Pulmonary Adenocarcinoma Patients Research Articles

Interleukin-8/CXCR1 Signaling Contributes to the Progression of Pulmonary Adenocarcinoma Resulting in Malignant Pleural Effusion.

Pulmonary adenocarcinoma (PADC) treatment limited efficacy in preventing tumor progression, often resulting in malignant pleural effusion (MPE). MPE is filled with various mediators, especially interleukin-8 (IL-8). However, the role of IL-8 and its signaling mechanism within the fluid microenvironment (FME) implicated in tumor progression warrants further investigation. Primary cultured cells from samples of patients with MPE from PADC, along with a commonly utilized lung cancer cell line, were employed to examine the role of IL-8 and its receptor, CXCR1, through comparative analysis. Our study primarily assessed migration and invasion capabilities, epithelial-mesenchymal transition (EMT), and cancer stem cell (CSC) properties. Additionally, IL-8 levels in MPE fluid versus serum, along with immunohistochemical expression of IL-8/CXCR1 signaling in tumor tissue and cell blocks were analyzed. IL-8/CXCR1 overexpression enhanced EMT and CSC properties. Furthermore, the immunocytochemical examination of 17 cell blocks from patients with PADC and MPE corroborated the significant correlation between upregulated IL-8 and CXCR1 expression and the co-expression of IL-8 and CXCR1 in MPE with distant metastasis. In summary, the IL-8/ CXCR1 axis in FME is pivotal to tumor promotion via paracrine and autocrine signaling. Our study provides a therapeutic avenue for improving the prognosis of PADC patients with MPE.

In stage IV pulmonary adenocarcinoma patients, treatment with Traditional Chinese Medicine alone gives prognostically superior results to treatment with Platinum-Based Chemotherapy alone

BackgroundAbout 30% of pulmonary stage IV adenocarcinomas die within 3 months of diagnosis. Western medical treatments with Platinum-Based Chemotherapy=PBC and tyrosine-kinase inhibitors Targeted Therapy=TT can improve prognosis. In China, Traditional Chinese Medicine herbal treatments (TCM) are often used in addition to PBC and TT. A considerable number of patients refuse Western medical treatments and use TCM alone. However, the survival impact of the latter is unknown. Hypotheses testedTreatment with TCM alone is prognostically superior to PBC alone. Addition of PBC or TT or both TT to TCM improves survival. MethodsIn this prospective observational, non-interventional study of 1017 consecutive first-onset stage IV NSCLC patients with up to 10 years follow-up, 261 who Died of Disease (DOD) within 3 months were omitted, as they never got the optimal Western medical therapies. All 218 non-adenocarcinomas were also omitted, leaving 538 stage IV adenocarcinomas treated by TCM alone (n = 29), PBC alone (N = 19) and TCM and other Western medical combinations (299 TCM and PBC, 50 TCM and TT, 141 TCM and PBC and TT) with 3 – 120 months follow-up. Survivals were compared using Alive with Disease (AWD) and DOD as endpoints. ResultsThe patients treated only with TCM had 7 months better median survival than those that received PBC alone (17 and 10 months). The patients that received TCM and PBC had a better median survival (24 months) than TCM alone and much better than PBC alone. None of the patients that received TCM alone survived > 54 months, whereas 18% of TCM and PBC patients survived much longer. Over the observation period of 3 – 120 months, survivals of TCM and TT, TCM and PBC and TT, and TCM and PBC were not different and therefore grouped as TCM and Western medicines. Median survival times of PBC alone and TCM alone were lower than that of TCM and Western medical treatments (p < 0.0001, 10, 17 and 27 months). ConclusionsPulmonary stage IV adenocarcinoma patients with at least 3 months survival, treated with TCM alone have a significantly better survival than those treated with PBC alone. Adding Western PBC, TT or both to TCM further improves prognosis.

"ThermoTRP" Channel Expression in Cancers: Implications for Diagnosis and Prognosis (Practical Approach by a Pathologist).

Temperature-sensitive transient receptor potential (TRP) channels (so-called "thermoTRPs") are multifunctional signaling molecules with important roles in cell growth and differentiation. Several "thermoTRP" channels show altered expression in cancers, though it is unclear if this is a cause or consequence of the disease. Regardless of the underlying pathology, this altered expression may potentially be used for cancer diagnosis and prognostication. "ThermoTRP" expression may distinguish between benign and malignant lesions. For example, TRPV1 is expressed in benign gastric mucosa, but is absent in gastric adenocarcinoma. TRPV1 is also expressed both in normal urothelia and non-invasive papillary urothelial carcinoma, but no TRPV1 expression has been seen in invasive urothelial carcinoma. "ThermoTRP" expression can also be used to predict clinical outcomes. For instance, in prostate cancer, TRPM8 expression predicts aggressive behavior with early metastatic disease. Furthermore, TRPV1 expression can dissect a subset of pulmonary adenocarcinoma patients with bad prognosis and resistance to a number of commonly used chemotherapeutic agents. This review will explore the current state of this rapidly evolving field with special emphasis on immunostains that can already be added to the armoire of diagnostic pathologists.

Study on the Correlation Between CT Features and Vascular Tumor Thrombus Together With Nerve Invasion in Surgically Resected Lung Adenocarcinoma.

BackgroundWe aimed to analyze the relationship between pulmonary adenocarcinoma patients with vascular tumor thrombus and nerve invasion and different CT features.MethodsThe preoperative CT scanning data of 86 patients with lung adenocarcinoma who underwent surgical resection in our hospital from January 2020 to January 2022 were analyzed in the form of retrospective analysis. The CT images of all patients were observed, and the relationship between them and vascular tumor thrombus and nerve invasion of lung adenocarcinoma was analyzed. At the same time, the sensitivity, specificity, and accuracy of enhanced CT and plain CT were compared to evaluate the diagnostic efficacy of both.ResultsThe results showed that the vascular tumor thrombus of lung adenocarcinoma was mainly related to the solid components and lobulated and calcified tumors in CT images, and the nerve invasion of lung adenocarcinoma was mainly related to the tumors with bronchial inflation sign in CT images (P < 0.05). The sensitivity, specificity, and accuracy of enhanced CT in the diagnosis of vascular tumor thrombus were 78.26%, 96.83%, and 91.86%, respectively, and the sensitivity, specificity, and accuracy in the diagnosis of nerve invasion were 75.00%, 98.72%, and 96.51%, respectively. The sensitivity, specificity, and accuracy of plain CT in the diagnosis of vascular tumor thrombus were 43.48%, 92.06%, and 79.07%, respectively, and the sensitivity, specificity, and accuracy in the diagnosis of nerve invasion were 25.00%, 94.87%, and 88.37%, respectively. The contrast showed that the sensitivity and accuracy of enhanced CT were higher than those of plain CT (P < 0.05), but the difference of specificity was not obvious (P > 0.05).ConclusionsSolid components and lobulated and calcified tumors in CT signs are closely related to vascular tumor thrombus of lung adenocarcinoma, while patients with bronchial inflation sign are related to nerve invasion.

Correlation of ROS1 (D4D6) Immunohistochemistry with ROS1 Fluorescence In Situ Hybridization Assay in a Contemporary Cohort of Pulmonary Adenocarcinomas.

Sambit K. MohantyObjective Repressor of Silencing ( ROS1 ) gene rearrangement in the lung adenocarcinomas is one of the targetable mutually exclusive genomic alteration. Fluorescence in situ hybridization (FISH), immunohistochemistry (IHC), next-generation sequencing, and reverse transcriptase polymerase chain reaction assays are generally used to detect ROS1 gene alterations. We evaluated the correlation between ROS1 IHC and FISH analysis considering FISH as the gold standard method to determine the utility of IHC as a screening method for lung adenocarcinoma. Materials and Methods A total of 374 advanced pulmonary adenocarcinoma patients were analyzed for ROS1 IHC on Ventana Benchmark XT platform using D4D6 rabbit monoclonal antibody. FISH assay was performed in parallel in all these cases using the Vysis ROS1 Break Apart FISH probe. Statistical Analysis The sensitivity, specificity, positive and negative likelihood ratios, positive and negative predictive values, and accuracy were evaluated. Results A total of 17 tumors were positive either by IHC or FISH analysis or both (true positive). Four tumors were positive by IHC (H-score range: 120-270), while negative on FISH analysis (false positive by IHC). One tumor was IHC negative, but positive by FISH analysis (false negative). The sensitivity, specificity, positive likelihood ratio, negative likelihood ratio, positive predictive value, negative predictive value, and accuracy were 94.4% (confidence interval [CI]: 72.71-99.86%), 63.6% (CI: 30.79-89.07%), 2.6 (CI: 1.18-5.72), 0.09 (CI: 0.01-0.62), 80.95% (CI: 65.86-90.35%), 87.5% (CI: 49.74-98.02%), and 82.76%, respectively. Conclusion ROS1 IHC has high sensitivity at a cost of lower specificity for the detection of ROS1 gene rearrangement. All IHC positive cases should undergo a confirmatory FISH test as this testing algorithm stands as a reliable and economic tool to screen ROS1 rearrangement in lung adenocarcinomas.

The genomic and transcriptome characteristics of lung adenocarcinoma patients with previous breast cancer

BackgroundBreast cancer and lung cancer are the top two malignancies in the female population and the number of patients with breast cancer and subsequent primary lung cancer has increased significantly in recent years. However, the unique molecular characteristics of this group of patients remains unclear.PurposeTo identify the genomic and transcriptome characteristics of primary lung adenocarcinoma patients with previous breast cancer by comparison with single primary lung adenocarcinoma (SPLA) patients.MethodsThe tumor and normal pulmonary tissue specimens of ten primary pulmonary adenocarcinoma patients with previous breast cancer (multiple primary cancer, MPC) and ten SPLA patients were prospectively collected. The whole exome sequencing (WES) and RNA sequencing (RNA-seq) were performed to analyze the gene mutation and expression differences between MPC and SPC patients.ResultsThe results of WES indicated that the mutations of TRIM73, DLX6 and CNGB1 only existed in MPC patients. The results of RNA-seq manifested the occurrence of second primary lung adenocarcinoma in breast cancer patients was closely associated with cytokine-cytokine receptor action, autophagy, PI3L-Akt, cAMP and calcium ion signaling pathways. Besides, the expression levels of FGF10 and VEGFA genes were significantly increased in MPC patients.ConclusionThe occurrence of second primary lung adenocarcinoma may be related to the cytokine-cytokine receptor action, autophagy, PI3L-Akt, cAMP and calcium ion signaling pathways. Furthermore, the mutations of TRIM73, DLX6 and CNGB1 and high expression of FGF10 and VEGFA might play an important role in the development of lung adenocarcinoma in breast cancer patients. However, more in-depth investigations are needed to verify above findings.

Adverse Event Profiles of Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors in Adenocarcinoma Lung Patients in North Sumatera Population

BACKGROUND: In early 2000, a new targeted therapy was introduced and appeared to be a medical revolution due to the great emergence of procedural treatments in lung cancers. This new target therapy has been developed recently, which is also accompanied by the development of molecular markers as medical guidance. AIM: This study aims to assess the side effect of the usage of epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) on lung adenocarcinoma patients in North Sumatera. METHODS: This study was a descriptive analysis study with consecutive sampling. Data was collected from the medical records of 50 pulmonary adenocarcinoma patients who have been treated by EGFR-TKI erlotinib and gefitinib. The statistical analysis was performed through SPSS software. RESULTS: From this study, the majority of subjects were in the age range of 50–60 years old (24%), had no smoking history (52%), and were in Stage IVA (62%) at the time of diagnosis. Allele-specific polymerase chain reaction was performed and showed that exon 19 was found as the commonest mutations (62%). After using the first generation of EGFR-TKI including erlotinib and gefitinib, the majority of subjects experienced Grade I toxicities (46%) involved skin (acneiform). CONCLUSION: The most common adverse event that is occurred in the cases was in skin disorders (72% of cases), which is particularly indicated by acne rash (46% of cases). The degree of toxicity during the medications was populously on degree 1 (46% of cases).

Observational Study of Paclitaxel-Carboplatin versus Pemetrexed-Carboplatin for Advanced Pulmonary Adenocarcinoma at Single-Centre in Indonesia

Platinum-based chemotherapy regimens with two types of drugs, such as paclitaxel-carboplatin and pemetrexedcarboplatin, are first-line therapy for pulmonary adenocarcinoma patients with negative epidermal growth factor receptor (EGFR) mutation. This study aimed to determine the efficacy, toxicity, and cost profile of paclitaxel-carboplatin compared to pemetrexed-carboplatin. This is a cross-sectional study. Pulmonary adenocarcinoma negative EGFR mutation naïve patients treated with paclitaxel-carboplatin or pemetrexed-carboplatin were included. Effectiveness was assessed based on the overall response rate (ORR) according to the response evaluation criteria in solid tumours (RECIST). A pharmacoeconomic analysis is performed based on clinical outcomes consisting of effectiveness and direct medical costs. Medical records from 21 patients with paclitaxel-carboplatin and 21 patients with pemetrexedcarboplatin were successfully evaluated. The effectiveness of the two chemotherapy regimens was not significantly different (OR, 1.25; 95% confidence interval, 0.34 to 4.64; p = 0.739). Frequent haematological toxicities experienced in the two groups were grade 1-2 anaemia, neutropenia, leukopenia. Grade 3 anaemia, leukopenia, and neutropenia were more common in the paclitaxel-carboplatin group. The two groups’ nonhematological toxicities were nausea vomitus and hair loss, with peripheral neuropathy more experienced by the paclitaxel-carboplatin group. Costminimization analysis reveals that the average cost per patient with pulmonary adenocarcinoma negative EGFR mutation with paclitaxel-carboplatin regimen was cheaper IDR 10,986,257.55 or 50.25%, compared to pemetrexedcarboplatin. In conclusion, there was no significant difference in the effectiveness of the two regimens. The most common adverse effects in both regimens were haematological toxicities. The average cost per patient with a paclitaxel-carboplatin regimen was cheaper compared to pemetrexed-carboplatin.

Predicting the Ki-67 proliferation index in pulmonary adenocarcinoma patients presenting with subsolid nodules: construction of a nomogram based on CT images.

The Ki-67 proliferation index (PI) reflects the proliferation of cells. However, the conventional methods for the acquisition of the Ki-67 PI, such as surgery and biopsy, are generally invasive. This study investigated a potential noninvasive method of predicting the Ki-67 PI in patients with lung adenocarcinoma presenting with subsolid nodules. This retrospective study enrolled 153 patients who presented with pulmonary adenocarcinoma appearing as subsolid nodules (SSNs) on computed tomography (CT) images between January 2015 and December 2018. Presence of LUAD with SSNs was confirmed by histopathology. Of these participants, 107 patients were from institution 1 and were divided into a training cohort and an internal validation cohort in a 7:3 ratio. The other 46 patients were from institution 2 and were enrolled as an external validation cohort. All patients underwent conventional CT scans with thin-slice (≤1.25 mm) reconstruction, and 1,316 quantitative radiomic features were extracted from the CT images for each nodule. The minimum redundancy maximum relevance and the least absolute shrinkage and selection operator were used for feature selection, and the radiomics signature was constructed based on these selected features. Clinical features were examined using univariate logistic regression analysis. The nomogram was developed based on the radiomics signature and the independent clinical risk factors. The Delong test and t test were employed for statistical analysis. The performance of different models was assessed by the receiver operating characteristic (ROC) curve. The diameter of the nodules [odds ratio (OR) =1.17; P=0.003] was identified as an independent predictive parameter. Both the radiomics signature and the nomogram suggested a good predictive probability for Ki-67 expression. For the radiomics signature, the area under the ROC curve (AUC) for the training cohort, the internal validation cohort, and the external validation cohort was 0.86 [95% confidence interval (CI): 0.77 to 0.95], 0.81 (95% CI: 0.64 to 0.98), and 0.77 (95% CI: 0.62 to 0.91), respectively. For the nomogram, the AUC for the training cohort, the internal validation cohort, and the external validation cohort was 0.86 (95% CI: 0.77 to 0.95), 0.80 (95% CI: 0.64 to 0.97), and 0.79 (95% CI: 0.65 to 0.94), respectively. There were no statistical differences in the AUCs between the radiomics signature and the radiomic nomogram in the training cohort or the validation cohorts (all P>0.05). The nomogram provides a novel strategy for determining the Ki-67 PI in predicting the proliferation of subsolid nodules, which may be beneficial for the management of patients with SSNs.

Prognostic value of ground glass opacity on computed tomography in pathological stage I pulmonary adenocarcinoma: A meta-analysis.

BACKGROUNDThe clinical role of ground glass opacity (GGO) on computed tomography (CT) in stage I pulmonary adenocarcinoma patients currently remains unclear.AIMTo explore the prognostic value of GGO on CT in lung adenocarcinoma patients who were pathologically diagnosed with tumor-node-metastasis stage I. METHODSA comprehensive and systematic search was conducted through the PubMed, EMBASE and Web of Science databases up to April 3, 2021. The hazard ratio (HR) and corresponding 95% confidence interval (CI) were combined to assess the association between the presence of GGO and prognosis, representing overall survival and disease-free survival. Subgroup analysis based on the ratio of GGO was also conducted. STATA 12.0 software was used for statistical analysis.RESULTSA total of 12 studies involving 4467 patients were included. The pooled results indicated that the GGO predicted favorable overall survival (HR = 0.44, 95%CI: 0.34-0.59, P < 0.001) and disease-free survival (HR = 0.35, 95%CI: 0.18-0.70, P = 0.003). Subgroup analysis based on the ratio of GGO further demonstrated that the proportion of GGO was a good prognostic indicator in pathological stage I pulmonary adenocarcinoma patients, and patients with a higher ratio of GGO showed better prognosis than patients with a lower GGO ratio did.CONCLUSIONThis meta-analysis manifested that the presence of GGO on CT predicted favorable prognosis in tumor-node-metastasis stage I lung adenocarcinoma. Patients with a higher GGO ratio were more likely to have a better prognosis than patients with a lower GGO ratio.

Chemotherapy Resistance in Remutation of Epidermal Growth Factor Receptor Wild Type Becomes a Positive Type and Back Becomes a Wild Type in A Patient with Lung Adenocarcinoma

Introduction: Lung cancer is the most common type of cancer worldwide (11.6%) and the leading cause of death due to cancer throughout the world. One type of lung cancer that is often found is Adenocarcinoma, 35-40%. Mutations in EGFR often occur in patients with pulmonary Adenocarcinoma, especially in Asia. Chemotherapy selection for pulmonary adenocarcinoma patients based on the status of their EGFR mutations. Positive EGFR mutations can get treatment with Tyrosine Kinase Inhibitors. Giving chemotherapy can affect changes in EGFR mutation status. Patients with chemotherapy treatment can experience resistance to chemotherapy either primary or acquired resistance through a variety of mechanisms.Case Description: we reported one case of a 56-year-old man with pulmonary adenocarcinoma who had a positive change in EGFR-type from wild type mutations and then returned to a wild type. Patients were initially diagnosed with wild-type pulmonary adenocarcinoma from EGFR examination of tissue biopsy and given conventional chemotherapy. During the evaluation, progression occurred so that the status of the EGFR mutation was examined using ct-DNA and the result was mutation deletion exon 19 so that the patient obtained Gefitinib. Due to progressive return, the patient again examined EGFR status from tissue biopsy obtained using pleuroscopy and obtained an EGFR wild type. Patients again get conventional chemotherapy.Discussion Changes in the status of EGFR mutation in pulmonary adenocarcinoma patients and chemotherapy resistance can occur in patients with chemotherapy treatment.Â

P56.04 Pathological Features & Prognosis of NSCLC Patients With Enteric Adenocarcinomas Without Expression of TTF-1 and Napsin A

Enteric differentiation can occur in lung adenocarcinoma, and when this component exceeds 50%, the tumor is classified as pulmonary adenocarcinoma with enteric differentiation (PAED). The enteric pattern of enteric lung adenocarcinoma shares morphologic and immunohistochemical features with colorectal adenocarcinoma and it consists of glandular and/or papillary structures sometimes with a cribriform pattern, lined by tumor cells that are mostly tall-columnar with nuclear pseudostratification, luminal necrosis, and prominent nuclear debris. Poorly differentiated tumors may have a more solid pattern. These tumors show at least one immunohistologic marker of enteric differentiation (CDX-2, CK20 or MUC2). Enteric adenocarcinoma is a rare histologic type of primary lung adenocarcinoma. Detailed clinical, pathological and molecular features about these subgroup of patients is lacking, particularly if TTF-1 and Napsin A aren't expressed. NSCLC patients who were diagnosed from January 2018 until March 2021 were identified by review of the patient records. Only lung adenocarcinoma patients whose tumors didn`t express either TTF-1 or Napsin A, but were positive for either CDX-2, CK20 or MUC2 were included in the data analysis. Primary tumor of the gastrointestinal tract was excluded either by PET-CT and/or CT and endoscopy (gastroscopy, colonoscopy, and rectoscopy). A total of fourteen (eight male (57,1%) and six female (42,9%) patients were identified in the patients` records. On average, the patients were 67 years old, the median age was 68. The youngest patient was 54 and the oldest one was 83 years old. Three patients were diagnosed at local stages (I-III), eleven patients had metastatic disease (stage IV). Four of these eleven patients had a mutation of the KRAS gene, which corresponds to 37%. This percentage is higher than the average frequency of mutations in the KRAS gene in pulmonary adenocarcinomas (25%). Half of the patients had a tumors with protein expression of PD-L1 (50%). Four patients of the complete cohort underwent surgical resection of the primary tumor and five patients received radiotherapy. Every patient, who got radiotherapy, suffered from stage IV. Three patients received irradiation of brain metastasis and two of bone metastasis. A systemic therapy was administered to nine patients. Seven patients had a combined chemo-/ immuntherapy as firstline treatment (either cisplatin, pemetrexed, and pembrolizumab or carboplatin, nab-paclitaxel, and atezolizumab) and one got only a combination chemotherapy (carboplatin and nab-paclitaxel). Median disease-free survival was eight, median progression-free survival was four months. Median overall survival could not be calculated. However, six and twelve months survival rates were 35.8 and 25.0 %, respectively. This is the far largest reported series of PAED patients without any expression of TTF1- or Napsin A. It seems that this subgroup of pulmonary adenocarcinoma patients has a poorer prognosis compared to other patients with lung adenocarcinomas.

Drug Repurposing Patent Applications April–June 2021

Drug Repurposing Patent Applications April–June 2021

Abstract 419: Presence of pulmonary tuberculosis impair survival in advanced EGFR mutation lung adenocarcinoma patients receiving epidermal growth factor receptor-tyrosine kinase inhibitor

Abstract Background Although studies have identified several clinicopathological factors that can predict the response to and survival on epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKI), few studies have clearly demonstrated the effect of EGFR-TKI in the treatment of patients with underlying pulmonary disease, such as pulmonary tuberculosis (PTB). In addition, cytochrome P450 (CYP) enzyme, CYP3A4, is involved in the metabolism of gefitinib. Previous study reported that in the presence of the anti-tuberculosis drug rifampicin, a potent CYP3A4 inducer, the geometric mean maximum concentration and area under the plasma concentration-time curve of gefitinib were significantly reduced. Thus, we conducted the study to evaluate the impact of PTB on survival for pulmonary adenocarcinoma (PAD) patients that underwent EGFR-TKI treatment. Methods Clinicopathologic data of PAD patients harboring EGFR mutations from the Guangzhou Chest hospital in China between 2017 and 2019 were reviewed retrospectively. Patients receiving EGFR-TKI treatment were divided into PTB and non-PTB groups. The differences in response to EGFR-TKIs and survival between the two groups were assessed. Formalin-fixed paraffin-embedded (FFPE) tumor tissues were used for the detection of alterations in the EGFR, ALK, ROS1, KRAS, BRAF, RET, MET, HER2, NRAS, and PIK3CA genes. Results A total of 1448 patients with PAD were reviewed. 223 patients (15.40%) had co-existing PTB, and 317 (21.89%) patients had EGFR-mutated tumors. Among the 223 patients with PTB, 21 (9.42%) harboring EGFR mutations (PTB group). From 296 non-PTB patients with EGFR mutations, 43 patients (non-PTB group) were randomly selected for subsequent analysis. The frequency of former smoker (57.14% vs. 13.95%, p=0.001) and poor performance status (23.81% vs. 6.98%, p=0.007) were significantly higher in the PTB group compared with the non-PTB group. After EGFR-TKIs treatment, the objective response rate (ORR, 58.14% vs.47.62%) as well as disease control rate (DCR, 97.67% vs.85.71) were higher in the non-PTB group than in the PTB group, but there was no statistical difference. In the survival analysis, both the median progression-free survival (PFS, 7.47 months vs. 11.77 months, p=0.038) and the overall survival (OS, 13.00 months vs. 20.00 months, p=0.0017) after EGFR-TKIs were significantly shorter in the PTB group than in the non-PTB group. Secondary data analysis showed that, for patients with 19Del mutation, or metastases sites less than 3, or using first-line EGFR-TKI, EGFR-TKIs treatment significantly prolonged the median PFS and OS in patients without PTB. Conclusion Presence of PTB may be associated with more frequent former smoker and poor performance status. PAD patients on EGFR-TKI treatment had a worse survival outcome if patients had co-existing PTB. Citation Format: Yalin Xie, Wei Zhou, An Lei, Zhan Huang, Li Weiwei, Changbin Zhu, Guanshan Zhu, Wenchang Cen. Presence of pulmonary tuberculosis impair survival in advanced EGFR mutation lung adenocarcinoma patients receiving epidermal growth factor receptor-tyrosine kinase inhibitor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 419.

Novel ETV1 mutation in small cell lung cancer transformation resistant to EGFR tyrosine kinase inhibitors.

e20568 Background: Non-small cell lung cancer (NSCLC) patients harboring mutations in the epidermal growth factor receptor (EGFR) gene dramatically respond to EGFR tyrosine kinase inhibitors (TKIs). However, these patients inevitably developed acquired resistance to TKIs. Among them, small cell lung cancer (SCLC) transformation is a relatively rare mechanism of resistance. However, the mechanism of SCLC transformation is largely unclear. Methods: We performed a 639 cancer-relevant gene panel to detect genetic differences of tissues before and after TKIs resistance caused by SCLC transformation. In vitro experiments were conducted to study the role of ETS variant transcription factor 1 (ETV1) on SCLC transformation and TKIs resistance. Results: We present two EGFR-mutant pulmonary adenocarcinoma (ADC) patients. One with EGFR exon 19 deletion (Ex19del) accepted first-line gefitinib treatment and then received osimertinib(AZD9291) treatment due to acquisition of EGFR-T790M mutation. A novel ETV1 mutation (p.P159S) was detected in SCLC samples after SCLC transformation when not coexisting with T790M. Another patient harbored an EGFR exon 21 mutation (p.L858R) with a long-lasting response to first-line gefitinib and then transformed to SCLC. A previously unreported ETV1 mutation (p.E462Q) was detected in SCLC tissue. In vitro, ETV1 p.E462Q and p.P159S mutations participated in neuroendocrine differentiation by inducing the expression of the neuroendocrine transcription factor, achaete-scute homolog 1 (ASCL1) and promoted H69 cells proliferation. Besides, ETV1 p.E462Q and p.P159S mutations were resistant to first-generation (gefitinib) and third-generation (osimertinib) TKIs after introducing into NCI-H358 cells. Conclusions: Novel ETV1 p.E462Q and p.P159S mutations were found in SCLC tissues of TKIs resistant patients, providing novel understanding of ETV1 involved in acquired resistance to EGFR-TKIs via SCLC transformation.

Single-Cell Expression Landscape of SARS-CoV-2 Receptor ACE2 and Host Proteases in Normal and Malignant Lung Tissues from Pulmonary Adenocarcinoma Patients.

Simple SummaryThe coronavirus disease 2019 (COVID-19) pandemic continues to spread rapidly on a global scale. When presenting with severe respiratory complications, COVID-19 results in markedly high death rates, particularly among patients with comorbidities such as cancer. Motivated by the ongoing global health crisis, we leveraged a growing in-house cohort of pulmonary tissues from lung cancer patients to analyze, at high resolution, the expression of host proteins implicated in the entryway of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) into lung epithelial cells. Our results identify key pathways in lung pathobiology and inflammation that offer the potential to identify novel markers and therapeutic targets that can be repurposed for clinical management of COVID-19, particularly among lung cancer patients, a population that represents over half a million individuals in the United States alone. The novel coronavirus SARS-CoV-2 is the causative agent of the COVID-19 pandemic. Severely symptomatic COVID-19 is associated with lung inflammation, pneumonia, and respiratory failure, thereby raising concerns of elevated risk of COVID-19-associated mortality among lung cancer patients. Angiotensin-converting enzyme 2 (ACE2) is the major receptor for SARS-CoV-2 entry into lung cells. The single-cell expression landscape of ACE2 and other SARS-CoV-2-related genes in pulmonary tissues of lung cancer patients remains unknown. We sought to delineate single-cell expression profiles of ACE2 and other SARS-CoV-2-related genes in pulmonary tissues of lung adenocarcinoma (LUAD) patients. We examined the expression levels and cellular distribution of ACE2 and SARS-CoV-2-priming proteases TMPRSS2 and TMPRSS4 in 5 LUADs and 14 matched normal tissues by single-cell RNA-sequencing (scRNA-seq) analysis. scRNA-seq of 186,916 cells revealed epithelial-specific expression of ACE2, TMPRSS2, and TMPRSS4. Analysis of 70,030 LUAD- and normal-derived epithelial cells showed that ACE2 levels were highest in normal alveolar type 2 (AT2) cells and that TMPRSS2 was expressed in 65% of normal AT2 cells. Conversely, the expression of TMPRSS4 was highest and most frequently detected (75%) in lung cells with malignant features. ACE2-positive cells co-expressed genes implicated in lung pathobiology, including COPD-associated HHIP, and the scavengers CD36 and DMBT1. Notably, the viral scavenger DMBT1 was significantly positively correlated with ACE2 expression in AT2 cells. We describe normal and tumor lung epithelial populations that express SARS-CoV-2 receptor and proteases, as well as major host defense genes, thus comprising potential treatment targets for COVID-19 particularly among lung cancer patients.

Mutation and drug-specific intracellular accumulation of EGFR predict clinical responses to tyrosine kinase inhibitors.

BackgroundClinical responses to EGFR tyrosine kinase inhibitors (TKIs) are restricted to tumors harboring specific activating mutations and even then, not all tyrosine kinase inhibitors provide clinical benefit. All TKIs however, effectively inhibit EGFR phosphorylation regardless of the mutation present.MethodsHigh-throughput, high-content imaging analysis, western blot, Reversed phase protein arrays, mass spectrometry and RT-qPCR.FindingsWe show that the addition of TKIs results in a strong and rapid intracellular accumulation of EGFR. This accumulation mimicked clinical efficacy as it was observed only in the context of the combination of a TKI-sensitive mutation with a clinically effective (type I) TKI. Intracellular accumulation of EGFR was able to predict response to gefitinib in a panel of cell-lines with different EGFR mutations. Our assay also predicted clinical benefit to EGFR TKIs on a cohort of pulmonary adenocarcinoma patients (hazard ratio 0.21, P=0.0004 [Cox proportional hazard model]) and could predict the clinical response in patients harboring rare mutations with unknown TKI-sensitivity. All investigated TKIs, regardless of clinical efficacy, inhibited EGFR phosphorylation and downstream pathway activation, irrespective of the mutation present. Intracellular accumulation of EGFR depended on a continued presence of TKI indicating (type I) TKIs remain associated with the protein even after its dephosphorylation. Accumulation therefore is likely caused by two consecutive conformational changes, induced by both activating mutation and TKI, that combined block EGFR-membrane recycling.InterpretationWe report on an assay that mimics the discrepancy between molecular and clinical activity of EGFR-TKIs, which may allow response prediction in vitro and helps understand the mechanism of effective inhibitors.

The urokinase-type plasminogen activator and inhibitors in resectable lung adenocarcinoma

BackgroundThe urokinase-type plasminogen activator (uPA) system is closely related to the occurrence and progression of cancer in many aspects. Previous studies demonstrated that the conclusions about the prognosis value of uPA, plasminogen activator inhibitor 1 (PAI-1) and plasminogen activator inhibitor 2 (PAI-2) in lung cancer are controversial, so this study was performed for the exploration of the predictive effect of uPA, PAI-1 and PAI-2 on the overall survival (OS) of resectable pulmonary adenocarcinoma patients. MethodsUPA, PAI-1 and PAI-2 expression levels were assayed by immunohistochemical staining based on tissue microarray (TMA) that is composed of formalin-fixed paraffin-embedded specimens from 84 resectable lung adenocarcinoma patients from July 2004 to June 2009. The relationship of IHC, mRNA expression levels of three molecules were investigated respectively. The three molecules’ relationship with clinicopathologic parameters and OS was explored by Chi-square, Kaplan-Meier, and Cox regression analyses. The Cancer Genome Atlas (TCGA) database was used to analyze differential gene expressions of RNA-sequencing data of pulmonary adenocarcinoma and normal tissues, and Kaplan-Meier methods were adopted to confirm the prognostic value of uPA, PAI-1 and PAI-2 in resectable lung adenocarcinoma in TCGA database and the R package MethylMix was used to conduct an analysis integrating methylation data and gene expression of RNA-sequencing data based on TCGA. ResultsUPA, PAI-1 and PAI-2 had much higher IHC expression levels in tumor than those in the normal tissues (uPA, Z = -10.511; PAI-1, Z = -4.836; PAI-2, Z = -6.794; all P < 0.0001). High DNA methylation level of gene uPA resulted in the decrease of its expression. In addition, expression level of PAI-2 was positively associated with tumor size (χ2 = 8.372, P = 0.004). Multivariate analyses showed TNM stage III was an independent adverse prognostic factor (hazard ratio = 3.736, 95 % confidence interval = 1.097–12.72, P = 0.035). Kaplan-Meier method revealed that uPA, PAI-1 and PAI-2 expression levels were not related to the OS for 84 resectable lung adenocarcinoma patients. According to TCGA data, PAI-1 expression level was identified as a potential adverse predictor for prognosis of resectable lung adenocarcinoma (Gehan-Breslow-Wilcoxon test, P = 0.025). ConclusionsOur data show that, the expression levels of uPA, PAI-1 and PAI-2 are significantly up-regulated in resectable lung adenocarcinoma. Besides, this study highlights PAI-1 as a latent adverse prognostic factor in resectable adenocarcinoma of lung.

Characteristics of gene mutations in Chinese single-center pulmonary adenocarcinoma patients and comparison with European and American pulmonary adenocarcinoma populations

Objective To explore the characteristics and significances of gene mutations in pulmonary adenocarcinoma, and to provide evidence for targeted medication. Methods High throughput sequencing based target-capture sequencing was performed in 104 patients with pulmonary adenocarcinoma to detect the mutational status of 56 cancer-related genes. All patients were diagnosed in the First People's Hospital of Kunshan from May 2017 to August 2018. The mutational characteristics of pulmonary adenocarcinoma was analyzed and compared with European and American pulmonary adenocarcinoma populations. The correlations between mutational characteristics and clinical features were analyzed, and the mutation sites for targeted medication were screened. Results Among 104 patients with pulmonary adenocarcinoma, totally 34 mutational genes were detected in 84 patients (81%, 84/104). Highly frequent mutations included epidermal growth factor receptor (EGFR) (49%, 51/104), TP53 (21%, 22/104), KRAS (13%, 14/104), and BRAF (6%, 6/104). Among all the 187 variants, 76% (142/187) were non-synonymous missense mutations, 13% (24/187) were small fragment deletions, 6% (12/187) were copy number variants, 3% (5/187) were small fragment insertions, and 2% (4/187) were nonsense site mutations. Among 104 patients with pulmonary adenocarcinoma, 34 targeted drug-associated mutations of 13 genes were detected in 68 patients (65%), and 19 (18%) patients harbored ≥ 2 targeted drug-associated mutations. EGFR mutations were more common in female patients than in male patients [62% (34/55)vs. 35% (17/49), χ2= 7.629, P= 0.006], while KRAS mutations were more frequent in male patients than in female patients [22% (11/49) vs. 5% (3/55), χ2= 6.424, P= 0.011]. The mutation frequencies of gene EGFR, TP53, KRAS, and CDKN2A in Chinese single-center (the First People's Hospital of Kunshan) and European and American adenocarcinoma populations were significantly different (all P < 0.05). Conclusions The molecular mutational characteristics of pulmonary adenocarcinoma are complex, and vary greatly among different populations. High throughput sequencing-based multiple-gene detection can reveal its mutational features comprehensively, and that has important roles in personal targeted medication guidance, drug-resistance monitoring and prognosis evaluation. Key words: Lung neoplasms; Adenocarcinoma; High-throughput nucleotide sequencing; Mutation; Molecular targeted therapy

The relationship between Epidermal Growth Factor Receptor (EGFR) mutation and computed tomography findings in lung adenocarcinoma

Background: Adenocarcinoma is the highest histology subtype of lung cancer. Epidermal Growth Factor Receptor (EGFR) is a factor that can predict the prognosis or response to treatment in patients with lung adenocarcinoma. Adenocarcinomas with EGFR mutations generally have a component of Ground Glass Opacity (GGO), smaller size, oval shape, multiple nodal metastases, and distant metastases.  The aim of this study was to determine the relationship between EGFR mutations and CT scan images in pulmonary adenocarcinoma patients.Methods: This was a retrospective analytical study consisting of 92 samples, which were categorized into the mutation group (n = 62) and wild group (n = 30). This study was conducted at Dr. Soetomo General Hospital from January 2015 – December 2017. The assessed CT-Scan findings were tumor size, shape, density, lymph node size, pleural effusion, and metastasis presence. The relationship was analyzed using the chi-square test and considered significant if the p-value was &lt; 0.05.Results: This study found a significant relationship between EGFR mutations status with tumor size ≤ 3 cm (p = 0.02), lymph node size &lt; 1.5 cm (p = &lt; 0.001) and metastasis (p = 0.026). However, tumor density, tumor form, and pleural effusion did not have significant relationship with EGFR mutation.Conclusion: Tumor size ≤ 3 cm, lymph node size &lt; 1.5 cm and presence of metastasis can be found in EGFR mutations pulmonary adenocarcinoma patients.