Quantitative mass spectrometry to interrogate proteomic heterogeneity in metastatic lung adenocarcinoma and validate a novel somatic mutation CDK12-G879V

AbstractLung cancer is the leading cause of cancer death both in men and women. Tumor heterogeneity is an impediment to targeted treatment of all cancers, including lung cancer. Here, we sought to characterize changes in tumor proteome and phosphoproteome by longitudinal, prospective collection of tumor tissue of an exceptional responder lung adenocarcinoma patient who survived with metastatic lung adenocarcinoma for more than seven years with HER2-directed therapy in combination with chemotherapy. We employed “Super-SILAC” and TMT labeling strategies to quantify the proteome and phosphoproteome of a lung metastatic site and ten different metastatic progressive lymph nodes collected across a span of seven years, including five lymph nodes procured at autopsy. We identified specific signaling networks enriched in lung compared to the lymph node metastatic sites. We correlated the changes in protein abundance with changes in copy number alteration (CNA) and transcript expression. To further interrogate the mass spectrometry data, patient-specific database was built incorporating all the somatic variants identified by whole genome sequencing (WGS) of genomic DNA from the lung, one lymph node metastatic site and blood. An extensive validation pipeline was built for confirmation of variant peptides. We validated 360 spectra corresponding to 55 germline and 6 somatic variant peptides. Targeted MRM assays demonstrated expression of two novel variant somatic peptides, CDK12-G879V and FASN-R1439Q, with expression in lung and lymph node metastatic sites, respectively. CDK12 G879V mutation likely results in a nonfunctional CDK12 kinase and chemotherapy susceptibility in lung metastatic sites. Knockdown of CDK12 in lung adenocarcinoma cells results in increased chemotherapy sensitivity, explaining the complete resolution of the lung metastatic sites in this patient.

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Tumour draining lymph node-generated CD8 T cells play a role in controlling lung metastases after a primary tumour is removed but not when adjuvant immunotherapy is used

Cancer Immunology Immunotherapy ◽

10.1007/s00262-021-02934-3 ◽

2021 ◽

Author(s):

Fear VS ◽

Forbes CA ◽

Neeve SA ◽

Fisher SA ◽

Chee J ◽

...

Keyword(s):

Lung Cancer ◽

Lymph Node ◽

Lymph Nodes ◽

Metastatic Disease ◽

Clinical Setting ◽

Primary Tumour ◽

Adjuvant Immunotherapy ◽

Time Of Surgery ◽

Lymph Node Resection ◽

Metastatic Lung

AbstractSurgical resection of cancer remains the frontline therapy for millions of patients annually, but post-operative recurrence is common, with a relapse rate of around 45% for non-small cell lung cancer. The tumour draining lymph nodes (dLN) are resected at the time of surgery for staging purposes, and this cannot be a null event for patient survival and future response to immune checkpoint blockade treatment. This project investigates cancer surgery, lymphadenectomy, onset of metastatic disease, and response to immunotherapy in a novel model that closely reflects the clinical setting. In a murine metastatic lung cancer model, primary subcutaneous tumours were resected with associated dLNs remaining intact, completely resected or partially resected. Median survival after surgery was significantly shorter with complete dLN resection at the time of surgery (49 days (95%CI)) compared to when lymph nodes remained intact (> 88 days; p < 0.05). Survival was partially restored with incomplete lymph node resection and CD8 T cell dependent. Treatment with aCTLA4 whilst effective against the primary tumour was ineffective for metastatic lung disease. Conversely, aPD-1/aCD40 treatment was effective in both the primary and metastatic disease settings and restored the detrimental effects of complete dLN resection on survival. In this pre-clinical lung metastatic disease model that closely reflects the clinical setting, we observe decreased frequency of survival after complete lymphadenectomy, which was ameliorated with partial lymph node removal or with early administration of aPD-1/aCD40 therapy. These findings have direct relevance to surgical lymph node resection and adjuvant immunotherapy in lung cancer, and perhaps other cancer, patients.

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FDG Uptake at Sequential Intervals After Radiotherapy (RT) or RT of Chemo-Radiotherapy (CT+RT) and its Predictive Value for Tumor Control Probability (TCP) of Metastatic Lung Cancer in Regional Lymph Nodes

International Journal of Radiation Oncology*Biology*Physics ◽

10.1016/j.ijrobp.2007.07.1705 ◽

2007 ◽

Vol 69 (3) ◽

pp. S494

Author(s):

N.C. Choi ◽

T. Chun ◽

M. Ancukiewicz ◽

A. Niemierko ◽

P. Fidias ◽

...

Keyword(s):

Lung Cancer ◽

Lymph Nodes ◽

Predictive Value ◽

Tumor Control ◽

Tumor Control Probability ◽

Metastatic Lung Cancer ◽

Regional Lymph Nodes ◽

Fdg Uptake ◽

Metastatic Lung

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EGFR TKI Combined with PD1 Inhibitor for EGFR Mutated Lung Cancer with Breast Metastasis

10.21203/rs.3.rs-431147/v1 ◽

2021 ◽

Author(s):

Xuyu Gu ◽

Chanchan Gao ◽

Longfei Wang ◽

Shiya Zheng

Keyword(s):

Lung Cancer ◽

Lung Adenocarcinoma ◽

Left Breast ◽

Axillary Lymph ◽

Breast Metastasis ◽

Lung Cancer Patients ◽

Metastatic Lung ◽

New Ideas ◽

Recurrent Pleural Effusion ◽

Egfr Tki

Abstract Background: Lung adenocarcinoma with breast metastasis is rare. In the present study, a case of an advanced patient with breast metastasis from lung adenocarcinoma with EGFR 21 exon p.L858R mutation who underwent EGFR TKI combined with PD1 inhibitor is reported.Case presentation: A 62-year-old female patient diagnosed with lung adenocarcinoma who had undergone six times disease progress and breast metastasis in fifth-time disease progress.The patient underwent left breast puncture and axillary lymph node in ultrasound-guided and the postoperative pathological diagnosis of metastatic lung adenocarcinoma was confirmed. And then gene detection showed EGFR 21 exon p.L858R mutation. Breast metastasis from lung adenocarcinoma was diagnosed and the patient is being treated with Almonertinib combined with PD1 inhibitor.Conclusion: Breast metastasis is rare and lung adenocarcinoma might be the primary disease. Gene indection is important. And for lung cancer patients with recurrent pleural effusion, visit of the breast should be included in the follow-up process. In addition, the treatment model of interspersed immunotherapy after EGFR resistance has brought new ideas for the treatment of lung cancer with breast metastasis.

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Endobronchial ultrasound-guided transbronchial needle aspiration for lung cancer staging: early experience in Brazil,

Jornal Brasileiro de Pneumologia ◽

10.1590/s1806-37132015000100004 ◽

2015 ◽

Vol 41 (1) ◽

pp. 23-30 ◽

Cited By ~ 5

Author(s):

Viviane Rossi Figueiredo ◽

Paulo Francisco Guerreiro Cardoso ◽

Márcia Jacomelli ◽

Sérgio Eduardo Demarzo ◽

Addy Lidvina Mejia Palomino ◽

...

Keyword(s):

Lung Cancer ◽

Lymph Node ◽

Lymph Nodes ◽

Cancer Staging ◽

Accurate Method ◽

Needle Aspiration ◽

Endobronchial Ultrasound ◽

Lymph Node Staging ◽

Ultrasound Guided ◽

Transbronchial Needle Aspiration

Objective: Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) is a minimally invasive, safe and accurate method for collecting samples from mediastinal and hilar lymph nodes. This study focused on the initial results obtained with EBUS-TBNA for lung cancer and lymph node staging at three teaching hospitals in Brazil. Methods: This was a retrospective analysis of patients diagnosed with lung cancer and submitted to EBUS-TBNA for mediastinal lymph node staging. The EBUS-TBNA procedures, which involved the use of an EBUS scope, an ultrasound processor, and a compatible, disposable 22 G needle, were performed while the patients were under general anesthesia. Results: Between January of 2011 and January of 2014, 149 patients underwent EBUS-TBNA for lymph node staging. The mean age was 66 ± 12 years, and 58% were male. A total of 407 lymph nodes were sampled by EBUS-TBNA. The most common types of lung neoplasm were adenocarcinoma (in 67%) and squamous cell carcinoma (in 24%). For lung cancer staging, EBUS-TBNA was found to have a sensitivity of 96%, a specificity of 100%, and a negative predictive value of 85%. Conclusions: We found EBUS-TBNA to be a safe and accurate method for lymph node staging in lung cancer patients.

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Almonertinib in the treatment of lung cancer with breast metastasis: a case report

10.21203/rs.3.rs-128250/v1 ◽

2020 ◽

Author(s):

Xuyu Gu ◽

Chanchan Gao ◽

Longfei Wang ◽

Shiya Zheng

Keyword(s):

Lung Cancer ◽

Lung Adenocarcinoma ◽

Left Breast ◽

Axillary Lymph ◽

Breast Metastasis ◽

Gene Detection ◽

Lung Cancer Patients ◽

Metastatic Lung ◽

Recurrent Pleural Effusion

Abstract BackgroundLung adenocarcinoma with breast metastasis is rare. In the present study, a case of an advanced patient with breast metastasis from lung adenocarcinoma with EGFR 21 exon p.L858R mutation who underwent TKI-inhibitors is reported.Case presentationA 62-year-old female patient diagnosed with lung adenocarcinoma who had undergone seven times disease progress and breast metastasis in sixth time disease progress.The patient underwent left breast puncture and axillary lymph node in ultrasound-guided and the postoperative pathological diagnosis of metastatic lung adenocarcinoma was confirmed. And then gene detection showed EGFR 21 exon p.L858R mutation. Breast metastasis for lung adenocarcinoma was diagnosed and the patient are being treated with Almonertinib.ConclusionBreast metastasis is rare and lung adenocarcinoma might be the primary disease. Gene indection is important. And for lung cancer patients with recurrent pleural effusion, visit of the breast should be included in the follow-up process.

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From Raw Pixels to Recurrence Image for Deep Learning of Benign and Malignant Mediastinal Lymph Nodes on Computed Tomography

10.36227/techrxiv.13246337 ◽

2020 ◽

Author(s):

Tuan Pham

Keyword(s):

Computed Tomography ◽

Lung Cancer ◽

Deep Learning ◽

Lymph Node ◽

Lymph Nodes ◽

Mediastinal Lymph Node ◽

Survival Rates ◽

Primary Lung Cancer ◽

Lymph Node Status ◽

Mediastinal Lymph Nodes

<div>Lung cancer causes the most cancer deaths worldwide and has one of the lowest five-year survival rates of all cancer types. It is reported that more than half of patients with lung cancer die within one year of being diagnosed. Because mediastinal lymph node status is the most important factor for the treatment and prognosis of lung cancer, the aim of this study is to improve the predictive value in assessing the computed tomography (CT) of mediastinal lymph-node malignancy in patients with primary lung cancer. This paper introduces a new method for creating pseudo-labeled images of CT regions of mediastinal lymph nodes by using the concept of recurrence analysis in nonlinear dynamics for the transfer learning. Pseudo-labeled images of original CT images are used as input into deep-learning models. Three popular pretrained convolutional neural networks (AlexNet, SqueezeNet, and DenseNet-201) were used for the implementation of the proposed concept for the classification of benign and malignant mediastinal lymph nodes using a public CT database. In comparison with the use of the original CT data, the results show the high performance of the transformed images for the task of classification. The proposed method has the potential for differentiating benign from malignant mediastinal lymph nodes on CT, and may provide a new way for studying lung cancer using radiology imaging. </div><div><br></div>

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Metastatic Lung Cancer Without Regional Lymph Node Swelling

CHEST Journal ◽

10.1378/chest.120.2.689 ◽

2001 ◽

Vol 120 (2) ◽

pp. 689-690 ◽

Cited By ~ 1

Author(s):

Hiroaki Satoh ◽

Hiroichi Ishikawa ◽

Yuko T. Yamashita ◽

Morio Ohtsuka ◽

Kiyohisa Sekizawa

Keyword(s):

Lung Cancer ◽

Lymph Node ◽

Regional Lymph Node ◽

Metastatic Lung Cancer ◽

Metastatic Lung ◽

Lymph Node Swelling

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Targeting β-tubulin/CCT-β complex induces apoptosis and suppresses migration and invasion of highly metastatic lung adenocarcinoma

Carcinogenesis ◽

10.1093/carcin/bgz137 ◽

2019 ◽

Vol 41 (5) ◽

pp. 699-710 ◽

Cited By ~ 3

Author(s):

Yan-Jin Liu ◽

Yu-Ju Chang ◽

Yu-Ting Kuo ◽

Po-Huang Liang

Keyword(s):

Lung Cancer ◽

Lung Adenocarcinoma ◽

Cancer Cells ◽

Prognostic Marker ◽

Epithelial Mesenchymal Transition ◽

Lung Cancer Cell Line ◽

Migration And Invasion ◽

Mesenchymal Transition ◽

Metastatic Lung ◽

Β Tubulin

Abstract Metastasis, the movement of cancer cells from one site to another, is responsible for the highest number of cancer deaths, especially in lung cancer patients. In this study, we first identified a prognostic marker of lung adenocarcinoma, TCP-1 β subunit (chaperonin-containing TCP-1β; CCT-β). We showed a compound that disrupted the interaction of CCT-β with β-tubulin killed a highly metastatic non-small cell lung cancer cell line CL1-5 through inducing Endoplasmic reticulum stress and caspases activation. Moreover, at the dosage of EC20, the compound inhibited migration and invasion of the lung cancer cells by suppressing matrix metalloproteinase (MMP)-2/9 and epithelial–mesenchymal transition (EMT)-related proteins through downregulating mitogen-activated protein kinases (MAPKs), Akt/β-catenin and integrin–focal adhesion kinase signaling pathways. Unlike the anticancer drugs, such as Taxol, that target the adenosine triphosphate site of β-tubulin, this study reveals a therapeutic target, β-tubulin/CCT-β complex, for metastatic human lung adenocarcinoma. The study demonstrated CCT-β as a prognostic marker. Targeting β-tubulin/CCT-β complex caused apoptosis and inhibited invasion/migration of CCT-β overexpressed, highly metastatic lung adenocarcinoma.

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Leukemoid reaction causing arterial thrombus in a patient with lung adenocarcinoma

BMJ Case Reports ◽

10.1136/bcr-2020-235389 ◽

2020 ◽

Vol 13 (10) ◽

pp. e235389

Author(s):

Zena Chahine ◽

Yazan Samhouri ◽

Thejus Jayakrishnan ◽

Dulabh Monga

Keyword(s):

Lung Cancer ◽

Lung Adenocarcinoma ◽

Cancer Progression ◽

Venous Stasis ◽

Leukemoid Reaction ◽

Painful Ulceration ◽

Metastatic Lung ◽

Arterial Insufficiency ◽

Wbc Count ◽

The Right

A leukemoid reaction is typically defined as white blood cell (WBC) count >50×109/L, predominantly neutrophil precursors, that are not due to tumour involvement in the bone marrow and not derived from clones. Leukemoid reactions associated with malignancy, known as paraneoplastic leukemoid reactions, are less common and are most notably seen with non-small cell lung cancer. A 64-year-old woman presented with right leg painful ulceration. On examination, she had multiple venous stasis ulcers more severe on the right, with no palpable pulses in her lower extremities. Her WBC count was 124×109/L and platelets were 517×109/L. Arterial dopplers showed limb-threatening arterial insufficiency which prompted right femoral endarterectomy. Few months earlier she was diagnosed with metastatic lung adenocarcinoma to the bone and she had leukemoid reaction with WBC 43.920× 109/L with 90% neutrophils. Repeat imaging showed progression of her malignancy and she passed shortly after. Inflammation is a key element of carcinogenesis and cancer progression. Among the different tumours, lung cancer is a non-haematologic malignancy that is most closely associated with leucocytosis. Some studies have found that leucocytosis was significantly associated with metastasis and shorter survival irrespective of other factors such as age or sex. The mechanism remains unclear however elevated levels of granulocyte colony-stimulating factor (CSF), granulocyte macrophage-CSF and interleukin 6 have been linked to this phenomena. The degree of leucocytosis seen in our patient is suggestive of CSF production leading to a paraneoplastic leukemoid reaction.

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