Invasive Adenocarcinoma Research Articles

Use of CT-derived radiomic features to preoperatively identify invasive mucinous adenocarcinoma in solitary pulmonary nodules ≤3 cm

ObjectiveIn this study, we aimed to utilize computed tomography (CT)-derived radiomics and various machine learning approaches to differentiate between invasive mucinous adenocarcinoma (IMA) and invasive non-mucinous adenocarcinoma (INMA) preoperatively in solitary pulmonary nodules (SPN) ≤3 cm. MethodsA total of 538 patients with SPNs measuring ≤3 cm were enrolled, categorized into either the IMA group (n = 50) or INMA group (n = 488) based on postoperative pathology. Radiomic features were extracted from non-contrast-enhanced CT scans and identified using the least absolute shrinkage and selection operator (LASSO) algorithm. In constructing radiomics-based models, logistic regression, support vector machines, classification and regression trees, and k-nearest neighbors were employed. Additionally, a clinical model was developed, focusing on CT radiological features. Subsequently, this clinical model was integrated with the most effective radiomic model to create a combined model. Performance assessments of these models were conducted, utilizing metrics such as the area under the receiver operating characteristic curve (AUC), DeLong's test, net reclassification index (NRI), and integrated discrimination improvement (IDI). ResultsThe support vector machine approach showed superior predictive efficiency, with AUCs of 0.829 and 0.846 in the training and test cohorts, respectively. The clinical model had AUCs of 0.760 and 0.777 in the corresponding cohorts. The combined model had AUCs of 0.847 and 0.857 in the corresponding cohorts. Furthermore, compared to the radiomic model, the combined model significantly improved performance in both the training (DeLong test P = 0.045, NRI 0.206, IDI 0.024) and test cohorts (P = 0.029, NRI 0.125, IDI 0.032), as well as compared to the clinical model in both the training (P = 0.01, NRI 0.310, IDI 0.09) and test cohorts (P = 0.047, NRI 0.382, IDI 0.085). Conclusionthe combined model exhibited excellent performance in distinguishing between IMA and INMA in SPNs ≤3 cm.

Clinical Multi-features Analysis of Cystic Lung Adenocarcinoma and Construction of Invasive Risk Prediction Model

Cystic lung cancer, a special type of lung cancer, has been paid more and more attention. The most common pathological type of cystic lung cancer is adenocarcinoma. The invasiveness of cystic lung adenocarcinoma is vital for the selection of clinical treatment and prognosis. The aim of this study is to analyze the multiple clinical features of cystic lung adenocarcinoma, explore the independent risk factors of its invasiveness, and establish a risk prediction model. A total of 129 cases of cystic lung adenocarcinoma admitted to the Department of Thoracic Surgery of the First Affiliated Hospital of Nanjing Medical University from January 2021 to July 2022 were retrospectively analyzed and divided into pre-invasive group [atypical adenomatous hyperplasia (AAH), adenocarcinoma in situ (AIS) and minimally invasive adenocarcinoma (MIA)] and invasive group [invasive adenocarcinoma (IAC)] according to pathological findings. There were 47 cases in the pre-invasive group, including 19 males and 28 females, with an average age of (51.23±14.96) years. There were 82 cases in the invasive group, including 60 males and 22 females, with an average age of (61.27±11.74) years. Multiple clinical features of the two groups were collected, including baseline data, imaging data and tumor markers. Univariate analysis, LASSO regression and multivariate Logistic regression analysis were used to screen out the independent risk factors of the invasiveness of cystic lung adenocarcinoma, and the risk prediction model was established. In univariate analysis, age, gender, smoking history, history of emphysema, neuron-specific enolase (NSE), number of cystic airspaces, lesion diameter, cystic cavity diameter, nodule diameter, solid components diameter, cyst wall nodule, smoothness of cyst wall, shape of cystic airspace, lobulation, short burr sign, pleural retraction, vascular penetration and bronchial penetration were statistically different between the pre-invasive group and invasive groups (P<0.05). The above variables were processed by LASSO regression dimensionality reduction and screened as follows: age, gender, smoking history, NSE, number of cystic airspaces, lesion diameter, cystic cavity diameter, cyst wall nodule, smoothness of cyst wall and lobulation. Then the above variables were included in multivariate Logistic regression analysis. Cyst wall nodule (P=0.035) and lobulation (P=0.001) were found to be independent risk factors for the invasiveness of cystic lung adenocarcinoma (P<0.05). The prediction model was established as follows: P=e^x/(1+e^x), x=-7.927+1.476* cyst wall nodule+2.407* lobulation, and area under the curve (AUC) was 0.950. Cyst wall nodule and lobulation are independent risk factors for the invasiveness of cystic lung adenocarcinoma, which have certain guiding significance for the prediction of the invasiveness of cystic lung adenocarcinoma.

Establishment and characterization of novel high mucus-producing lung tumoroids derived from a patient with pulmonary solid adenocarcinoma

Among mucus-producing lung cancers, invasive mucinous adenocarcinoma of the lung is a rare and unique subtype of pulmonary adenocarcinoma. Notably, mucus production may also be observed in the five subtypes of adenocarcinoma grouped under the higher-level diagnosis of Invasive Non-mucinous Adenocarcinomas (NMA). Overlapping pathologic features in mucus-producing tumors can cause diagnostic confusion with significant clinical consequences. In this study, we established lung tumoroids, PDT-LUAD#99, from a patient with NMA and mucus production. The tumoroids were derived from the malignant pleural effusion of a patient with lung cancer and have been successfully developed for long-term culture (> 11 months). Karyotyping by fluorescence in situ hybridization using an alpha-satellite probe showed that tumoroids harbored aneuploid karyotypes. Subcutaneous inoculation of PDT-LUAD#99 lung tumoroids into immunodeficient mice resulted in tumor formation, suggesting that the tumoroids were derived from cancer. Xenografts from PDT-LUAD#99 lung tumoroids reproduced the solid adenocarcinoma with mucin production that was observed in the patient's metastatic lymph nodes. Immunoblot analysis showed MUC5AC secretion into the culture supernatant of PDT-LUAD#99 lung tumoroids, which in contradistinction was barely detected in the culture supernatants of NCI-A549 and NCI-H2122 pulmonary adenocarcinoma cells known for their mucin-producing abilities. Here, we established a novel high-mucus-producing lung tumoroids from a solid adenocarcinoma. This preclinical model may be useful for elucidating the pathogenesis of mucus-producing lung cancer.

Progressive changes in the protein expression profile of alveolar septa in early-stage lung adenocarcinoma.

Adenocarcinomas show a stepwise progression from atypical adenomatous hyperplasia (AAH) through adenocarcinoma in situ (AIS) to invasive adenocarcinoma (IA). Immunoglobulin superfamily containing leucine-rich repeat (ISLR) is a marker of tumor-restraining cancer-associated fibroblasts (CAFs), which are distinct from conventional, strongly α-smooth muscle actin (αSMA)-positive CAFs. Fibroblastactivation protein (FAP) has been focused on as a potential therapeutic and diagnostic target of CAFs. We investigated the changes in protein expression during adenocarcinoma progression in the pre-existing alveolar septa by assessing ISLR, αSMA, and FAP expression in normallung, AAH, AIS, and IA. Fourteen AAH, seventeen AIS, and twenty IA lesions were identified and randomly sampled. Immunohistochemical analysis was performed to evaluate cancer-associated changes and FAP expression in the pre-existing alveolar structures. Normal alveolar septa expressed ISLR. The ISLR level in the alveolar septa decreased in AAH and AIS tissues when compared with that in normal lung tissue. The αSMA-positive area gradually increased from the adjacent lung tissue (13.3% ± 15%) to AIS (87.7% ± 14%), through AAH (70.2% ± 21%). Moreover, the FAP-positive area gradually increased from AAH (1.69% ± 1.4%) to IA (11.8% ± 7.1%), through AIS (6.11% ± 5.3%). Protein expression changes are a feature of CAFs in the pre-existing alveolar septa that begin in AAH. These changes gradually progressed from AAH to IA through AIS. FAP-positive fibroblasts may contribute to tumor stroma formation in early-stage lung adenocarcinoma, and this could influence the development of therapeutic strategies targeting FAP-positive CAFs for disrupting extracellular matrix formation.

Correlation between Radiological Characteristics, PET-CT and Histological Subtypes of Primary Lung Adenocarcinoma-A 102 Case Series Analysis.

Background and Objectives: Lung cancer is the second most common form of cancer in the world for both men and women as well as the most common cause of cancer-related deaths worldwide. The aim of this study is to summarize the radiological characteristics between primary lung adenocarcinoma subtypes and to correlate them with FDG uptake on PET-CT. Materials and Methods: This retrospective study included 102 patients with pathohistologically confirmed lung adenocarcinoma. A PET-CT examination was performed on some of the patients and the values of SUVmax were also correlated with the histological and morphological characteristics of the masses in the lungs. Results: The results of this analysis showed that the mean size of AIS-MIA (adenocarcinoma in situ and minimally invasive adenocarcinoma) cancer was significantly lower than for all other cancer types, while the mean size of the acinar cancer was smaller than in the solid type of cancer. Metastases were significantly more frequent in solid adenocarcinoma than in acinar, lepidic, and AIS-MIA cancer subtypes. The maximum standardized FDG uptake was significantly lower in AIS-MIA than in all other cancer types and in the acinar predominant subtype compared to solid cancer. Papillary predominant adenocarcinoma had higher odds of developing contralateral lymph node involvement compared to other types. Solid adenocarcinoma was associated with higher odds of having metastases and with higher SUVmax. AIS-MIA was associated with lower odds of one unit increase in tumor size and ipsilateral lymph node involvement. Conclusions: The correlation between histopathological and radiological findings is crucial for accurate diagnosis and staging. By integrating both sets of data, clinicians can enhance diagnostic accuracy and determine the optimal treatment plan.

Predictive value of CT and 18F-FDG PET/CT features on spread through air space in lung adenocarcinoma

BackgroundLung adenocarcinoma, a leading cause of cancer-related mortality, demands precise prognostic indicators for effective management. The presence of spread through air space (STAS) indicates adverse tumor behavior. However, comparative differences between 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography(PET)/computed tomography(CT) and CT in predicting STAS in lung adenocarcinoma remain inadequately explored. This retrospective study analyzes preoperative CT and 18F-FDG PET/CT features to predict STAS, aiming to identify key predictive factors and enhance clinical decision-making.MethodsBetween February 2022 and April 2023, 100 patients (108 lesions) who underwent surgery for clinical lung adenocarcinoma were enrolled. All these patients underwent 18F-FDG PET/CT, thin-section chest CT scan, and pathological biopsy. Univariate and multivariate logistic regression was used to analyze CT and 18F-FDG PET/CT image characteristics. Receiver operating characteristic curve analysis was performed to identify a cut-off value.ResultsSixty lesions were positive for STAS, and 48 lesions were negative for STAS. The STAS-positive was frequently observed in acinar predominant. However, STAS-negative was frequently observed in minimally invasive adenocarcinoma. Univariable analysis results revealed that CT features (including nodule type, maximum tumor diameter, maximum solid component diameter, consolidation tumor ratio, pleural indentation, lobulation, spiculation) and all 18F-FDG PET/CT characteristics were statistically significant difference in STAS-positive and STAS-negative lesions. And multivariate logistic regression results showed that the maximum tumor diameter and SUVmax were the independent influencing factors of CT and 18F-FDG PET/CT in STAS, respectively. The area under the curve of maximum tumor diameter and SUVmax was 0.68 vs. 0.82. The cut-off value for maximum tumor diameter and SUVmax was 2.35 vs. 5.05 with a sensitivity of 50.0% vs. 68.3% and specificity of 81.2% vs. 87.5%, which showed that SUVmax was superior to the maximum tumor diameter.ConclusionThe radiological features of SUVmax is the best model for predicting STAS in lung adenocarcinoma. These radiological features could predict STAS with excellent specificity but inferior sensitivity.

Abstract CT278: [DREAM] Double lung transplant registry aimed for lung-limited malignancies - a prospective registry study for medically refractory cancers

Abstract BackgroundAdenocarcinoma in situ (AIS) and minimally invasive adenocarcinoma (MIA) are listed as ‘special circumstances’ for lung transplantation according to a consensus document from the International Society for Heart and Lung Transplantation (ISHLT) (Weill D et al., 2015). Five studies have reported on lung transplantation in carefully selected subsets of patients with multifocal lung adenocarcinoma (Raemdonck DV et al., 2016; Glanville AR et al., 2018). The 5-year survival rate of bilateral sequential lung transplantation was estimated at over 50% in patients with multifocal BAC, invasive adenocarcinoma, and NSCLC (Ahmad U et al., 2012; Paloyan EB et al., 2000; Zorn GL et al., 2003; de Perrot M et al., 2004). Another a case series reported a post-transplant recurrence-free survival of 23 to 56 months in three patients (Garver RI et al., 1999). Moreover, there is an unmet need for patients who have lung-limited metastasis after successful treatment for primary tumors such as sarcomas or colorectal cancer (CRC). As with liver transplantation for CRC patients who have liver-confined metastases (Dueland S et at., 2020; Hernandez-Alejandro R et al., 2022), the applicability of lung transplantation in lung-limited metastatic patients should be explored. There is also an unmet need for patients with respiratory failure with a history of cancer in the last 5 years. MethodsThis is a prospective registration trial to evaluate outcomes of patients who undergo double lung transplantation for the treatment of the select groups of medically refractory cancers (primary lung cancers or metastatic cancers in lungs). Overall survival (OS), disease-free survival (DFS), allograft rejection (AR) and allograft survival (AS) as well as molecular and genetic biomarkers will be monitored to investigate the correlation with prognosis.The study duration will be 10 years including surveillance. Recruitment is to occur during the first 5 years of the study. The goal is to enroll 125 participants through the Northwestern Medicine Clinical Programs.Essential Criteria:1.The tumor should be without any extrapulmonary metastasis as determined by standard of care diagnostic and staging workup.2.All standard of care or experimental oncological treatments known to improve survival should have failed or deemed infeasible 3.Patients should meet the general criteria for lung transplant evaluation and listing Study cohorts:•Cohort A: Primary lung cancers - Examples include, but not limited to, invasive mucinous/non-mucinous non-small cell lung cancers and multifocal carcinomas.•Cohort B: Metastatic cancers to the lung only - Examples include, but not limited to, germ cell tumors, head &amp; neck tumors, colorectal tumors, renal cell tumors, testicular cancers.•Cohort C: Respiratory failure with a history of cancer in the last 5 years- Examples include, but not limited to interstitial lung disease (ILD), pulmonary fibrosis (idiopathic or secondary), advanced chronic obstructive pulmonary disease (COPD), bronchiectasis, emphysema, cystic fibrosis (CF), emphysema due to alpha-1 antitrypsin deficiency, and pulmonary arterial hypertension (PAH) Clinical trial registry number : NCT05671887.Enrollment began November 16, 2022. Trial is open and continues to enroll participants as of Jan 8, 2024. Citation Format: Young Kwang Chae, Liam Il-Young Chung, Rade Tomic, Ankit Bharat. [DREAM] Double lung transplant registry aimed for lung-limited malignancies - a prospective registry study for medically refractory cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT278.

Nanoparticles for Augmenting Therapeutic Potential and Alleviating the Effect of Di(2-ethylhexyl) Phthalate on Gastric Cancer.

Changes in diet culture and modern lifestyle contributed to a higher incidence of gastrointestinal-related diseases, including gastritis, implicated in the pathogenesis of gastric cancer. This observation raised concerns regarding exposure to di(2-ethylhexyl) phthalate (DEHP), which is linked to adverse health effects, including reproductive and developmental problems, inflammatory response, and invasive adenocarcinoma. Research on the direct link between DEHP and gastric cancer is ongoing, and further studies are required to establish a conclusive association. In our study, extremely low concentrations of DEHP exerted significant effects on cell migration by promoting the epithelial-mesenchymal transition in gastric cancer cells. This effect was mediated by the modulation of the PI3K/AKT/mTOR and Smad2 signaling pathways. To address the DEHP challenges, our initial design of TPGS-conjugated fucoidan, delivered via pH-responsive nanoparticles, successfully demonstrated binding to the P-selectin protein. This achievement has not only enhanced the antigastric tumor efficacy but has also led to a significant reduction in the expression of malignant proteins associated with the condition. These findings underscore the promising clinical therapeutic potential of our approach.

Fusing Diverse Decision Rules in 3D-Radiomics for Assisting Diagnosis of Lung Adenocarcinoma.

This study aimed to develop an interpretable diagnostic model for subtyping of pulmonary adenocarcinoma, including minimally invasive adenocarcinoma (MIA), adenocarcinoma in situ (AIS), and invasive adenocarcinoma (IAC), by integrating 3D-radiomic features and clinical data. Data from multiple hospitals were collected, and 10 key features were selected from 1600 3D radiomic signatures and 11 radiological features. Diverse decision rules were extracted using ensemble learning methods (gradient boosting, random forest, and AdaBoost), fused, ranked, and selected via RuleFit and SHAP to construct a rule-based diagnostic model. The model's performance was evaluated using AUC, precision, accuracy, recall, and F1-score and compared with other models. The rule-based diagnostic model exhibited excellent performance in the training, testing, and validation cohorts, with AUC values of 0.9621, 0.9529, and 0.8953, respectively. This model outperformed counterparts relying solely on selected features and previous research models. Specifically, the AUC values for the previous research models in the three cohorts were 0.851, 0.893, and 0.836. It is noteworthy that individual models employing GBDT, random forest, and AdaBoost demonstrated AUC values of 0.9391, 0.8681, and 0.9449 in the training cohort, 0.9093, 0.8722, and 0.9363 in the testing cohort, and 0.8440, 0.8640, and 0.8750 in the validation cohort, respectively. These results highlight the superiority of the rule-based diagnostic model in the assessment of lung adenocarcinoma subtypes, while also providing insights into the performance of individual models. Integrating diverse decision rules enhanced the accuracy and interpretability of the diagnostic model for lung adenocarcinoma subtypes. This approach bridges the gap between complex predictive models and clinical utility, offering valuable support to healthcare professionals and patients.

Diagnostic Accuracy of a Computed Tomography-Guided Transthoracic Needle Biopsy for Ground-Glass Opacities and Subsolid Pulmonary Nodules.

Purpose The increasing use of computed tomography (CT) imaging has led to the detection of more ground-glass nodules (GGNs) and subsolid nodules (SSNs), which may be malignant and require a biopsy for proper diagnosis. Approximately 75% of persistent GGNs can be attributed to adenocarcinoma in situ or minimally invasive adenocarcinoma. A CT-guided biopsy has been proven to be a reliable procedure with high diagnostic performance. However, the diagnostic accuracy and safety of a CT-guided biopsy for GGNs and SSNs with solid components ≤6 mm are still uncertain.The aim of this study is to assess the diagnostic accuracy of a CT-guided core needle biopsy (CNB) for GGN and SSNs with solid components ≤6 mm. Methods This is a retrospective study of patients who underwent CT-guided CNB for the evaluation of GGNs and SSNs with solid components ≤6 mm between February 2020 and January 2023. Biopsy findings were compared to the final diagnosis determined by definite histopathologic examination and clinical course. Results A total of 22 patients were enrolled, with a median age of 74 years (IQR: 68-81). A total of 22 nodules were assessed, comprising 15 (68.2%) SSNs with a solid component measuring ≤6 mm and seven (31.8%) pure GGNs. The histopathological examination revealed that 12 (54.5%) were diagnosed as malignant, nine (40.9%) as benign, and one (4.5%) as non-diagnostic. The overall diagnostic accuracy and sensitivity for malignancy were 86.36% and 85.7%, respectively. Conclusion A CT-guided CNB for GGNs and SSNs with solid components measuring ≤6 mm appears to have a high diagnostic accuracy.

Diagnostic Value of Combined High-resolution Computed Tomography and Artificial Intelligence-Aided Diagnosis System in Prediction of Benign and Malignant Pulmonary Ground-Glass Nodules

Background: The widespread use of high-resolution computed tomography (HRCT) in lung cancer screening has allowed for an increased detection rate of ground-glass nodules (GGNs) in the lung. Hence, obtaining the correct clinical diagnosis of benign and malignant GGNs has become crucial. Objectives: Most artificial intelligence and computer-aided diagnosis (AI-CAD) systems for the classification of pulmonary GGNs fail to extract CT features. This study used HRCT and AI to analyze the CT features of GGNs to improve the prediction of benign and malignant pulmonary GGNs. Patients and Methods: This case-control study was performed on a malignant group consisting of patients and a benign group consisting of controls. A total of 204 patients with GGNs were recruited and divided into 2 groups according to their pathological results. Group A consisted of 69 cases with precursor glandular lesions (atypical adenomatous hyperplasia [AAH] and adenocarcinoma in situ [AIS]), inflammatory nodules, and benign nodules. Group B consisted of 135 cases with invasive lesions (minimally invasive adenocarcinoma [MIA], invasive adenocarcinoma [IAC], and other malignant lesions). Various CT features were compared between the 2 groups. The diagnostic efficacy of an AI-CAD system and radiologists’ reports for benign and malignant nodules were analyzed. A multivariate logistic regression analysis was performed to determine independent predictors of malignant GGN. A model that combined the AI system and manual extraction of radiological features was constructed. The receiver operating characteristic (ROC) curve was used to evaluate the diagnostic efficiency of the model. Results: Significant differences were found between malignant and benign groups according to the following 7 CT features: The GGN size (long and short diameters), vacuole sign, air bronchogram sign, vascular convergence sign, vascular perforator sign, interlobular septal obstruction sign, and spiculation (P &lt; 0.05). The volume and mean CT values of precursor glandular lesions of the lungs were significantly different from those of invasive lesions (P &lt; 0.05). The logistic regression model showed that the sensitivity and specificity of the AI system in diagnosing malignant groups were 0.756 and 0.696, respectively. The sensitivity and specificity of radiologists’ reports in diagnosing the malignant groups were 0.726 and 0.783, respectively. The combination of the 2 had a sensitivity of 0.768 and a specificity of 0.793. Conclusion: Prediction of the nature of GGNs based on CT features, including the vacuole sign, vascular perforator sign, and interlobular septal obstruction sign, were relatively accurate for a preliminary diagnosis. The AI system had a poorer diagnostic accuracy for GGNs than radiologists’ reports of CT images. The combination of AI and radiologists’ reports showed the highest diagnostic efficacy.

Claudin18.2 expression and its clinicopathological feature in adenocarcinoma from various parts

AimsTo clarify claudin18.2 expression and its clinicopathological features in various cancers, especially in lung adenocarcinoma.MethodsImmunohistochemistry staining and fluorescence in situ hybridisation (FISH) were performed to detect claudin18.2 expression and CLDN18...

Effect of Risk Factor Score on Early Recurrence After Pancreatectomy for Invasive Pancreatic Ductal Adenocarcinoma.

This study aimed to identify the risk factors for early recurrence (ER) after pancreatic ductal adenocarcinoma (PDAC) resection to create a novel scoring system for ER and analyze their effect on the recurrence pattern. Sixty patients with PDAC who underwent pancreatectomy were included. The predicted risk factors for ER were analyzed. A new score defining ER was created and analyzed for recurrence pattern and prognosis. Independent predictors included high CA 19-9 (≥147 U/ml), high lymph node ratio (LNR of ≥0.1277), and no adjuvant chemotherapy (AC). The 5-year overall survival rates with a score of 0, 1, and 2 were 55.8%, 11.0%, and 0%, respectively. In the moderate- risk score group, prognosis was improved by induction of AC within 58 days. Preoperative high CA19-9, high LNR, and no AC could be ER predictors. Induction of postoperative chemotherapy within 58 days may improve prognosis.

Clinical significance of postoperative folate receptor-positive circulating tumor cells (FR + CTCs) for long-term prognosis in patients with invasive adenocarcinoma (IAC) of the lung.

The aim of the study was to evaluate the prognostic value of postoperative folate receptor-positive circulating tumor cell (FR + CTC) detection in patients with stage I-III invasive adenocarcinoma (IAC) treated with surgery. Patients with lung adenocarcinoma (LUAD) who underwent surgical resection in Peking University Cancer Hospital and received postoperative FR + CTC analysis from July 2016 to January 2021 were retrospectively collected. Comparisons between or among groups were made using the Kruskal-Wallis or Mann-Whitney U tests. Survival curves were estimated using the Kaplan-Meier method and compared using the log-rank test. Cox proportional hazard regression analyses were performed to explore the factors predicting recurrence and survival. There were significant differences between the high and low groups in terms of age (p = 0.002), postoperative CA199 (p = 0.038), and postoperative SCC (p = 0.024). There were no significant differences in the other indicators (all p>0.05). N stage 1, N stage 2, and neoadjuvant therapy (NAT) were independent risk factors for disease recurrence and death; pleural invasion (PI), and nerve invasion were independent risk factors for death. The Kaplan-Meier curve showed a notable trend for a worse disease-free survival (DFS) or overall survival (OS) for patients with high levels of FR + CTCs in our study, but none of these were statistically significant. The detection of FR + CTCs postoperatively was an independent predictor of recurrence in patients treated for stage I-III IAC. Standardized detection methods and optimal time points for assessment should be established in future studies.

Abstract 4097: LNP-mRNA neoantigen vaccines to intercept progression of pre-invasive to invasive lung adenocarcinoma

Abstract The widespread use of chest computed tomography in lung cancer screening has led to the detection of ground-glass opacity (GGO) nodules, which typically harbor pre-invasive or minimally invasive adenocarcinoma and 20-40% of GGO nodules progress to invasive lung adenocarcinoma within 4 years. Lack of approved treatments to intercept disease progression has imposed challenges in the clinical management of patients with GGOs. Previous studies showed that GGO nodules have substantially lower rates of HLA deletions than invasive/metastatic lung cancer, suggesting that GGO nodules constitute a critical window of vulnerability for immune interception. We therefore sought to identify the most immunogenic and cytotoxic neoantigens in patients with GGO nodules and to develop LNP-mRNA cancer vaccines to intercept the disease progression from pre-invasive to invasive adenocarcinoma. Whole exome and RNA sequencing of a large cohort (&amp;gt;300) patients identified potential neoantigen candidates, with KRAS-G12C, KRAS-G12D and EGFR-L858R as the most frequently predicted shared neoantigens consistent with &amp;gt;40% GGO patient population harboring either mutant KRAS or EGFR driver oncogenes. LNP-mRNA vaccines targeting KRAS-G12C and EGFR-L858R showed marked immunogenicity as determined by ELISPOT assays. Moreover, KRAS-G12C vaccination induced CD4+ T cell responses whereas EGFR-L858R vaccination triggered CD8+ T cell responses. Both these vaccines are being tested in GGO immunoprevention studies. Our data suggest the potential of KRAS and EGFR vaccines in the treatment of early disease, particularly in EGFR mutant patients who fail to respond to immunotherapy. Citation Format: Yongfeng He, Sijin Luo Zhong, Bhavneet Bhinder, Geoffrey Markowitz, Arshdeep Singh, Eric Gardner, Myung Soo Ko, Nasser K. Altorki, Shaoyi Jiang, Vivek Mittal. LNP-mRNA neoantigen vaccines to intercept progression of pre-invasive to invasive lung adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4097.

Abstract 6495: Lenvatinib as a potential treatment option for invasive mucinous lung adenocarcinoma

Abstract Introduction: Invasive mucinous adenocarcinoma (IMA) accounts for approximately 4-20% of non-small-cell lung carcinoma (NSCLC). Genetic alterations and RNA sequencing analysis of IMAs reveal a unique mucinous signature similar to gastrointestinal mucinous tumors. Due to its rarity, focused clinical trials for IMA patients are often not feasible. These patients respond poorly to platinum-based conventional chemotherapy, or immunotherapy. Lenvatinib is a multitargeted-TKI with demonstrated activity in patients with RET fusion-positive lung adenocarcinoma, thyroid, hepatocellular and gastric carcinoma. Methods: Here, we present two RET fusion-negative mucinous lung adenocarcinoma cases that received a multitargeted TKI lenvatinib with a clinical and survival benefit. Results: Case #1: An 81-year-old female initially diagnosed with cT4N0M0 IMA (TTF1 and CDX2 focally positive) was started on neoadjuvant treatment for a 12cm tumor. She underwent right thoracotomy/right lower lobectomy/mediastinal lymph node dissection, and pathology confirmed ypT4N1M0 mucinous adenocarcinoma. Three months post-operatively, the patient had disease progression in the lungs. She had no targetable mutations. She had four subsequent lines of treatment including nivolumab/nab-paclitaxel as the fourth-line treatment. After six months of nivolumab/nab-paclitaxel, lenvatinib was added to the combination due to clear disease progression evident on imaging. After twelve cycles of nivolumab/nab-paclitaxel/lenvatinib combination treatment, patient achieved a partial response per RECIST 1.1 (-35.7% change from baseline to current). The patient reported less dyspnea and increased activity tolerance. Approximately nine months after the start of the treatment, patient showed progressive lung disease. The patient died after one more line treatment with 41 months of total overall survival. Case#2: A 56-year-old male initially diagnosed with stage IVA IMA (TTF1 negative). After four lines of treatments, patient was started on lenvatinib alone. The patient reported marked improvement in dyspnea and pain and increased activity tolerance with lenvatinib. Imaging confirmed treatment response after three months of treatment. The patient was subsequently enrolled in the double lung transplant (DLT) registry aimed for lung-limited malignancies (D.R.E.A.M.) registry study (NCT05671887), and he is alive with 25 months follow-up since DLT. Conclusion: We report two cases of metastatic RET fusion-negative mucinous lung adenocarcinoma, in which treatment with the multitargeted TKI Lenvatinib led to significant clinical improvement. Biological rationale to explain the effect of lenvatinib in invasive mucinous lung adenocarcinoma needs to be explored. Citation Format: Tarik Demir, Carolyn Moloney, Liam Il-Young Chung, Young Kwang Chae. Lenvatinib as a potential treatment option for invasive mucinous lung adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6495.

Abstract 5633: Unravelling the pleiotropic role of HNF4α in invasive mucinous adenocarcinoma of the lung (IMA)

Abstract IMA is a distinct subtype of lung adenocarcinoma (LUAD), marked by a cellular identity shift from a pulmonary to a gastric lineage with the loss of the pulmonary lineage specifier NKX2-1. This distinctive transformation underscores the complexity of lung cancer heterogeneity and highlights the critical role of lineage-specifying transcription factors in dictating tumor behavior. Notably, both human and murine models of IMA overexpress HNF4α, a known lineage specifier for gastric differentiation in the adult mouse mucosa. Also, concomitant deletion of Hnf4a and Nkx2-1 at tumor initiation impairs tumor growth and the extent of HNF4α in regulating IMA tumor growth, cellular identity and drug response remains unknown at large. Here, we utilized genetically engineered mouse models (GEMM) that relies on a sequential recombination strategy to delete Hnf4a in established tumors. We induce tumor formation through intratracheal delivery of Flp-O virus, activating the expression of mutant KRASG12D and Cre in lung epithelial cells. Tamoxifen administration recombines either Nkx2-1 alone (KN) or in combination with Hnf4a (KNH). We have extensively studied the phenotypic role of HNF4α in GEMM and organoids and identified gene sets regulated by HNF4α in IMA at the bulk level. To complement our findings, we profiled both the tumor and stromal compartments via scRNAseq analysis on our GEMM to gain insights into the cellular diversity within the tumor microenvironment (TME) and the role HNF4α plays. Additionally, we performed ChIPSeq in organoids to elucidate the genome occupancy of HNF4α and determine the mechanisms of gene regulation in IMA. We find that deletion of Hnf4a impairs tumor growth in GEMM and this is phenocopied in organoids. We identified numerous differentially expressed genes (DEGs) in KNH compared to KN and validated several DEGs in vivo. GSEA analysis reveals a significant involvement in regulating cellular identity and suggests a potential impact on anti-tumor immune responses. To this, our scRNAseq data revealed an enrichment of N2-TAN (tumor associated neutrophils) associated genes in KNH compared to KN, suggesting a nuanced interplay between HNF4α and the TME. Additionally, HNF4α exhibited dual functionality, acting as an activator and indirectly as a repressor by modulating the activity of other transcription factors like FOXA1. FOXA1 was found to bind de novo target genes following the loss of HNF4α. These findings so far collectively illuminate the multifaceted role of HNF4α in IMA, primarily driving tumorigenesis in a cell autonomous manner and secondarily skewing the TME towards a protumor via N2-TAN following loss of HNF4α in tumors. Citation Format: Headtlove Essel Dadzie, Gabriela Fort, Katherine Gillis, Pengshu Fang, Walter Orellana, Eric L. Snyder. Unravelling the pleiotropic role of HNF4α in invasive mucinous adenocarcinoma of the lung (IMA) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5633.

Abstract 2397: Double lung transplantation (DLT) in patients with stage IVA lung-limited non-small cell lung carcinoma (NSCLC): A case series

Abstract Introduction: Despite technological advances and expanded indications in lung transplantation, lung cancer constituted less than 0.1% of the lung transplantation over the past two decades. DLT may offer curative treatment for stage IVA NSCLC patients without extrapulmonary disease. We present a case series of consecutive NSCLC patients who underwent DLT. Methods: Patients treated with DLT were identified between 09/2021 and 09/2023 at Canning Thoracic Institute of Northwestern University. All patients had enrolled in the DLT registry aimed for lung-limited malignancies (DREAM) study (NCT05671887). Exclusion criteria include: presence of extrapulmonary disease and medical ineligibility for lung transplantation. All patients were followed up with computed tomography and tumor-informed ctDNA assay every 12 weeks. Results: Five patients with stage IVA NSCLC who underwent DLT were included. Three (60%) patients had invasive mucinous, and two (40%) had invasive non-mucinous adenocarcinoma histology. One of the two invasive non-mucinous patients had acinar, and the other had mixed lepidic, papillary, and acinar histology. Patients were aged 56-70; one (20%) was Asian, four (80%) were White, three (60%) were male, and two (40%) had a history of smoking. No patient had a past medical history of interstitial lung disease (ILD) or chronic obstructive pulmonary disease (COPD). All patients had high oxygen requirements before DLT due to cancer progression. Pre-transplant endobronchial ultrasound and evaluation of bilateral pneumonectomy lungs found no lymph node involvement (pN0). One patient had an epidermal growth factor receptor (EGFR) mutated cancer and but had failed relevant targeted therapy prior to transplant. All patients had disease progression on standard of care treatments with/without clinical trials. The indication for DLT was respiratory failure or refractory cancer for all patients. After DLT, one patient had a recurrence of the disease at 18 months with a 1cm solid nodule and was treated with stereotactic body radiotherapy (SBRT). Both original and recurrent tumors had invasive mucinous adenocarcinoma histology, negative PD-L1 expression, and the same JAK3 c.2174C&amp;gt;T, P725L mutated clone. It suggests that the recurrence likely arose from the original cancer. Transplant rejection did not occur in any of the cases. Following the transplant, there was no requirement for oxygen therapy for any patient. All patients are alive with 25, 15, 6, 3, and 1-month posttransplant follow-up. Conclusion: Five patients underwent DLT successfully without significant complications. Notably, one patient (25 months post-transplant) experienced cancer recurrence 18 months post-transplant and was effectively treated with SBRT. Ongoing DREAM study will continue to investigate the role of DLT in stage IVA NSCLC patients (especially in pN0). Citation Format: Young Kwang Chae, Tarik Demir, Liam Il-Young Chung, Carolyn Moloney, Rade Tomic, Ankit Bharat. Double lung transplantation (DLT) in patients with stage IVA lung-limited non-small cell lung carcinoma (NSCLC): A case series [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2397.

Abstract 2975: Vitamin D receptor signaling limits DNA damage at early stage of prostate tumorigenesis and prevents tumor aggressiveness

Abstract Prostate cancer (PCa) is the most common visceral neoplasm and the second leading cause of cancer-related deaths in male of western societies. Low circulating vitamin D levels and reduced expression of its receptor (VDR) correlate with PCa risk and severity, but the clinical use of vitamin D is limited by its pro-calcemic activities. To characterize the role of VDR in PCa, PTEN(i)pe-/− mice, that recapitulate the human disease and in which the tumor suppressor gene PTEN is selectively inactivated in prostatic epithelial cells (PECs) at adulthood, were compared to PTEN/VDR(i)pe-/− mice in which PECs are PTEN and VDR-deficient. Histological analysis showed that prostatic intraepithelial neoplasia (PIN) are formed between 1-3 months after gene inactivation (AGI). Importantly, VDR-deficiency increased by 2-fold the PECs proliferation rate as early as 1-month AGI. At this stage, RNA-seq and immunohistochemistry analysis revealed the presence of oxidative DNA damage selectively in VDR-deficient PINs. Moreover, a 4-week supplementation with the antioxidant N-acetyl cysteine reduced oxidative DNA damage in PTEN/VDR(i)pe-/- prostates, and normalized the number of Ki-67+ cells to the levels of PTEN(i)pe-/- ones. After 3 months AGI, both PTEN(i)pe-/- and PTEN/VDR(i)pe-/- tumors entered in a latency phase characterized by cellular senescence. However, the prostate weight in PTEN/VDR(i)pe-/− mice was 2-fold higher than in PTEN(i)pe-/− mice 12 months AGI. In addition, tumors of PTEN(i)pe-/− were mostly composed of non-invasive PIN-like adenocarcinoma, whereas invasive adenocarcinoma, sarcomatoid and squamous-cell carcinoma were observed in those of PTEN/VDR(i)pe-/- mice. Using single cell and spatial transcriptomics, we unraveled the presence of epithelial cells with epithelial-mesenchymal transition (EMT) hallmarks in PTEN/VDR(i)pe-/− prostate 10 months AGI. In addition, immunophenotyping revealed a higher infiltration of neutrophils, also termed as myeloid-derived suppressive cells and implicated in EMT and metastasis dissemination, in PTEN/VDR(i)pe-/− prostates compared to PTEN(i)pe-/− ones. Moreover, pan-cytokeratin-positive micro-metastasis were detected in lymph nodes and livers of PTEN/VDR(i)pe-/− mice, but not in those of PTEN(i)pe-/- mice, demonstrating that VDR-deficiency in PECs promotes aggressive PCa. Thus, VDR signaling exerts a protective role on PTEN-deficient PECs by limiting the oxidative-stress and proliferation during PINs initiation, and prevents PCa progression. Citation Format: Kateryna Len, Justine Gantzer, Nicolas Le May, Christelle Thibault-Carpentier, Daniel Metzger, Gilles Laverny. Vitamin D receptor signaling limits DNA damage at early stage of prostate tumorigenesis and prevents tumor aggressiveness [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2975.

Abstract 3933: Comprehensive molecular characterization of mitochondrial mutational landscape across the evolution of lung adenocarcinoma

Abstract The human mitochondrial genome is prone to genetic alterations, which lead to somatic mutations, changes in mtDNA copy number and altered expression of respiratory chain subunits. This is in part due to the fact that mtDNA has a limited ability to repair itself when it is damaged. Although a buildup of somatic mutations in mtDNA has been associated with increased cancer risk, the role of mtDNA alterations in malignant transformation of lung adenocarcinoma has not been addressed. Therefore, a clear understanding of changes in mtDNA along the pathway of lung tumorigenesis is critical for identifying molecular biomarkers related to carcinogenesis and tumor progression. Like all solid tumors, lung adenocarcinoma is thought to be initiated and to progress through a series of genetic alterations, including changes in mtDNA. Lungs resected for primary adenocarcinomas often harbor minute discrete foci of cytologically atypical pneumocyte proliferations designated as atypical adenomatous hyperplasia (AAH). Evidence suggests that AAH represents an initial step in the progression to adenocarcinoma in situ (AIS), minimally invasive adenocarcinoma (MIA) and ultimately fully invasive adenocarcinoma (ADA). In this study we used a unique cohort of 52 patients with matched specimens (n=133) representing different steps of disease progression (AAH, AIS, and MIA) coupled with novel ultra-deep mitochondrial sequencing (mtDNA-Seq) method to assess the mtDNA mutational landscape throughout the continuum of lung adenocarcinoma development. Utilizing a custom bioinformatics workflow, somatic mutations were detected in a subset of the premalignant non-invasive lesions, with overall higher mutational load observed in MIA and ACA specimens. Additionally, large degree of inter-patient heterogeneity were observed for mtDNA copy numbers in conjunction with the clonal histological evolution of pulmonary neoplasia. Moreover, an appreciable number of coding and non-coding mutations from regulatory regions of the mtDNA were detectable in the precursor AAH lesions and the continuum of LUAD progression. Majority of shared mutations showed heteroplasmic transition with increase in fractional abundance in ADA, compared to the AHH lesions, thereby indicating spatial clonal expansion as they progressed histologically. Here we report the first comprehensive characterization of mitochondrial mutational landscape in dynamic evolution of lung adenocarcinoma, and provide insight into the heterogeneity of clonal events associated with the progression from noninvasive to malignant disease. Citation Format: Alka Singh, Santanu Dasgupta, Ashwin L. Koppayi, Lisa Rooper, Vasudha Mishra, David Sidransky, Nishant Agrawal, Karthik Suresh, Evgeny Izumchenko. Comprehensive molecular characterization of mitochondrial mutational landscape across the evolution of lung adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3933.