Integrated genomic and DNA methylation analysis of patients with advanced non-small cell lung cancer with brain metastases

Background Brain metastasis is a common and lethal complication of non-small cell lung cancer (NSCLC). It is mostly diagnosed only after symptoms develop, at which point very few treatment options are available. Therefore, patients who have an increased risk of developing brain metastasis need to be identified early. Our study aimed to identify genomic and epigenomic biomarkers for predicting brain metastasis risk in NSCLC patients. Methods Paired primary lung tumor tissues and either brain metastatic tissues or cerebrospinal fluid (CSF) samples were collected from 29 patients with treatment-naïve advanced NSCLC with central nervous system (CNS) metastases. A control group comprising 31 patients with advanced NSCLC who died without ever developing CNS metastasis was also included. Somatic mutations and DNA methylation levels were examined through capture-based targeted sequencing with a 520-gene panel and targeted bisulfite sequencing with an 80,672 CpG panel. Results Compared to primary lung lesions, brain metastatic tissues harbored numerous unique copy number variations. The tumor mutational burden was comparable between brain metastatic tissue (P = 0.168)/CSF (P = 0.445) and their paired primary lung tumor samples. Kelch-like ECH-associated protein (KEAP1) mutations were detected in primary lung tumor and brain metastatic tissue samples of patients with brain metastasis. KEAP1 mutation rate was significantly higher in patients with brain metastasis than those without (P = 0.031). DNA methylation analysis revealed 15 differentially methylated blocks between primary lung tumors of patients with and without CNS metastasis. A brain metastasis risk prediction model based on these 15 differentially methylated blocks had an area under the curve of 0.94, with 87.1% sensitivity and 82.8% specificity. Conclusions Our analyses revealed 15 differentially methylated blocks in primary lung tumor tissues, which can differentiate patients with and without CNS metastasis. These differentially methylated blocks may serve as predictive biomarkers for the risk of developing CNS metastasis in NSCLC. Additional larger studies are needed to validate the predictive value of these markers.

Case Report: Primary Bilateral Minimally Invasive Adenocarcinoma of the Lungs in an 11-Year-Old Child: A Rare Case

There are many types of benign and malignant tissue, but primary lung tumor is very rare in children and often remains undiagnosed until after distant metastasis has occurred. Few cases of early lung adenocarcinoma in children have been reported. However, this case concerns an 11-year-old child with primary bilateral minimally invasive adenocarcinoma. As far as we know, this is the youngest reported case of its type.

Upfront Brain Treatments Followed by Lung Surgery Improves Survival for Stage IV Non-small Cell Lung Cancer Patients With Brain Metastases: A Large Cohort Analysis

Background: Current treatment guidelines for stage IV non-small cell lung cancer (NSCLC) with brain metastases recommend brain treatments, including surgical resection and radiotherapy (RT), in addition to resection of the primary lung tumor. Here, we investigate the less-studied impact of treatment sequence on the overall survival.Methods: The National Cancer Database was queried for NSCLC patients with brain metastases who underwent surgical resection of the primary lung tumor (n = 776). Kaplan-Meier survival curves with log-rank test and propensity score stratified Cox regression with Wald test were used to evaluate the associations between various treatment plans and overall survival (OS).Results: Compared to patients who did not receive any brain treatment (median OS = 6.05 months), significantly better survival was observed for those who received brain surgery plus RT (median OS = 26.25 months, p < 0.0001) and for those who received brain RT alone (median OS = 14.49 months, p < 0.001). Patients who received one upfront brain treatment (surgery or RT) before lung surgery were associated with better survival than those who received lung surgery first (p < 0.05). The best survival outcome (median OS 27.1 months) was associated with the sequence of brain surgery plus postoperative brain RT followed by lung surgery.Conclusions: This study shows the value of performing upfront brain treatments followed by primary lung tumor resection for NSCLC patients with brain metastases, especially the procedure of brain surgery plus postoperative brain RT followed by lung surgery.

Primary pulmonary epithelioid sarcoma: a case report

Background Epithelioid sarcoma most frequently occurs in the dermal or subcutaneous area of the distal extremities. To date, there have been three cases of primary pulmonary epithelioid sarcoma reported. We report a case of epithelioid sarcoma that is considered a primary lung tumor. Case presentation A 65-year-old asymptomatic Asian male patient underwent chest radiography during a routine health examination, and an abnormal mass was detected. His past medical history was unremarkable. He smoked 40 cigarettes every day and had slightly obstructive impairment on spirometry. He worked as an employee of a company and had no history of asbestos exposure. He underwent partial resection of the right lung by thoracoscopy. A histological examination of the tumor revealed a cellular nodule of epithelioid and spindle-shaped cells. Some of the tumor cells displayed rhabdoid features and reticular arrangement in a myxomatous stroma. Immunohistochemically, the tumor cells were positive for vimentin, smooth muscle actin (SMA), CD34, and epithelial membrane antigen (EMA); loss of the BAF47/INI1 protein in the tumor cells was also confirmed. A diagnosis of epithelioid sarcoma was established. Careful screening by whole-body positron emission tomography for another primary lesion after surgery did not detect any possible lesion. He had no cutaneous disease. Conclusion To our knowledge, this is the fourth case of a proximal-type epithelioid sarcoma considered as a primary lung tumor.

Assessing tumor metabolic heterogeneity of non-small cell lung cancer with total body PET-CT imaging on the uExplorer: Analysis of dynamic changes of 18F-FDG uptake.

e20549 Background: Total body positron emission tomography (PET) of uExplorer enables imaging of highly quantitative parameters beyond the standardized uptake value (SUV). The aim of this prospective study is to assess the dynamic changes of 2-deoxy-2-[18F]fluoro-D-glucose ([18F]FDG) uptake in characterizing tumor heterogeneity of non-small cell lung cancer (NSCLC). Methods: Sixteen NSCLC patients were prospectively enrolled in a prospective study (NCT04654234, GASTO-1067) between September 2020 and December 2020. All patients underwent a dynamic total-body 18F-FDG PET/CT scan before any treatment. The primary lung tumor, metastatic regional lymph node and inflammatory lymph node were manually delineated by a nuclear medicine physician and a radiation oncologist. Total Body PET was acquired between 0 – 60 mins after the injection of FDG from the subject’s feet. We compared lesion heterogeneity and different image-derived PET metrics including the SUV-mean, Patlak-derived influx rate constant (Ki) and distribution volume (DV). Results: The SUV-mean and Ki-mean of primary lung tumor and metastatic lymph node were significantly higher than inflammatory lymph node (p < 0.001), while there was no significantly different of DV(p > 0.05). By the scatter plot of SUV-mean and Ki-mean of primary lung tumor, 9 patients had been separated into high dynamic FDG metabolic (H-DFM) group and 7 in low DFM(L-DFM) group. The SUV-mean(p = 0.0002) and Ki-mean(p = 0.0002) of primary lung tumor were significantly higher in H-DFM group, whereas there is no difference in metastatic lymph node of both group. Interestingly, the SUV-mean and Ki-mean of primary lung tumor were higher than that of metastatic lymph node(p = 0.0002) in H-DFM group. On the contrast, the SUV-mean and Ki-mean of primary lung tumor were lower than that of metastatic lymph node(p = 0.05) in L-DFM group. There is no significant difference of DV-mean among primary lung tumor, metastatic lymph node and inflammatory lymph node in both arms. Conclusions: The results demonstrated that dynamic parameters from total body PET scan has the potential of providing complementary information of tumor heterogeneity in NSCLC than conventional static SUV imaging. The characteristics of H-DFM and L-DFM group could be taken into account for evaluation of further treatment response.

Dynamic 18F-FDG Total body PET Imaging as a predictive marker of induction chemo-immunotherapy response in locally advanced non-small cell lung cancer.

e20551 Background: The purpose of this study was to evaluate the efficacy of dynamic 18F-FDG total body PET imaging as a predictive maker of induction chemo-immunotherapy response in locally advanced non-small cell lung cancer(NSCLC) by a prospective study. Methods: Stage IIIA-IIIC NSCLC patients were prospectively enrolled in a prospective total body PETCT study ( NCT04654234, GASTO-1067) and a randomized phase II clinical trial ( NCT04085250) between September 2020 and December 2020. All patients underwent a dynamic total-body 18F-FDG PET/CT scan before any treatment and after 2 cycles of induction chemo-immunotherapy (docetaxel+cisplatin+nivolumab). The primary lung tumor, metastatic regional lymph node and inflammatory lymph node before and after treatment were manually delineated by a nuclear medicine physician and a radiation oncologist. Total Body PET was acquired between 0 – 60 mins after the injection of FDG from the subject’s feet. Patients was separated into high dynamic FDG metabolic (H-DFM) group and low DFM(L-DFM) group by the scatter plot of SUV-mean and Ki-mean of primary lung tumor. We compared lesion heterogeneity and different image-derived PET metrics including the metabolic tumor volume(MTV), SUV total lesion glycolysis(SUV-TLG), Patlak-derived influx rate constant (Ki) TLG (Ki-TLG). Results: Fifteen patients were analyzed, 8 patients was in H-DFM group and 7 in L-DFM group. Patients in H-DFM group had significant decreased levels of MTV(p < 0.001), SUV-TLG(p < 0.001) and Ki-TLG(p < 0.001) both in primary lung tumor and metastatic lymph node by the induction chemo-immuotherapy. However, patients in L-DFM group only had a significant reduction of MTV in primary lung tumor(p < 0.05). There was no significant difference in the MTV of metastatic lymph node(p > 0.5), the SUV-TLG(p > 0.5) and Ki-TLG(p > 0.5) of primary lung tumor and metastatic lymph node, before and after induction chemo-radiotherapy. Conclusions: Patients in H-DFM group had the better treatment response of induction chemo-immunotherapy with significant decreased levels of MTV, SUV-TLG and Ki-TLG. Dynamic 18F-FDG Total body PET Imaging could be regard as a potential predictive marker of induction chemo-immunotherapy response in the setting of LA-NSCLC.

Radiation Exposure–Induced Changes in the Immune Cells and Immune Factors of Mice With or Without Primary Lung Tumor

Recent studies have demonstrated that radiation activates in situ antitumor immunity and consequently induced a synergistic effect of radiotherapy and immunotherapy. However, studies related to radiation-induced changes in immune system of tumor-bearing mice are limited, which are of great significance to improve the efficacy of radioimmunotherapy. In this study, we first established a primary lung tumor mouse model using urethane. Then part of the right lung of the mouse was exposed to X-ray irradiation with a computed tomography–guided small animal irradiator and the changes of immune cells in both peripheral blood and spleen were determined by flow cytometry. Besides, the levels of both cytokines and immunoglobulins in mouse serum were detected by a protein chip. We found that B lymphocytes increased while CD8+ T lymphocytes reduced significantly. Interleukin-3 (IL-3), IL-6, regulated upon activation, normally T-expressed, and presumably secreted factor (RANTES), and vascular endothelial growth factor (VEGF) were found to be decreased after tumor formation, and the similar results have also been observed with kappa, IgG3, IgE, IgM, and IgG2a. After irradiation, lower concentrations of IgD, kappa, and IgM were found in the serum. Our findings indicate that localized tumor irradiation caused some obvious changes like inhibiting the ability of innate immunity, and these changes may be useful in predicting prognosis.