survival (OS). RESULTS: One randomized controlled trial (RCT) and three retrospective studies were included in this meta-analysis, covering a total of 354 patients. The results showed that there was no significant difference between with-pemetrexed arm and non-pemetrexed arm in RR (OR 1.43, 95% CI 0.85-2.41, P=0.18), DCR (OR 1.5, 95% CI 0.94-2.39, P=0.09), and 1-year SR (OR 1.47, 95% CI 0.79-2.74, P=0.22). But the with-pemetrexed chemotherapeutic regimens significantly improved the PFS (HR 0.61, 95% CI 0.46-0.81, P=0.0005) and OS (HR 0.62, 95% CI 0.42-0.90, P=0.01). CONCLUSION: The second-line with-pemetrexed chemotherapeutic regimens provided significantly longer PFS and OS than non-pemetrexed chemotherapeutic regimens. These findings indicate that the with-pemetrexed chemotherapeutic regimen may be an optimal second-line chemotherapeutic regimen for patients with advanced NSCLC following EGFR-TKI failure.