Metastatic Lung Adenocarcinoma Research Articles

Brigatinib-associated autoimmune hepatitis: A case report

Brigatinib is a next-generation anaplastic lymphoma kinase (ALK) inhibitor that targets a wide variety of ALK mutations and ROS1 rearrangements. While pancreatic enzyme elevations due to brigatinib are well known, we wanted to present a case that caused liver toxicity. ALK and ROS1 translocations were detected in a 58-year-old patient diagnosed with metastatic lung adenocarcinoma. In the patient who had a good response with brigatinib, more than 5-fold elevation was detected in liver enzymes at the fifth month of treatment. After excluding other hepatitis factors, the patient was thought to have autoimmune hepatitis, and methylprednisolone was started and liver enzymes were decreased. Increased creatine kinase and lipase levels are common side effects associated with brigatinib, while liver toxicity is rare. Autoimmune hepatitis due to brigatinib was considered because of hepatic toxicity that developed in the fifth month of treatment and responded well to steroids.

The prognostic effect of metastasis patterns on overall survival in organ metastatic lung adenocarcinoma

The effect of various metastases patterns on the prognosis of lung adenocarcinoma (AD) remains unknown. The purpose of our retrospective study is to determine whether various metastases patterns have a prognostic impact on patients with organ metastatic lung AD. Patient data was extracted from the Surveillance, Epidemiology, and End Results (SEER) database. The Kaplan-Meier method was chosen for the evaluation of overall survival (OS) rate. Univariable and multivariable Cox regression analyses were conducted to evaluate independent prognostic factors. In the SEER database, 12,228 patients with IV lung AD were retrieved in total. And 78.78% of those patients (9633/12,228) suffered from one of brain, lung, liver or bone metastasis due to disease progression. It was found that the most common site in patients with metastatic lung AD was brain (21.20%), and the least common site of metastasis was liver (3.50%). Patients who suffered single lung metastatic showed relatively good OS, and the median survival time was 11 months (95% CI 0.470-0.516). For those with 2 metastatic sites, data analysis suggested that the median survival times of patients with bone and lung metastasis (10 months; 95% CI 0.469-0.542) were better than others. For those with 3 metastatic sites, data analysis suggested that metastatic pattern had no effect on the OS. Brain is the most common single metastasis site of lung AD. Compared with the other 3 metastatic sites, patients with lung metastasis had better survival results. Deeper knowledge of metastatic patterns will help doctors to better understand the prognosis and formulate more appropriate treatment plans.

Abstract 863: Predictive value of baseline inter-sites heterogeneity measured by radiomics in metastatic lung adenocarcinomas

Abstract Imaging can capture phenotypic intra- and inter-tumoral heterogeneities. Radiomics provides a radiophenotypic quantification but has mostly focused on single tumors, letting apart metastatic patients. Our aim was to develop inter-site heterogeneity indices (ISHIs) using radiomics and to investigate their predictive value regarding treatment response and overall survival (OS) in lung adenocarcinoma patients. All measurable target lesions per RECIST with volume>1cm3 from consecutive adult patients with newly-diagnosed metastatic lung adenocarcinoma were segmented on contrast-enhanced CT-scan to extract 121 3D-radiomics features (RFs). Four methods were developed to quantify the dissimilarity (Ds) between the lesion profiles from a same patient in the radiomics space, namely: Centroid-to-Lesion (CL), Lesion-to-Lesion (LL), Primitive-to-Lesion (PL) - followed by mean, range and standard deviation (SD) of those distances -, and using clustering to define lesion groupings and calculating grouping diversity with Shannon Entropy (SE). Associations between the 10 resulting ISHIs and disease control rate (DCR), objective response rate (ORR) to first-line treatment and OS were investigated in univariate and stepwise multivariate analyses including cofounding variables (performance status, sex, age, staging, number of metastatic sites, liver and bone metastases). 167 patients (62 women, median age: 62.3 years) were included between 2016 and 2019, and randomly separated into one experimental (N=117 [70%], 546 lesions) and one validation (N=50 [30%], 232 lesions) cohorts. Higher ISHIs were systematically found in patients without disease control, without objective response and with worse OS. Range(Ds-PL) was independently associated with DCR in both cohorts (odds ratio [OR]=1.30, P=0.02 and OR=1.50, P=0.02, respectively). Range(Ds-PL) was independently associated with ORR in the validation cohort (OR=1.46, P=0.049 versus OR=1.23, P=0.055 in the experimental cohort). SE was independently correlated with OS in the experimental cohort (hazard ratio [HR]=2.39, P=0.005) whereas Range(Ds-PL) was selected in the last regression step in the validation cohort (HR=1.16, P=0.08). None of the ISHIs was associated with PD-L1 status; however, trend towards lower ISHI values were observed in EGFR, ALK and ROS1 altered tumors versus the others. Radiomics-based ISHIs were associated with ORR, DCR and OS and appeared as promising metrics to deepen our understanding of the clinical implication of intra-patient inter-tumor heterogeneity. Correlation assessment between radiomics-based ISHIs and tumor heterogeneity evaluated by a baseline ctDNA profiling (FondationOne® Liquid CDx) before treatment in metastatic lung adenocarcinoma patients is ongoing and will be presented. Citation Format: Mathilde Lafon, Sophie Cousin, Mélissa Alamé, Michèle Kind, Antoine italiano, Amandine Crombé. Predictive value of baseline inter-sites heterogeneity measured by radiomics in metastatic lung adenocarcinomas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 863.

Abstract 811: Development of a NOX-ROS nanoinhibitor for enhancing response to radiotherapy in lung cancer cells while mitigation radiation-induced inflammation and injury in the normal lung tissue

Abstract Objective: One of the unmet clinical challenges is that many tumors remain insensitive to radiotherapy owing to intrinsic resistance or acquired resistance that leads to tumor progression or recurrence. Moreover, radiation-induced acute injury and chronic inflammation in normal tissues limit the radiation dose that can be applied to the tumor, and tolerable doses are often linked to suboptimal tumor control—even accepting side effects that lead to decreased quality of life. Our goal of the study is to develop a nanoformulated radiosensitizer that inhibits NOX-ROS signal pathway to enhance therapeutic response in tumor cells while reducing radiotoxicity in normal tissues. Methods: We developed a biomaterial-based nanoparticle radiosensitizer that acts upon abnormal redox status and altered metabolism in tumor cells to trigger a cascade of changes in signal pathways to enhance response to radiotherapy. This CD44-targeted radiosensitizer consists of a biodegradable and bioactive hyaluronic acid nanoparticle (HANP) encapsulated with a dual NOX1/4 inhibitor, GKT831 (HANP/GKT831). Orthotopic and subcutaneous NSCLC tumor mouse models using a WRJ388 cell line that was isolated from a metastatic lung adenocarcinoma in a lymph node of a KrasG12D/Lkb1null GEMM mouse were established for evaluation of the effect on the inhibition of tumor growth and protection of normal tissue after the treatment with intravenous administrations of HANP/GKT831 at 5 mg/kg (twice per week for five times) combined with radiation (2 Gy/each dose, twice per week for five times). The anti-tumor effect, immune response, and inflammation in the normal lung tissues were investigated using histological and immunofluorescence analyses. Results: Our results showed that HANP/GKT831 had stronger inhibitory effects on ROS generation and cell proliferation than that of GKT831 in mouse NSCLC tumor cells in vitro. Systemic injection of HANP/GKT831 combined with radiation had the strongest inhibition on tumor growth (~79%) compared with the combination of non-nanoformulated GKT831 with radiation treated mouse group (<50%). HANP/GKT831 combined with radiation led to an increased tumor specific CD8+ T cells in tumors and markedly reduced the level of myeloid derived suppressive cells (CD11b+/GR1+) in tumors. Furthermore, the combination of radiation and HANP/GKT831 reduced inflammatory cytokines, such as IFN-γ and TNF-α, and cells (CD11b+ cells) in the irradiated normal lung tissues. Conclusion: HANP/GKT831 is a biomaterial-based nanoparticle radiosensitizer that acts upon abnormal redox status and altered metabolism in tumor cells to trigger a cascade of changes in signal pathways to enhance the response of tumor cells to radiotherapy. It also has the potential to reduce the radiation-induced inflammatory response in normal lung tissues. Citation Format: Lei Zhu, Lumeng Zhang, Tongrui Liu, Wei Ping Qian, Wei Zhou, Lily Yang. Development of a NOX-ROS nanoinhibitor for enhancing response to radiotherapy in lung cancer cells while mitigation radiation-induced inflammation and injury in the normal lung tissue [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 811.

First presentation of metastatic lung cancer as groin necrotizing fasciitis

Introduction: A B is a 64-year-old female who presented to the emergency department with fever, chill, and a swollen tender lump in the groin. She had a high white cell count of 14.0 × 109/L and a C-reactive protein (CRP) of 190 mg/L. She proceeded to have an urgent computed tomography (CT) scan. Case Report: A B had a past medical history of poorly controlled diabetes (HbA1c = 11%) which she was non-compliant to medication. She also had an 80-pack year smoking history. A CT scan performed showed severe cellulitis with a collection with a suggestion of necrotizing fasciitis. She was taken to theater urgently for debridement. Histological examination of the debrided tissue however showed poorly differentiated adenocarcinoma which was consistent with metastatic lung adenocarcinoma. Conclusion: This is the first case recorded of lung cancer with metastasis to the groin and presenting as a necrotizing soft tissue infection.

Abstract 5752: Enhancer amplification defines lineage addiction in human lung adenocarcinoma

Abstract Lung cancer is the most common cause of death from cancer worldwide, and lung adenocarcinoma (LUAD) is the most common type of lung cancer. NKX2-1 (also known as TTF-1, TITF-1) is a lineage defining transcription factor for normal lung development. In LUAD, NKX2-1 is a highly specific and sensitive marker for both primary and metastatic LUADs, with 85-90% expressing NKX2-1. We and others identified that NKX2-1 as the most significantly amplified gene in LUAD, with 22.5% of primary LUADs exhibiting copy number gains. NKX2-1 is amplified as the earliest stages of LUAD development, and NKX2-1 amplification is a truncal event in multi-region LUAD evolution. Despite strong evidence for an oncogenic role for NKX2-1, little is known about the mechanisms of NKX2-1 activation, or how its oncogenic regulation drives LUAD. Here, we identify recurrent focal amplification targeting a super-enhancer (SE) of NKX2-1 as a driving event in LUAD. Using epigenomic data from LUAD cell lines and tumors, we identify this region as a alveolar lineage super-enhancer (NKX2-1 SE) that is specifically active in NKX2-1(+) LUAD cell lines and primary tumors. Notably, this region is co-amplified with NKX2-1 in 96-100% of NKX2-1-amplified samples, suggesting this region a critical component of the NKX2-1 amplicon. Using endogenous ChIP-seq and exogenous luciferase assays, we show the enhancer activity of the NKX2-1 SE is comprised of three constituent enhancers, and demonstrate that the key enhancer elements can activate transcription of the NKX2-1 promoter. Using CRISPR inhibition (CRISPRi) and CRISPR activation (CRISPRa) in LUAD cell lines expressing high or low levels of NKX2-1, we show that activity of the NKX2-1 SE defines endogenous NKX2-1 expression. Using RNA-seq, ChIP-seq, and ATAC-seq, we find that NKX2-1 controls the transcriptional and epigenomic landscape of lung adenocarcinoma. NKX2-1 knockdown activates an epithelial-mesenchymal transition (EMT) gene signature and downregulates an alveolar differentiation signature, including critical markers of LUAD differentiation, such as NAPSA, SFTPA1/2, and HOPX, at which NKX2-1 mediates lineage enhancer accessibility to regulate target gene expression. Global clustering of LUAD cell lines by RNA-seq or H3K27ac ChIP-seq identifies a distinct NKX2-1(+) cluster, and we find that NKX2-1 directly regulates the genes (57/97) and enhancers that distinguish this subpopulation. Using genome-wide shRNA and CRISPR screens, we identify a NKX2-1 dependency in NKX2-1(+) LUAD cell lines, and find that the majority of NKX2-1(+) LUAD cell lines (11/14) assayed are dependent on NKX2-1. Our data demonstrates that enhancer amplification is a hallmark of oncogenic NKX2-1 activation in LUAD, through which NKX2-1 drives a lineage addicted state and oncogenic cell proliferation. This suggests that NKX2-1 is a critical defining oncogene for LUAD, and that targeting of NKX2-1 or its enhancer may suppress LUAD. Citation Format: John Louis Pulice, Matthew Meyerson. Enhancer amplification defines lineage addiction in human lung adenocarcinoma. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5752.

Abstract 3472: A tumor draining lymph node CD8 T cell memory response is pivotal for a decrease in recurrence after neoadjuvant anti PD-1 therapy for NSCLC

Abstract Background: Non-small cell lung cancer (NSCLC) is the leading cause of cancer death worldwide. Even at early stages, death rates remain disproportionately high due to metastatic recurrence. Recently, blockade of the PD-1/PD-L1 axis has shown impressive increases in recurrence-free survival in a subset of patients. While efforts to decrease relapse have focused on decreasing residual micrometastatic disease at the time of definitive treatment, PD-1 directed therapy may allow for an adaptive immune response and the establishment of anti-tumor immunosurveillance. Building on results from a clinically relevant murine model of metastatic relapse after tumor resection and robust assays on systematically characterized tumor, lymph node and blood samples of early-stage lung cancer patients, we posit that immunologic CD8 T cell memory may be a primary mechanism of metastatic protection. Methods: We utilized a syngeneic murine model of metastatic lung adenocarcinoma (344SQ) after resection of tumor, tumor draining lymph node (tdLN) and non-draining lymph nodes (ndLN). Using bioluminescent imaging (BLI) and flow cytometric analysis we monitored T cell kinetics and anti-tumor activity after administration of anti-PD-1 antibody and/or KD033, a fusion antibody combining a high affinity anti-PD-L1 IgG1 antibody with an IL-15Rα sushi binding domain. Tumor/tdLN and ndLN T cells were characterized for PD-1/TCF-1/CD62L/CD44/CXCR5 memory phenotypes. In parallel, we analyzed resected tumor, tdLN and ndLN from early-stage NSCLC patients. Results: tdLN from murine models and early-stage patients maintain robust PD-1+ CXCR5+ CD8 T cell memory phenotypes not significantly found in the primary tumor, ndLN and peripheral blood. Neoadjuvant treatment with PD-1 blockade alone had a heterogenous response, with robust proliferation of T cell central and stem cell memory populations (CM & SCM) at the tdLN in responders compared to non-responders (p<0.05). Combination therapy with IL-15Rα agonist (KD033) potentiated diverse PD-1+ CXCR5+ CD8 stem cell like memory subsets in the tdLN and subsequent response at the primary tumor (100%) as well as displayed superior protection against metastatic recurrence up to 200 days compared to PD-1 inhibition or KD033 alone (median survival undetermined vs. 120d, 161d respectively p<0.05). Removal of tdLN or blockade of lymph node migration with FTY720 prior to therapy decreased a population of SCM and CM CD8 T cells found in the primary tumor, decreased primary tumor response and altered systemic memory subpopulations in the ndLN (p<0.05). Conclusions: Our data strongly points to a T cell memory response within the tumor draining lymph node as a possible driver of protection from systemic cancer recurrence, laying the groundwork for a new therapeutic strategy aimed at establishing CD8 immunosurveillance for protection from cancer recurrence. Citation Format: Tatiana Delgado Cruz, Geoffrey J. Markowitz, Mitchell Martin, Arshdeep Singh, Shelley Yang Bai, Nasser Altorki, Timothy McGraw, Vivek Mittal, Jonathan Villena-Vargas. A tumor draining lymph node CD8 T cell memory response is pivotal for a decrease in recurrence after neoadjuvant anti PD-1 therapy for NSCLC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3472.

Spontaneous Regression of Metastatic Lung Adenocarcinoma Following a Core Biopsy.

Samhouri, Bilal F. MD*; Dimou, Anastasios MD†; Boland, Jennifer M. MD‡; Edell, Eric S. MD* Author Information

A 30-year-old Woman with Multiple-Sites Metastasis Lung Adenocarcinoma and Coronavirus-19 Disease (COVID-19)

Background: Adenocarcinoma is the most common Non-Small Cell Lung Cancer (NSCLC) in non-smokers in Indonesia. It often metastasizes in multiple sites. Metastasis is a negative predictor for prognosis in lung adenocarcinoma. In this covid pandemic era we present a case of a 30-years-old woman with adenocarcinoma and multiple-sites metastasis, and Coronavirus-19 Disease (COVID-19).
 Case: A 30-year-old woman came to our hospital with multiple complaints of hearing loss, visual loss, and occasional shortness of breath. The patient had a history of wild-type EGFR adenocarcinoma and has been treated with 4 cycles of gemcitabine. She also presented with a lump in her neck. Further examination revealed multiple metastasis tumours in her brain, right eye, neck, and spine. Pleural fluid examination also showed a malignant pleural effusion. Nasopharyngeal swab using reverse transcriptase-polymerase chain reaction (rt-PCR) method revealed that she also suffers from COVID-19 with positive swab result. Despite adequate treatment, she rapidly deteriorates and passed away in hospital.
 Discussion: Management in this patient is complex due to multiple complications and limitation of management given in COVID-19 isolation ward. She presented with multiple equally complicated metastasis, in which treatment priority should be carefully assessed. Despite treatment by multiple specialists, her problems still persist and proved to be fatal.
 Conclusion: Although metastasis is common in adenocarcinoma, multiple metastasis is uncommon, and this case highlights the need of careful management priority in such patients in COVID-19 pandemic setting.
 Keywords: Adenocarcinoma, Multiple Metastasis, Lung Cancer, COVID-19

The role of concurrent amplification of PD-L1, PD-L2 and JAK2 in metastatic lung adenocarcinoma as a biomarker of immune checkpoint inhibitor response: a case report

Background: Immune checkpoint inhibitors (ICIs) have transformed the landscape of care for many malignancies, including non-small cell lung cancer (NSCLC). That said, ICIs are associated with significant immune related adverse events (IrAE) and most patients do not benefit. As a result, significant efforts have been devoted to identifying biomarkers able to predict response to ICIs.

Metastatic Lung Adenocarcinoma to the Oral Cavity

Primary oral neoplasms are relatively common. They tend to have positive neck adenopathy at presentation. Metastatic deposits are rare, and mainly reported to the soft tissue of the oral cavity and to the jawbones. The possible primaries include gastrointestinal and genitourinary tracts. We report a case of an oral cavity mass with initial complaint of toothache and neck swelling with multiple neck nodes. Biopsies taken from the left retromolar trigone and supraclavicular lymph node revealed poorly differentiated metastatic adenocarcinoma. Computed tomography scan suggested primary lung cancer. Early detection of lung cancer should be the clinician’s concern. The presence of an oral mass already indicates a late stage of lung cancer with poor prognosis.

Concurrent tuberculous pericarditis and lung adenocarcinoma presenting with cardiac tamponade

Mycobacterium tuberculosis (MTB) infection and lung malignancies are both important causes of pericardial effusion (PE), particularly in developing nations such as South Africa. They are each associated with significant morbidity and mortality and pose several public health challenges for the region. This case study discussed a 58-year-old man who presented acutely with a large PE complicated by cardiac tamponade. Pericardial fluid analysis was positive for TB and further cytopathological evaluation revealed metastatic lung adenocarcinoma. Dual diagnoses are rare; however, considering the rising incidences of lung cancer and its predisposition for infectious diseases, this may be under-reported in TB endemic regions. This case highlighted the importance of considering other causes of PE that may aggravate presentation, leading to life-threatening cardiac tamponade. Further research is needed to understand the impact of rising cancer incidences and ongoing burden of infectious diseases in sub-Saharan Africa.Contribution: The insights of this case study include the paucity of data surrounding diagnosis and treatment of lung cancer in non-smokers available for South Africa. The current data that are available is for the developed world only. Some evidence incidence might be related to exposure of biofuels, which has significance for our local population and requires more exact research.

Bevacizumab-Induced Thrombotic Microangiopathy (TMA) in Metastatic Lung Adenocarcinoma Patients Receiving Nivolumab Combined with Bevacizumab, Carboplatin and Paclitaxel: Two Case Reports

Anti-programmed death-1 (PD-1)/programmed death ligand 1 (PD-L1) immune checkpoint inhibitors (ICIs), combined with bevacizumab and platinum-based chemotherapy, have shown promising efficacy in treating metastatic non-squamous cell lung cancer in phase 3 clinical trials. However, drug-induced nephrotoxicity is an uncommon but threatening adverse effect when using this combination therapy, and should be evaluated and managed carefully. Here, we present two patients experiencing late-onset asymptomatic heavy proteinuria during the clinical trial. Kidney biopsies performed finally identified bevacizumab-induced thrombotic microangiopathy (TMA), and the proteinuria was decreased after discontinuing bevacizumab permanently. Our report suggests that a kidney biopsy is needed for those receiving ICIs in combination with bevacizumab and chemotherapy and experiencing nephrotoxicity such as heavy proteinuria.

Prognostic Role of Biologically Active Volume of Disease in Patients With Metastatic Lung Adenocarcinoma

BackgroundNumber of metastatic sites can identify patient populations with non–small cell lung cancer (NSCLC) that benefit from aggressive therapy. Total volume of disease is also relevant. We evaluated the prognostic impact of biologically active volume of disease (BaVD) on patients with metastatic lung adenocarcinoma. Materials and MethodsPositron emission tomography/computerized tomography (PET/CT) scans from patients with newly diagnosed lung adenocarcinoma prior to starting any therapy were identified. SUV thresholds of 3 and 4 were used to auto-contour all FDG avid areas. Kaplan-Meier analysis and Cox regression were performed to examine influence on OS. ResultsOne hundred forty-eight patients were included in the analysis. The median BaVD when using an SUV threshold of 3 was 122.8 mL. The median BaVD when using an SUV threshold of 4 was 46.2 mL When stratified by median BaVD using an SUV of 3, median OS was higher for patients with <=122.8 mL (2.12 years) compared to patients with >122.8 mL (1.46 years) (log-rank P = .001). Similarly, when stratified by median BaVD using an SUV of 4, median OS was higher for patients with <=46.2 mL (1.91 years; 95% CI: 1.65-3.22 years) compared to patients with >46.2 mL (1.48 years; 95% CI: 1.07-1.80 years) (log-rank P = .007). On multivariable analysis, BaVD was significantly associated with OS when using an SUV threshold of 3 (HR: 20.169, P < .001) and 4 (HR: 4.117, P < .001). ConclusionBaVD is an important prognostic factor in metastatic lung adenocarcinoma and may aid identification of patients with limited disease who may be candidates for more aggressive therapies.

Single-cell transcriptomic analyses provide insights into the cellular origins and drivers of brain metastasis from lung adenocarcinoma.

Brain metastasis (BM) is the most common intracranial malignancy causing significant mortality, and lung cancer is the most common origin of BM. However, the cellular origins and drivers of BM from lung adenocarcinoma (LUAD) have yet to be defined. The cellular constitutions were characterized by single-cell transcriptomic profiles of 11 LUAD primary tumor (PT) and 10 BM samples (GSE131907). Copy number variation (CNV) and clonality analysis were applied to illustrate the cellular origins of BM tumors. Brain metastasis-associated epithelial cells (BMAECs) were identified by pseudotime trajectory analysis. By using machine-learning algorithms, we developed the BM-index representing the relative abundance of BMAECs in the bulk RNA-seq data indicating a high risk of BM. Therapeutic drugs targeting BMAECs were predicted based on the drug sensitivity data of cancer cell lines. Differences in macrophages and T cells between PTs and BMs were investigated by single-cell RNA (scRNA) and immunohistochemistry and immunofluorescence data. CNV analysis demonstrated BM was derived from subclones of PT with a gain of chromosome 7.We then identified BMAECs and their biomarker, S100A9. Immunofluorescence indicated strong correlations of BMAECs with metastasis and prognosis evaluated by the paired PT and BM samples from Peking Union Medical College Hospital. We further evaluated the clinical significance of the BM-index and identified 7 drugs that potentially target BMAECs. This study clarified possible cellular origins and drivers of metastatic LUAD at the single-cell level and laid a foundation for early detection of LUAD patients with a high risk of BM.

Identification and validation of a muscle failure index to predict prognosis and immunotherapy in lung adenocarcinoma through integrated analysis of bulk and single-cell RNA sequencing data.

It was previously reported that the production of exerkines is positively associated with the beneficial effects of exercise in lung adenocarcinoma (LUAD) patients. This study proposes a novel scoring system based on muscle failure-related genes, to assist in clinical decision making. A comprehensive analysis of bulk and single cell RNA sequencing (scRNA-seq) of early, advanced and brain metastatic LUAD tissues and normal lung tissues was performed to identify muscle failure-related genes in LUAD and to determine the distribution of muscle failure-related genes in different cell populations. A novel scoring system, named MFI (Muscle failure index), was developed and validated. The differences in biological functions, immune infiltration, genomic alterations, and clinical significance of different subtypes were also investigated. First, we conducted single cell analysis on the dataset GSE131907 and identified eight cell subpopulations. We found that four muscle failure-related genes (BDNF, FNDC5, IL15, MSTN) were significantly increased in tumor cells. In addition, IL15 was widely distributed in the immune cell population. And we have validated it in our own clinical cohort. Then we created the MFI model based on 10 muscle failure-related genes using the LASSO algorithm, and MFI remained an independent prognostic factor of OS in both the training and validation cohorts. Moreover, we generated MFI in the single-cell dataset, in which cells with high MFI received and sent more signals compared to those with low MFI. Biological function analysis of both subtypes revealed stronger anti-tumor immune activity in the low MFI group, while tumor cells with high MFI had stronger metabolic and proliferative activity. Finally, we systematically assessed the immune cell activity and immunotherapy responses in LUAD patients, finding that the low MFI group was more sensitive to immunotherapy. Overall, our study can improve the understanding of the role of muscle failure-related genes in tumorigenesis and we constructed a reliable MFI model for predicting prognosis and guiding future clinical decision making.

Chylothorax in the Setting of Lung Malignancy.

Chylothorax refers to chyle within the pleural space, which frequently arises from an interruption in the thoracic duct or because of reduced lymphatic drainage. Pleural fluid that is white/milky in appearance, with a triglyceride concentration of greater than 110 mg/dL, strongly supports the diagnosis of chylothorax. Chylothorax is nearly always exudative. Transudative chylothorax is extremely rare and typically presents due to a secondary cause, such as liver cirrhosis, nephrotic syndrome, or congestive heart failure. We present a case of chylothorax that occurs in the setting of lung adenocarcinoma. A 65-year-old African American man with a past medical history of metastatic right lung adenocarcinoma presented with dyspnea and palpitations. He denied fever, orthopnea, and paroxysmal nocturnal dyspnea. Therapeutic drainage of the left pleural effusion resulted in 650 mL of milky-white fluid. Pleural fluid analysis demonstrated a triglyceride concentration of 520 mg/dL, a pleural/serum protein ratio of 0.41, a pleural/serum lactate dehydrogenase (LDH) ratio of 0.26, a total pleural LDH of 127 IU/L, and a cholesterol level of 58 mg/dL. This effusion can be classified as transudative as per Light's criteria and exudative as per Heffner's and pleural cholesterol criteria. A subsequent pleural fluid cytology found malignant cells consistent with lung adenocarcinoma. Malignancy is the most common cause of nontraumatic, exudative chylothorax. Light's criteria misinterpret about 25% of transudative effusions as exudative. Therefore, to minimize this error, a combination of the 3-criterial consideration is ideal.

Extensive Epipericardial Fat Necrosis in a Case of Metastatic Adenocarcinoma of Lung

Epipericardial fat necrosis is an uncommon benign and self-limiting condition that leads patients to the emergency department owing to the onset of acute pleuritic chest pain. Fat necrosis in adipose tissue can occur at various sites: in the breast and subcutaneous fat after trauma, peripancreatic fat in pancreatitis, and epiploicappendagitis.[1,2] Rarely, it may occur within the epipericardial fat. Since the first description by Jackson et al.,[3] only 35 cases have been published in the English literature, and extensive epipericardial fat necrosis (EFN) is currently described as an extremely rare disease.[4] The aetiology of EFN remains unknown, but some theories have been proposed to explain its origin. Acute torsion of a vascular pedicle is described in some cases, although the presence of a vascular pedicle has been described in only two patients who underwent surgery.[4] Furthermore, increased intrathoracic pressure due to heavy lifting or Valsalva's manoeuvre might trigger rapid changes in capillary pressure, leading to haemorrhagic necrosis, especially if pre-existing structural abnormalities of the adipose tissue, such as lipoma, hamartoma or lipomatosis, are present.[5] Both males and females are affected, and neither age predilections nor pre-disposing factors have been described.[4]

Establishing a metastasis-related diagnosis and prognosis model for lung adenocarcinoma through CRISPR library and TCGA database.

Existing biomarkers for diagnosing and predicting metastasis of lung adenocarcinoma (LUAD) may not meet the demands of clinical practice. Risk prediction models with multiple markers may provide better prognostic factors for accurate diagnosis and prediction of metastatic LUAD. An animal model of LUAD metastasis was constructed using CRISPR technology, and genes related to LUAD metastasis were screened by mRNA sequencing of normal and metastatic tissues. The immune characteristics of different subtypes were analyzed, and differentially expressed genes were subjected to survival and Cox regression analyses to identify the specific genes involved in metastasis for constructing a prediction model. The biological function of RFLNA was verified by analyzing CCK-8, migration, invasion, and apoptosis in LUAD cell lines. We identified 108 differentially expressed genes related to metastasis and classified LUAD samples into two subtypes according to gene expression. Subsequently, a prediction model composed of eight metastasis-related genes (RHOBTB2, KIAA1524, CENPW, DEPDC1, RFLNA, COL7A1, MMP12, and HOXB9) was constructed. The areas under the curves of the logistic regression and neural network were 0.946 and 0.856, respectively. The model effectively classified patients into low- and high-risk groups. The low-risk group had a better prognosis in both the training and test cohorts, indicating that the prediction model had good diagnostic and predictive power. Upregulation of RFLNA successfully promoted cell proliferation, migration, invasion, and attenuated apoptosis, suggesting that RFLNA plays a role in promoting LUAD development and metastasis. The model has important diagnostic and prognostic value for metastatic LUAD and may be useful in clinical applications.

COVID-19 infection during treatment with pembrolizumab in combination with chemotherapy for the treatment of lung adenocarcinoma

The use of pembrolizumab with chemotherapy in first-line treatment of patients with advanced non-small cell lung cancer (NSCLC) is an opportunity for patients to suppress their disease and increase their chances of life extension. COVID-19 (Coronavirus Disease 2019) vaccination is an opportunity for cancer patients to reduce their risk of disease and have a benign disease course. In this report, we present a benign course of SARS-CoV-2 (Severe Acute Respiratory Syndrome Coronavirus 2 ) infection in 68-year-old patient with metastatic lung adenocarcinoma undergoing chemoimmunotherapy who had previously received full COVID-19 vaccination. The control CT scans performed after 3 months of treatment showed partial regression of the tumor mass. On control tomography after 6 months, an intensification of fibro-consolidative changes and ground glass opacities were described. The lesions were characteristic of a history of SARS-CoV-2 infection. The neoplastic lesions described on tomography showed stabilization. After 9 months, long-term stabilization of the disease was achieved. Patients undergoing immunotherapy or chemoimmunotherapy may be at risk of developing severe COVID-19. Therefore, vaccination against SARS-CoV-2 should be strongly recommended in lung cancer patients undergoing immunotherapy.