Efficacy and safety of local ablative therapy for patients with NSCLC and coexisting interstitial lung disease.

BACKGROUND: The effective therapeutic approach is still an unmet need for patients diagnosed with both lung cancer and interstitial lung disease (ILD). This is primarily due to the possible risk of ILD exacerbation caused by surgery or radiotherapy. The current study aimed to investigate the efficacy and safety of local ablative therapy (LAT) for this specific population. METHODS: Consecutive patients with non-small cell lung cancer (NSCLC) and ILD who received LAT between January 2018 and August 2022 were enrolled, and propensity score matching (PSM) was utilized to match the non-ILD group. The primary endpoint was recurrence-free survival (RFS), and secondary endpoints included overall survival (OS), adverse events (AEs) and hospital length of stay (HLOS). RESULTS: The PSM algorithm yielded matched pairs in the ILD group (n = 25) and non-ILD group (n = 72) at a ratio of 1:3. There were no statistically significant differences in RFS (median 16.4 vs. 18 months; HR = 1.452, p = 0.259) and OS (median: not reached vs. 47.9 months; HR = 1.096, p = 0.884) between the two groups. Meanwhile, no acute exacerbation of ILD was observed in the ILD group. However, the incidence of pneumothorax, especially pneumothorax requiring chest tube drainage, was significantly higher (36.0% vs. 11.2%, p = 0.005) among patients with NSCLC and co-existing ILD, which resulted in longer HLOS (p = 0.045). CONCLUSION: Although ILD was associated with a higher incidence of pneumothorax, the efficacy of LAT for NSCLC patients with ILD was comparable to those without ILD, suggesting that LAT might be a reliable and effective treatment option for this population, particularly in the early stage.

Association of PD-L1 expression with efficacy of alectinib in advanced NSCLC patients with ALK fusion.

BACKGROUND: Programmed cell death-ligand 1 (PD-L1) expression was found to be a biomarker of inferior efficacy of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in EGFR-mutated non-small cell lung cancer (NSCLC). However, whether PD-L1 expression could also serve as a similar biomarker in anaplastic lymphoma kinase (ALK)-positive patients, especially for those treated with front-line alectinib, remains unclear. The aim of the study is to investigate the association of PD-L1 expression and efficacy of alectinib in this setting. METHODS: From January 2018 to March 2020, 225 patients with ALK-rearranged lung cancer were consecutively collected at Shanghai Pulmonary Hospital, Tongji University. Baseline PD-L1 expression was detected using immunohistochemistry (IHC) in 56 patients of advanced ALK-rearranged lung cancer who received front-line alectinib. RESULTS: Among the 56 eligible patients, 30 (53.6%) were PD-L1 expression negative, 19 (33.9%) patients had TPS 1%-49% and 7 (12.5%) had TPS ≥ 50%.We found no statistically significant associations between PD-L1 positivity and objective response rate (ORR, 90.0% vs. 80.8%, p = 0.274) or progression-free survival (PFS, not reached vs. not reached, HR: 0.98, 95 %CI: 0.37-2.61, p = 0.97) in patients treated with alectinib. Meanwhile, patients with PD-L1 high expression (TPS ≥ 50%) had a trend of longer PFS (not reached vs. not reached, p = 0.61). CONCLUSIONS: PD-L1 expression might not serve as a predict biomarker for the efficacy of front-line alectinib in ALK-positive NSCLC patients.

ICI plus chemotherapy prolonged survival over ICI alone in patients with previously treated advanced NSCLC.

OBJECTIVES: Immune checkpoint inhibitors (ICI) monotherapy was standard of care in second-line treatment of patients with advance non-small cell lung cancer (NSCLC). This study aims to investigate the efficacy of ICI plus chemotherapy in patients with previously treated advanced NSCLC. PATIENTS AND METHODS: An investigator-initiated trial (IIT) aiming to evaluate the efficacy and safety of ICI in combination with chemotherapy as second line and beyond for patients with advanced NSCLC was undergone at Shanghai Pulmonary Hospital (ChiCTR1900026203). Patients who received ICI monotherapy as second or later line setting during the same period were also collected as a comparator. RESULTS: From April 2018 to June 2019, 31 patients were included into this IIT study, simultaneously 51 patients treated with ICI monotherapy were selected as a comparator. ICI plus chemotherapy showed a significantly higher ORR (35.5% vs. 15.7%, p=0.039), prolonged PFS (median: 5.6 vs. 2.5 months, p = 0.013) and OS (median: NE vs. 12.6 months, p = 0.038) compared with ICI alone. In the subgroup of negative PD-L1 expression (9 patients in combination group and 12 patients in monotherapy group), ICI plus chemotherapy also had a favorable ORR (44.4% vs. 8.3%, p = 0.119), longer PFS (median: 6.5 vs 3.0 months, p < 0.05) and OS (median: NE vs. 8.2 months, p = 0.117). Meanwhile, the addition of chemotherapy did not increase immune-related adverse events. CONCLUSIONS: ICI plus chemotherapy showed superior ORR, PFS and OS than ICI alone patients with previous treated advanced NSCLC. These findings warrant further investigation.

Case Report: Abscopal Effect of Microwave Ablation in a Patient With Advanced Squamous NSCLC and Resistance to Immunotherapy.

Currently, immunotherapy has been a backbone in the treatment of advanced non-small cell lung cancer (NSCLC) without driver gene mutations. However, only a small proportion of NSCLC patients respond to immune checkpoint inhibitors, and majority of patients with initial response will develop acquired resistance at 5 years, which usually manifests as oligo-progression or oligo-metastases. Evidence from multiple clinical trials indicates that local consolidative therapies could improve the prognosis of oligometastatic NSCLC patients. Herein, we reported a case of advanced squamous lung cancer which showed a durable abscopal effect from microwave ablation after acquired resistance of immunotherapy.

Adenocarcinoma of High-Grade Patterns Associated with Distinct Outcome of First-Line Chemotherapy or EGFR-TKIs in Patients of Relapsed Lung Cancer.

PURPOSE: High-grade patterns (micropapillary/solid/complex gland) are associated with a higher recurrence rate and shorter disease-free survival. Thus far, it remains unclear whether the efficacy of first-line anticancer therapy is different from that of the other adenocarcinoma subgroups for patients with high-grade patterns. The study aimed to investigate the association between an adenocarcinoma with high-grade patterns with the outcomes of first-line treatment in patients with lung cancer. PATIENTS AND METHODS: Patients with a high-grade pattern adenocarcinoma (more than 20% of micropapillary/solid components/complex glandular patterns) were retrospectively analyzed between June 2015 and June 2017. Patients' clinical characteristics and treatment outcomes were compared with those of the remaining control adenocarcinoma subgroups. RESULTS: In total, 239 patients with adenocarcinoma, including 115 (48.1%) high-grade patterns and 124 (51.9%) control groups, were enrolled. Patients' clinical characteristics such as age, sex, smoking status, and stage were similar between the two groups. Among them, 108 patients received first-line chemotherapy, and 131 received epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs). In the chemotherapy group, adenocarcinoma of high-grade patterns had a significantly lower objective response rate (ORR; 15.6% vs 36.4%, P=0.045), shorter progression-free survival (PFS; median 4.1 vs 5.4 months, P=0.007) and overall survival (OS, median 19.6 vs 23.8 months, P=0.048) compared with the control group. As for these treated with EGFR-TKIs, a similar ORR (70.7% vs 72.1%, P=0.703), PFS (median 11.3 vs 13.9 months, P=0.065) and OS (median 34.1 vs 29.6%, p=0.575) were observed between these two groups. CONCLUSION: An adenocarcinoma with high-grade patterns is associated with inferior outcomes to first-line chemotherapy in relapsed lung cancer. Patients who received chemotherapy had a significantly shorter PFS and OS and lower ORR than control subjects, while there was no difference in the EGFR-TKI cohort. This study is the first to report the distribution of adenocarcinoma with high-grade patterns.

High discrepancy in thrombotic events in non-small cell lung cancer patients with different genomic alterations.

BACKGROUND: Acute complications, such as venous thromboembolism (VTE), are common in patients with advanced severe lung cancers. However, current VTE risk scores cannot adequately identify high-risk patients with non-small cell lung cancer (NSCLC). The study proposed to elucidated the incidence of thromboembolism (TE) in patients with different oncogenic aberrations and the impact of these aberrations on the efficacy of targeted therapy in patients with NSCLC. METHODS: A systemic review was conducted in Web of Science, PubMed, Embase and the Cochrane Library to evaluate the incidence of TE in different molecular subtypes of NSCLC. Data from patients diagnosed of advanced NSCLC who harboring anaplastic lymphoma kinase (ALK) or ROS proto-oncogene 1 receptor tyrosine kinase (ROS1) rearrangements since 2016 to 2019 were also retrospectively collected. A meta-analysis with random-effects model, sensitivity analysis and publication bias were performed. The principal summary measure was incidence of thrombotic events in NSCLC patients. And the efficacy of tyrosine kinase inhibitor (TKI) therapy was compared between the two subgroups. RESULTS: A total of 5,767 cases from 20 studies were included in the analysis of the incidence of thrombosis in patients with different oncogenic alterations. The pooled analysis showed a higher risk of thrombosis in ROS1-fusion types (41%, 95% CI: 35-47%) and ALK-fusion types (30%, 95% CI: 24-37%) than in EGFR-mutation (12%, 95% CI: 8-17%), KRAS-mutation (25%, 95% CI: 13-50%), and wild-type (14%, 95% CI: 10-20%) cases. A high prevalence of thrombosis (ALK: 24.4%; ROS1: 32.6%) was observed in the Shanghai Pulmonary Hospital (SPH) cohort of 224 patients with ALK or ROS1 fusion. Furthermore, patients with embolism had significantly shorter progression-free survival (PFS) after TKI therapy than those without embolism, both in the ALK+ cohort (5.6 vs. 12.9 months, P<0.0001) and in the ROS1+ cohort (9.6 vs. 17.6 months, P=0.0481). CONCLUSIONS: NSCLC patients with ALK/ROS1 rearrangements are more likely to develop thrombosis than patients with other oncogenic alterations. Thrombosis may also be associated with an inferior response and PFS after TKI therapy.

Role of hypoxia in cancer therapy by regulating the tumor microenvironment.

AIM: Clinical resistance is a complex phenomenon in major human cancers involving multifactorial mechanisms, and hypoxia is one of the key components that affect the cellular expression program and lead to therapy resistance. The present study aimed to summarize the role of hypoxia in cancer therapy by regulating the tumor microenvironment (TME) and to highlight the potential of hypoxia-targeted therapy. METHODS: Relevant published studies were retrieved from PubMed, Web of Science, and Embase using keywords such as hypoxia, cancer therapy, resistance, TME, cancer, apoptosis, DNA damage, autophagy, p53, and other similar terms. RESULTS: Recent studies have shown that hypoxia is associated with poor prognosis in patients by regulating the TME. It confers resistance to conventional therapies through a number of signaling pathways in apoptosis, autophagy, DNA damage, mitochondrial activity, p53, and drug efflux. CONCLUSION: Hypoxia targeting might be relevant to overcome hypoxia-associated resistance in cancer treatment.

The value of miR-155 as a biomarker for the diagnosis and prognosis of lung cancer: a systematic review with meta-analysis.

BACKGROUND: Recently, a growing number of studies have reported the coorelation between miR-155 and the diagnosis and prognosis of lung cancer, but results of these researches were still controversial due to insufficient sample size. Thus, we carried out the systematic review and meta-analysis to figure out whether miR-155 could be a screening tool in the detection and prognosis of lung cancer. METHODS: A meta-analysis of 13 articles with 19 studies was performed by retrieving the PubMed, Embase and Web of Science. We screened all correlated literaters until December 1st, 2018. For the diagnosis analysis of miR-155 in lung cancer, sensitivity (SEN), specificity (SPE), positive likelihood ratio (PLR), negative likelihood ratio (NLR), diagnostic odds ratio (DOR) and area under the ROC curve (AUC) were pooled to evaluate the accuracy of miRNA-155 in the diagnosis of lung cancer. For the prognosis analysis of miR-155 in lung cancer, the pooled HRs and 95% CIs of miR-155 for overall survival/disease free survival/progression-free survival (OS/DFS/PFS) were calculated. In addition, Subgroup and meta-regression analyses were performed to distinguish the potential sources of heterogeneity between studies. RESULTS: For the diagnostic analysis of miR-155 in lung cancer, the pooled SEN and SPE were 0.82 (95% CI: 0.72-0.88) and 0.78 (95% CI: 0.71-0.84), respectively. Besides, the pooled PLR was 3.75 (95% CI: 2.76-5.10), NLR was 0.23 (95% CI: 0.15-0.37), DOR was 15.99 (95% CI: 8.11-31.52) and AUC was 0.87 (95% CI: 0.84-0.90), indicating a significant value of miR-155 in the lung cancer detection. For the prognostic analysis of miR-155 in lung cancer, up-regulated miRNA-155 expression was not significantly associated with a poor OS (pooled HR = 1.26, 95% CI: 0.66-2.40) or DFS/PFS (pooled HR = 1.28, 95% CI: 0.82-1.97). CONCLUSIONS: The present meta-analysis demonstrated that miR-155 could be a potential biomarker for the detection of lung cancer but not an effective biomarker for predicting the outcomes of lung cancer. Furthermore, more well-designed researches with larger cohorts were warranted to confirm the value of miR-155 for the diagnosis and prognosis of lung cancer.

4-Hydroxy estrogen metabolite, causing genomic instability by attenuating the function of spindle-assembly checkpoint, can serve as a biomarker for breast cancer.

Sex hormone metabolism is altered during mammary gland tumorigenesis, and different metabolites may have different effects on mammary epithelial cells. This study aimed to evaluate associations between urinary sexual metabolite levels and breast cancer risk among premenopausal women of Mainland China. The molecular metabolism of the cancer-related metabolites was also explored based on the clinical data. The sex hormone metabolites in the urine samples of patients with breast cancer versus normal healthy women were analyzed comprehensively. Among many alterations of sex hormone metabolisms, 4-hydroxy estrogen (4-OH-E) metabolite was found to be significantly increased in the urine samples of patients with breast cancer compared with the normal healthy controls. This was the most important risk factor for breast cancer. Several experiments were conducted in vitro and in vivo to probe this mechanism. 4-Hydroxyestradiol (4-OH-E2) was found to induce malignant transformation of breast cells and tumorigenesis in nude mice. At the molecular level, 4-OH-E2 compromised the function of spindle-assembly checkpoint and rendered resistance to the anti-microtubule drug. Further, transgenic mice with high expression of CYP1B1, a key enzyme of 4-hydroxy metabolites, were established and stimulated with estrogen. Cancerous tissue was found to appear in the mammary gland of transgenic mice.

miR-942 promotes tumor migration, invasion, and angiogenesis by regulating EMT via BARX2 in non-small-cell lung cancer.

Epithelial-mesenchymal transition (EMT) has an important function in cancer. Recently, microRNAs have been reported to be involved in EMT by regulating target genes. miR-942 is considered a novel oncogene in esophageal squamous cell carcinoma. However, its role in non-small-cell lung cancer (NSCLC) has not been investigated. In this study, the expression of miR-942 in NSCLC patients tumor and paired adjacent tissues were assessed by quantitative real-time polymerase chain reaction and in situ hybridization. Transwell, wound healing, tube formation, and tail vein xenograft assays were conducted to assess miR-942's function in NSCLC. Potential miR-942 targets were confirmed using dual-luciferase reporter assays, immunohistochemistry, immunoblot, and rescue experiments. The results showed miR-942 is relatively highly expressed in human NSCLC tissues and cells. In vitro assays demonstrated that overexpression of miR-942 promoted cell migration, invasion, and angiogenesis. Tail vein xenograft assays suggested that miR-942 contributed to NSCLC metastasis in vivo. Three bioinformatics software was searched, and BARX2 was predicted as a downstream target of miR-942. Direct interaction between them was validated by dual-luciferase assays. Rescue experiments further confirmed that BARX2 overexpression could reverse functional changes caused by miR-942. Moreover, miR-942 increased EMT-associated proteins N-cadherin and vimentin by inhibiting BARX2, while E-cadherin expression is reduced. In summary, this study reveals that miR-942 induces EMT-related metastasis by directly targeting BARX2, which may provide a potential therapeutic strategy for NSCLC.

Association between TNF-ɑ-308G/A polymorphism and esophageal cancer risk: An updated meta-analysis and trial sequential analysis.

Background: TNF-α-308G/A (rs1800629) polymorphism has been previously implicated in the susceptibility to esophageal cancer, but results of these studies remained controversial or ambiguous. A meta-analysis was conducted to provide a more reliable conclusion about the association between TNF-ɑ-308G/A polymorphism and risk of esophageal cancer. Methods: Databases such as PubMed, EMBASE, Web of Science and CNKI were searched for relevant articles published till June 1, 2018. We used the pooled odds ratios (ORs) with 95% confidence intervals (CIs) to evaluate the strength of such associations. Subgroup analysis was carried out according to ethnicity, source of controls and genotyping method. A trial sequential analysis (TSA) was performed to reduce the risk of type I error and evaluate whether the results of our meta-analysis were credible. Results: A total of 9 published case-control studies with 1,435 esophageal cancer patients and 3,762 healthy controls were identified. Overall, our results indicated no significant correlation between TNF-α-308G/A polymorphism and increased risk of esophageal cancer in the fixed-effects model (allele model: pooled OR=1.11, 95% CI: 0.96-1.27, homozygote model: pooled OR=1.23, 95% CI: 0.77-1.95, heterozygote model: pooled OR=1.14, 95% CI: 0.97-1.35, dominant model: pooled OR=1.14, 95% CI: 0.97-1.34 and recessive model: pooled OR=1.00, 95% CI: 0.64-1.56). Subgroup analysis by ethnicity, source of controls and genotyping method showed no significant increase in the risk of esophageal cancer. TSA results need further investigation with a large sample size to certify such association. Conclusions: This meta-analysis study suggested no significant association between TNF-ɑ-308G/A polymorphism and the risk of esophageal cancer.

Role of hypoxia-induced exosomes in tumor biology.

PURPOSE: Hypoxia is a major regulator of angiogenesis and always influences the release of exosomes in various types of tumors. The present review aimed to assess the role of hypoxia-induced exosomes in the tumor biology. METHODS: The relevant publications were retrieved from PubMed using keywords such as hypoxia, exosome, extracellular vesicles, tumor, cancer, and other similar terms. RESULTS: Recent studies have shown that cancer cells produce more exosomes under hypoxic conditions than do parental cells under normoxic conditions. The secretion and function of exosomes could be influenced by hypoxia in various types of cancer. Hypoxia-induced exosomes play critical roles in tumor angiogenesis, invasion, metastasis, and the immune system. CONCLUSIONS: These findings provide new insights into the complex networks underlying cellular and genomic regulation in response to hypoxia and might provide novel and specific targets for future therapies.

Association between VEGF Gene Polymorphisms and the Susceptibility to Lung Cancer: An Updated Meta-Analysis.

BACKGROUND AND OBJECTIVE: The association between vascular endothelial growth factor (VEGF) gene polymorphisms (-2578C/A, +936C/T, and -460C/T) and lung cancer risk has been extensively studied in the last decades, but currently available results remain controversial or ambiguous. Therefore, we conducted a meta-analysis to assess whether the relationship between the VEGF gene and lung cancer susceptibility exists. METHODS: The meta-analysis was conducted by searching the databases PubMed, Embase, and Web of Science covering all eligible studies published up to October 1, 2017. The pooled odds ratios (ORs) as well as their 95% confidence intervals (CIs) were utilized to evaluate the possible associations. Publication bias of relevant studies was examined via Begg's funnel plots and Egger's regression tests. RESULTS: This meta-analysis included 13 published case-control studies covering 4477 patients with lung cancer and 4346 healthy controls, who had been accrued from December 1992 to July 2012. For the overall eligible data collected in our meta-analysis, it indicated that VEGF +936C/T, -460C/T, and -2578C/A polymorphisms did not correlate with the elevated lung cancer risk in all genetic comparison models. Moreover, VEGF +460T/C polymorphism was found to be significantly associated with susceptibility to lung cancer in these models (allele model: pooled OR = 1.12, 95% CI: 1.00-1.26, P = 0.184; homozygote model: pooled OR = 1.51, 95% CI: 1.12-2.03, P = 0.821), but no significant results were detected in Caucasian populations. CONCLUSIONS: VEGF +936C/T, -460C/T, and -2578C/A polymorphisms were not associated with the risk of lung cancer. The VEGF +460T/C polymorphism might be a risk factor for lung cancer only in Asian populations.

MiR-598 Suppresses Invasion and Migration by Negative Regulation of Derlin-1 and Epithelial-Mesenchymal Transition in Non-Small Cell Lung Cancer.

BACKGROUND/AIMS: MicroRNAs regulate a wide range of biological processes of non-small cell lung cancer (NSCLC). Although miR-598 has been reported to act as a suppressor in osteosarcoma and colorectal cancer, the physiological function of miR-598 in NSCLC remains unknown. In this study, the role of miR-598 in NSCLC was investigated. METHODS: Quantitative real-time polymerase chain reaction (qRT-PCR) was conducted to estimate the expression of miR-598 and Derlin-1 (DERL1) in both NSCLC tissues and cell lines. Immunohistochemistry (IHC) analyzed the association between the miR-598 expression and epithelial-mesenchymal transition (EMT) hallmark genes (E-cadherin, Vimentin) by staining the tumors representative of the high- and low-expression groups. The effect of miR-598 and DERL1 on invasion and migration was determined in vitro using transwell and wound-healing assays. The molecular mechanism underlying the relevance between miR-598 and DERL1 was elucidated by luciferase assay and Western blot. Western blot assessed the expression levels of EMT hallmark genes in cell lines. Xenograft tumor formation assay was conducted as an in vivo experiment. RESULTS: In this study, a relatively low level of miR-598 and high DERL1 expressions were found in NSCLC specimens and cell lines. IHC results established a positive correlation between the miR-598 expression and E-cadherin and a negative with Vimentin. DERL1 was verified as a direct target of miR-598 by luciferase assay. In vitro, the over-expression of miR-598 negatively regulated DERL1 and EMT for the suppression of invasion and migration. In vivo, the over-expression of miR-598 could inhibit tumor cell metastasis in NSCLC. CONCLUSIONS: These findings for the first time revealed that miR-598, as a tumor suppressor, negatively regulate DERL1 and EMT to suppress the invasion and migration in NSCLC, thereby putatively serving as a novel therapeutic target for NSCLC clinical treatment.

Exosomal miRNAs and miRNA dysregulation in cancer-associated fibroblasts.

PURPOSE: The present review aimed to assess the role of exosomal miRNAs in cancer-associated fibroblasts (CAFs), normal fibroblasts (NFs), and cancer cells. The roles of exosomal miRNAs and miRNA dysregulation in CAF formation and activation were summarized. METHODS: All relevant publications were retrieved from the PubMed database, with key words such as CAFs, CAF, stromal fibroblasts, cancer-associated fibroblasts, miRNA, exosomal, exosome, and similar terms. RESULTS: Recent studies have revealed that CAFs, NFs, and cancer cells can secrete exosomal miRNAs to affect each other. Dysregulation of miRNAs and exosomal miRNAs influence the formation and activation of CAFs. Furthermore, miRNA dysregulation in CAFs is considered to be associated with a secretory phenotype change, tumor invasion, tumor migration and metastasis, drug resistance, and poor prognosis. CONCLUSIONS: Finding of exosomal miRNA secretion provides novel insights into communication among CAFs, NFs, and cancer cells. MicroRNA dysregulation is also involved in the whole processes of CAF formation and function. Dysregulation of miRNAs in CAFs can affect the secretory phenotype of the latter cells.