BACKGROUND:There have been no studies examining the relationship between statin use and lung cancer survival in the U.S. Military Health System (MHS), a universal healthcare system. This study assessed whether statin use after lung cancer diagnosis is associated with overall survival among MHS beneficiaries with lung cancer. METHODS:This study was based on the Military Cancer Epidemiology (MilCanEpi) database, a database linking the DoD's Central Cancer Registry (CCR) and the MHS Data Repository (MDR). The study subjects were MHS beneficiaries diagnosed with non-small cell lung cancer (NSCLC). Information on statin use was extracted from the database. Time-dependent Cox proportional hazard regression model was used to estimate hazard ratios (HRs) and 95 % confidence intervals (95 % CIs) comparing post-diagnosis use of statin relative to non-users. RESULTS:Among the 5096 patients, 864 patients used a statin after NSCLC diagnosis. Compared to individuals who never used statin, increased cumulative use of statin (per one-year of use) among the users conferred a significantly improved survival with an adjusted HR of 0.82 (95 % CI=0.75-0.90). In stratified analysis, the survival benefit or its tendency associated with increased cumulative use was observed regardless of age, race, sex, tumor stage, comorbidity index or baseline use. CONCLUSIONS:Post-diagnosis statin use was associated with improved survival among NSCLC patients in a universal healthcare system.

Abstract Solid tumors develop through a complex series of genome and downstream expression alterations that interact with the local tissue microenvironment, leading to a transformed cell and malignant phenotype. With massive multi-omic data, recent proteogenomics studies have jointly analyzed RNA and protein expression to uncover new gene regulatory relationships; however, many of these studies focused on single tumor types and lack a generalizable view of joint RNA and protein expression. Here, we present the first pan-cancer analysis of sample-wise RNA to protein correlation (SRPC). We re-analyzed over 1,000 tumors across 10 tumor types from published proteogenomic data from the Clinical Proteomic Tumor Analysis Consortium (CPTAC) and the Applied Proteogenomics OrganizationaL Learning and Outcomes (APOLLO) Research Network. We identified a wide range of SRPC across all tumors (ρ range: -0.08 to 0.70, median: 0.45). We then analyzed tumor pathologic and molecular characteristics versus the range of SRPC. High SRPC tumors had high tumor purity by pathology review, by somatic DNA whole exome sequencing, and by RNA and protein purity scores. In contrast, low SRPC tumors had high immune cell and stromal cell expression scores as inferred by either protein or RNA based signatures. We observed marked differences in cell type populations estimated by expression in different SRPC tumor tranches (low SRPC: macrophages, endothelial cells, cancer-associated fibroblasts; high SRPC: CD4+ Th2 cells). Tumors expressed signaling pathways depending on their SRPC (low SRPC: hypoxia, inflammatory response, and KRAS signaling; high SRPC: DNA repair and E2F targets). SRPC also stratifies tumors with distinct somatic DNA alterations (low SRPC: HRAS and NF2; high SRPC: TP53, MEN1, high Tumor Mutational Burden and high DNA chromosomal instability). Finally, we found that cancer driver genes displayed divergent gene-wise RNA to protein correlations (GRPC) among tumor types with a median absolute deviation interquartile range of 0.1 - 0.2, suggesting tumor-type-specific regulation. In summary, divergent RNA and protein expression is driven, in part, by tumor microenvironment composition across tumor types. Tumors with a diverse cellular microenvironment display a summation of RNA and protein expression resulting from this cell type diversity leading to a low SRPC, while tumors predominated by tumor cells display coordinated RNA and protein expression levels resulting from a pure clonal or cell type leading to a high SRPC. This first deep analysis into sample-wise RNA to protein correlation represents a large proteogenomic community resource for informing biomarker analysis by modality and by tranches of tumor microenvironment. The views expressed in this abstract are solely of the authors and do not reflect the official policy of the Departments of Army/Navy/Air Force, Department of Defense, USUHS, HJF, or U.S. Government. Citation Format: Joseph LaMorte, Nicholas Bateman, Thomas Conrads, Robert F. Browning, Craig D. Shriver, Robert L. Kortum, Matthew D. Wilkerson. Divergent proteogenomic gene expression is driven by microenvironment across tumor types [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 4944.

Abstract The expression subtypes of lung adenocarcinoma (LUAD) capture tumors with distinct pathway activity, mutations and histopathology and also differentiate clinical outcomes. The microenvironments of these subtypes, proximal-inflammatory (PI), proximal-proliferative (PP), and terminal respiratory unit (TRU), have been described generally as immune hot, immune moderate and immune cold, respectively, but otherwise have not been analyzed at high resolution. Here, we aimed to characterize and compare tumor microenvironments between LUAD subtypes. Using spatially barcoded arrays and cDNA libraries (10x Genomics), we sequenced the spatial transcriptomes of a 6.5mm2 plane of 14 LUAD tumors from the Applied Proteogenomics and Organizational Learning Outcomes (APOLLO) program. Spatial transcriptomes had a median of 3,560 spots and a median of 4,026 genes detected per spot. First, collapsing the spatial array to a bulk measurement per sample, we applied our published expression subtype predictor classifying 4 PI, 5 PP, and 5 TRU cases. We then decomposed each tumor’s spatial expression profile by unsupervised clustering, followed by signature scoring and collapsing into tumor, immune, and stroma tumor microenvironment (TME) components. Twelve of the fourteen tumors harbored multiple components while two tumors had one component. The region areas of TME components showed trends among the subtypes, with PI having the greatest immune area and PP having the greatest tumor area. Within each tumor, we calculated differentially-expressed genes between each TME component. Comparing TME genes to the subtype predictor genes, we found significant overlap (chi-square p << 0.001). This indicates that genes that are variable among bulk tumors also have variability within tumors. We then predicted expression subtype for decomposed compartments. Five tumors had the same expression subtype across their TME components, which we refer to as single subtype tumors. However, six tumors had more than one expression subtype prediction among the tumor’s TME components, which we call ‘multi-subtype tumors’. Multi-subtype tumors had lower bulk subtype prediction scores than single-subtype tumors (p < 0.01), indicating that the TME diversity among tumors affects the bulk expression subtype. Interestingly, the six multi-subtype tumors were in the PP and PI subtypes, suggesting greater TME component diversity than TRU. Calculating the spatial compactness of the tumors through continuity indices, we found that PI subtype trended with greater intermixing of TME components. In summary, the bulk LUAD expression subtypes capture differences between tumors and within tumors related to the tumor microenvironment. The views expressed in this abstract are solely of the authors and do not reflect the official policy of the Departments of Army/Navy/Air Force, Department of Defense, USUHS, HJF, or U.S. Government. Citation Format: Shaoqiu He, Camille Alba, Savannah Kounelis-Wuillaume, Teri J. Franks, Martin L. Doughty, Robert F. Browning, Craig D. Shriver, Clifton L. Dalgard, APOLLO Research Network, Matthew D. Wilkerson. Spatial decomposition of lung adenocarcinoma expression subtypes reveals tumor microenvironment characteristics [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 1142.

Pre-cancerous lung lesions are commonly initiated by activating mutations in the RAS pathway, but do not transition to lung adenocarcinomas (LUAD) without additional oncogenic signals. Here, we show that expression of the extracellular matrix protein Tenascin-C (TNC) is increased in and promotes the earliest stages of LUAD development in oncogenic KRAS-driven lung cancer mouse models and in human LUAD. TNC is initially expressed by fibroblasts and its expression extends to tumor cells as the tumor becomes invasive. Genetic deletion of TNC in the mouse models reduces early tumor burden and high-grade pathology and diminishes tumor cell proliferation, invasion, and focal adhesion kinase (FAK) activity. TNC stimulates cultured LUAD tumor cell proliferation and migration through engagement of αv-containing integrins and subsequent FAK activation. Intringuingly, lung injury causes sustained TNC accumulation in mouse lungs, suggesting injury can induce additional TNC signaling for early tumor cell transition to invasive LUAD. Biospecimens from patients with stage I/II LUAD show TNC in regions of FAK activation and an association of TNC with tumor recurrence after primary tumor resection. These results suggest that exogenous insults that elevate TNC in the lung parenchyma interact with tumor-initiating mutations to drive early LUAD progression and local recurrence.

Lung cancer is a leading cause of cancer deaths worldwide and has complex underlying genetic drivers, subtypes and immune cell types. Molecular analysis of bulk tumors has repeatedly identified key somatic driver genes and subtypes in lung cancer. However, these key molecular strata of bulk lung tumors still contain significant heterogeneity which if characterized in finer detail may reveal new tumor microenvironment factors and lead to improved patient prognostication and therapy options. Here, we sought to compare the tumor microenvironments of lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC) through spatial transcriptomics. Using four frozen lung tumors and three with replicated sections (n = 7), we sequenced spatial transcriptomes using the 10X Visium platform and illumina sequencing to measure up to 5,000 latticed-spots throughout 6.5 mm2 of the tumor surface area. Data analysis revealed a large number of latticed-spots per tumor (median 3,486) with a large number of genes detected per median spot (tumor median 4,427). Through unsupervised clustering of spots in each tumor, we found between 8 and 10 clusters per tumor with distinct pathway activities, including multiple immune-enriched clusters per tumor (range: 3-5). Immune-enriched clusters in one LUAD tumor displayed a spatial shape consistent with tertiary lymphoid structures (TLS). Concordantly, this cluster overexpressed both B cell and T cell pathways and as well as a TLS signature from liver cancer. Interestingly by bulk tumor RNA analysis, this TLS+ tumor was classified to be in the terminal respiratory unit expression subtype, which is an immune-mild bulk subtype. This supports that the TLS signal can be a unique property of spatial expression in lung cancer that may be unobservable by bulk tumor RNA sequencing. Then to compare global spatial heterogeneity among tumors, we calculated an index of expression spatial continuity and found LUSC tumors to have more contiguous expression patterns than LUAD tumors (mean 0.60 vs 0.54). We also quantified expression diversity across all tumor latticed-spots and found that LUSC tumors had greater values compared to LUAD tumors (mean 0.37 vs 0.27). Together, our results suggest that LUSC has a more contiguous and heterogeneous tumor expression microenvironment than LUAD. TLS are predictive of immune checkpoint inhibitor response in many other tumor types, and our results suggest that spatial transcriptomics may also identify this responsiveness in lung cancer. Future, larger cohorts of lung tumors are needed to determine recurrent spatial properties associated with patient outcome and treatment response. The views expressed in this abstract are solely of the authors and do not reflect the official policy of the Departments of Army/Navy/Air Force, Department of Defense, USUHS, HJF, or U.S. Government. Citation Format: Matthew D. Wilkerson, Savannah Kounelis-Wuillaume, Camille Alba, Teri J. Franks, Martin L. Doughty, Robert L. Kortum, Robert F. Browning, Clifton L. Dalgard, Craig D. Shriver. Tumor microenvironment differences between lung cancer subtypes revealed by spatial transcriptomics. [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 4622.

INTRODUCTION:Granulomatosis with Polyangiitis (GPA) is one of the antineutrophilic cytoplasmic autoantibody-associated vasculitides (ANCA-AV) that typically presents with the triad of necrotizing granulomatous inflammation of the small arteries in the upper and lower respiratory tract and kidneys.GPA can be mistaken for alternative etiologies such as malignancy, infection, sarcoidosis, or other inflammatory disorders (1).Among patients with GPA, 90% have involvement of the upper airways/ears (2), 77-85% will develop glomerulonephritis within the first two years, and only 24% will have pulmonary nodules on initial presentation (3).It is exceedingly rare to have an initial presentation of GPA with isolated lower respiratory tract findings.To our knowledge this is the first case report of GPA initially presenting with isolated lung nodules prior to progressing to multi-organ GPA.Here we present the case of an 82-year-old man with sub-acute progressive dyspnea found to have multiple large, bilateral pulmonary nodules and mediastinal lymphadenopathy highly suspicious for malignancy, ultimately diagnosed with GPA. CASE PRESENTATION:The patient was an 82-year-old male with limited past medical history seen at an urgent care for progressively worsening dyspnea and chronic cough.Chest x-ray demonstrated a non-specific nodular density in the right lateral lung base and he was treated for presumed acute bronchitis.Patient's symptoms of productive cough, dyspnea on exertion, weight loss, and night sweats/chills continued for 6 weeks, prompting a CT chest with contrast showing multiple large pulmonary nodules and mediastinal lymphadenopathy concerning for a new malignancy.PET scan revealed pulmonary nodules and cervical, mediastinal, and retroperitoneal lymph nodes which were highly PET avid.The patient was taken for expedited CBCT/Veran ENB system guided brushings, FNA, and forceps biopsy of one of the right middle lobe nodules as well as EBUS mediastinal lymph node screening, and BAL.Nodular erythematous mucosa was observed on the airway exam.EBUS lymph node screen demonstrated normal appearing lymph nodes.Transbronchial biopsy demonstrated submucosal chronic inflammatory cells which were non-specific and most consistent with a necrotizing granulomatosis.Culture, AFB, and fungal culture resulted as negative.One-week later, the patient was found to have hematuria with a new acute kidney injury and re-admitted.Lab evaluation revealed C-ANCA positivity to 1:640 and PR3 antibody positivity.Renal biopsy showed focal necrotizing glomerulonephritis, pauci-immune type, consistent with an ANCA-AV.Patient was started on immunosuppressive therapy with high dose corticosteroids and rituximab.He demonstrated rapid clinical improvement with improved dyspnea, cough, and renal function.Repeat CT scan obtained two weeks after initiation of therapy showed significant interval decrease in size and number of pulmonary nodules and lymphadenopathy.DISCUSSION: This case highlights the unique diagnostic challenge of GPA when, in rare circumstances, it presents with lower respiratory tract lesions preceding systemic involvement.It remains important to rule out malignancy and clinicians should be aware that inflammation in GPA can start in the lower respiratory tract prior to involvement of any other systems. CONCLUSIONS:The early diagnosis of GPA is important as it can lead to irreversible destruction of affected organs and responds very well to therapy.

Background:Self-expandable metallic (SEM) airway stents are an important approach to treating malignant central airway obstruction (CAO). Standard over-the-while (OTW) stent needs the guidance of a guide-wire. It should be implanted under flouroscopy or the guidance of bronchoscope visualization. In this study, we evaluated the operation time and safety between OTW stent and a novel through-the-scope (TTS) SEM airway stent.Methods:In this multi-center, randomized, parallel-group superiority study, malignant CAO patients were enrolled randomly assigned (2:1) to the TTS stent implantation group (TTS group) or the standard OTW stent group (OTW group) in six sites across China. The entire process of all surgical procedures was recorded by video. Primary endpoint was the operation time of the airway stent implantation and secondary endpoint was the success rate of the stent implantation as well as its efficacy and safety.Results:From May 15, 2017, to December 30, 2018, 148 patients were enrolled from the six sites. We analyzed 134 patients (including 91 patients from the TTS group and 43 patients from the OTW group) according to the per-protocol set. There were no significant differences in the ages, genders, underlying diseases, and stenosis sites between the two groups. The operation time in the TTS group was significantly shorter than that in the OTW group (104±68 vs. 252±111 seconds, P<0.001). Compared to the OTW group, the efficacy of stent implantation (97.80% vs. 90.70%, P=0.093) and rate of first-time successful stent implantation (78.02% vs. 74.42%, P=0.668) were higher in the TTS group, but did not reach statistically significance. The rates of granulation (28.57% vs. 41.86%, P=0.128) and restenosis (15.38% vs. 30.23%, P=0.064) in the TTS group were slightly lower as compared with the OTW group without achieving statistical significance.Conclusions:The TTS stent implantation procedure time was significantly shorter than that of the OTW airway stent with similar efficacy and complications, which might reduce the risk and flexibility of stent implantation.Trial Registration:Chinese Clinical Trial Registry ChiCTR-IOR-17011431.

Background Sarcoidosis is a multisystem granulomatous disorder with unclear etiology. Morbidity and mortality vary based on organ involvement, with cardiac sarcoidosis (CS) associated with higher mortality; despite this, CS remains underdiagnosed. The Heart Rhythm Society (HRS) expert consensus statement recommends screening sarcoidosis patients for CS utilizing a symptom screen, EKG, and echocardiogram (TTE), while the American Thoracic Society (ATS) guideline recommends only EKG and symptom screening. These recommendations, however, are based on limited data with recommendations for further studies. Research question The purpose is to evaluate the prevalence of abnormal screening tests in patients with sarcoidosis and the correlation of these tests with the subsequent diagnosis of CS. A specific emphasis was placed on evaluating the sensitivity of the recommendations versus the sensitivity of a modified criteria. Study design and Methods: This study retrospectively evaluated a database of prospectively enrolled patients from a tertiary military academic center. All patients who underwent imaging with cardiac MRI and/or FDG-PET were identified. These results were correlated with screening studies (symptom screen, EKG, TTE, and ambulatory rhythm monitoring (ARM)) and used to calculate sensitivity, specificity, and positive and negative predictive values for each test. Using a clinical diagnosis of CS as the reference standard, the sensitivity and specificity of the HRS criteria were calculated and compared to a modified screening rubric developed a priori, consisting of minor changes to the criteria and the addition of ARM. Results This study evaluated 114 patients with sarcoidosis with 132 advanced imaging events, leading to a diagnosis of CS in 36 patients. Utilizing HRS screening recommendations, the sensitivity for CS was 63.9%, while the modified criteria increased sensitivity to 94.4%. Interpretation This study suggests that the HRS guidelines lack sensitivity to effectively screen for CS and that a modified screening model which includes ARM may be more effective.

Background: Endobronchial navigation is performed in a variety of ways, none of which are meeting all the clinicians' needs required to reach diagnostic success in every patient. We sought to characterize precurved and steerable guiding sheaths (GS) in endobronchial targeting for lung biopsy using cone beam computed tomography (CBCT) based augmented fluoroscopy (AF) image guidance. Methods: Four precurved GS (EdgeTM 45, 90, 180, 180EW, Medtronic) and two steerable GS [6.5 F Destino Twist (DT), Oscor; 6 F Morph, BioCardia] were evaluated alone and in combination with an electromagnetic tracking (EM) guide and biopsy needles in three experimental phases: (I) bench model to assess GS deflection and perform biopsy simulations; (II) ex vivo swine lung comparing 2 steerable and 2 precurved GS; and (III) in vivo male swine lung to deliver a needle (n=2 swine) or to deliver a fiducial marker (n=2 swine) using 2 steerable GS. Ex vivo and in vivo image guidance was performed with either commercial or prototype AF image guidance software (Philips) based on either prior CT or procedural CBCT. Primary outcomes were GS delivery angle (θGS) and needle delivery angle (θN) in bench evaluation and needle delivery error (mm) (mean ± se) for ex vivo and in vivo studies. Results: The steerable DT had the largest range of GS delivery angles (θN: 0–114°) with either the 21 G or 19 G biopsy needle in the bench model. In ex vivo swine lung, needle delivery errors were 8.7±0.9 mm (precurved Edge 90), 5.4±1.9 mm (precurved Edge 180), 4.7±1.2 mm (steerable DT), and 5.6±2.4 mm (steerable Morph). In vivo, the needle delivery errors for the steerable GS were 6.0±1.0 mm (DT) and 15±7.0 mm (Morph). In vivo marker coil delivery was successful for both the steerable DT and morph GS. A case report demonstrated successful needle biopsy with the steerable DT. Conclusions: Endobronchial needle delivery with AF guidance is feasible without a bronchoscope with steerable GS providing comparable or improved accuracy compared to precurved GS.

Holtzclaw, Arthur MD*; McKay, Sean MD*; Mullenix, Phillip MD†; Browning, Robert MD*Author Information

TOPIC: Disorders of the Pleura TYPE: Fellow Case Reports INTRODUCTION: Calcified pleural lesions have both benign and malignant etiologies. Benign lesions can originate from previous trauma, prior pleural infections, hemothorax, or asbestos exposures, and are often focal and limited1,2. Malignant lesions often involve metastatic disease from mesenchymal tumor origin, such as osteosarcoma, chondrosarcoma, or mesothelioma1,3. We describe a case of a patient with metastatic chondrosarcoma manifesting with extensive calcification of the parietal and visceral pleura. CASE PRESENTATION: A 67 year old man was referred to pulmonary for a new subcarinal soft tissue mass on chest CT. He had been previously diagnosed with chondrosarcoma in 2016 and underwent treatment via a radical right proximal humerus excision and shoulder arthroplasty, with final pathology revealing grade 2 conventional chondrosarcoma, mixed hyaline and myxoid, without metastatic foci.Screening chest CT in 2020 noted a new, partially calcified subcarinal soft tissue mass and adjacent lymphadenopathy with moderate hypermetabolism on a positron emission tomography scan (PET/CT). Bronchoscopy with endobronchial ultrasound transbronchial needle aspiration (EBUS-TBNA) subcarinal lymph node and adjacent posterior mass confirmed metastatic disease.He subsequently developed rapidly progressive dyspnea on exertion over the following month. Repeat chest CT revealed extensive development of circumferential nodularity and calcification of the right visceral and parietal pleura with a large pleural effusion. Thoracentesis improved dyspnea despite limited reexpansion of the lung and noted loculation of the effusion. Pleuroscopic evaluation of the complicated space was undertaken to remove loculations and optimize placement of an indwelling pleural catheter (IPC) for his malignant effusion. Despite difficulty with trocar insertion into the calcified pleural space, placement of the IPC was successful with improvement in his dyspnea. DISCUSSION: Metastatic pleural involvement of chondrosarcoma is rare, and can occur in the setting of direct extension in locoregional disease or hematogenous spread from other sites of primary involvement. Metastatic disease has been noted to be more prevalent in the dedifferentiated and mesenchymal subtypes4. Manifestations of metastatic pleural involvement are typically pleural calcifications that can be profound in the rapid evolution and extent of calcified involvement. Management is often palliative, as in this case, with drainage of any associated pleural effusions and attempts to mitigate accompanying dyspnea. CONCLUSIONS: This case of metastatic chondrosarcoma with extensive visceral and parietal pleural involvement is rare and infrequently noted in the literature. Palliative management with thoracentesis and IPC placement was complicated by the pervasive pleural calcification that prevented ultrasound imaging and made access to the pleural space difficult and dangerous. REFERENCE #1: Sureka B, Thukral BB, Mittal MK, Mittal A, Sinha M. Radiological review of pleural tumors. Indian J Radiol Imaging. 2013;23(4):313-320 DISCLOSURES: No relevant relationships by Robert Browning, source=Web Response, value=Grant/Research Support Removed 04/29/2021 by Robert Browning, source=Web Response No relevant relationships by Robert Browning, source=Web Response, value=Consulting fee Removed 04/29/2021 by Robert Browning, source=Web Response No relevant relationships by Robert Browning, source=Web Response, value=Consulting fee Removed 04/29/2021 by Robert Browning, source=Web Response No relevant relationships by Sean McKay, source=Web Response No relevant relationships by Philip Mullenix, source=Web Response No relevant relationships by Caitlin Nickens, source=Web Response No relevant relationships by John Shumar, source=Web Response

Abstract Lung adenocarcinoma is a highly lethal tumor that displays extensive molecular heterogeneity of which deep characterization may drive therapeutic development and improve clinical outcomes. Through the Applied Proteogenomics Organizational Learning and Outcomes (APOLLO) research network, we utilized five molecular profiling technologies (DNA whole genome sequencing, RNA sequencing, total and phospho-proteomics by mass spectrometry, and reverse phase protein arrays [RPPA]) to characterize a longitudinally-annotated cohort of 87 lung adenocarcinomas. Through whole genome sequencing, we identified molecular signatures from patterns of somatic SNVs, indels, and large structural alterations that stratified tumors into three groups associated with patient smoke exposures. We also identified TP53, EGFR, KRAS, and STK11 as recurrently mutated genes, which together represent 80% of the cohort, in addition to genes mutated in smaller cohort subsets (e.g. RBM10), fusion genes, and pathogenic germline variants. To characterize tumor proteomes, we quantified >7,000 proteins and >10,000 phosphopeptides by mass spectrometry and >300 species by RPPA. Matched RNAs and proteins were typically positively correlated across samples (median ρ = 0.49). Through quantitative trait loci analyses, we identified genes whose RNA and protein expression levels were significantly modified by somatic mutations. We then classified tumors into RNA expression subtypes and found coordinated proteogenomic alterations and distinct clinical associations: terminal respiratory unit subtype – EGFR mutations and RNA/protein overexpression, acinar histology, non-smokers; proximal-proliferative subtype – STK11 mutations and RNA/protein underexpression, high smoking signature; proximal-inflammatory subtype – high tumor mutational burden. We also identified phospho-peptide signatures associated with these subtypes, including downregulation of CDK1/2 targets in terminal respiratory unit tumors. Protein co-expression network analysis discovered biologically-diverse pathway activities of the RNA expression subtypes. To interrogate somatic mutations in the context of molecular pathways, we projected DNA alterations onto known interaction networks and identified four subtypes with markedly distinct proteomic and microenvironment characteristics. Finally, several molecular characteristics were found to significantly predict patient outcomes, including RNA expression subtype classification against metastasis-free survival. Thus, our integrative, proteogenomic characterization of lung adenocarcinoma uncovered novel tumor biology and identified potential molecular markers for predicting patient outcomes. The views expressed in this abstract are solely of the authors and do not reflect the official policy of the Departments of Army/Navy/Air Force, Department of Defense, USUHS, HJF, or U.S. Government. Citation Format: Anthony R. Soltis, Nicholas W. Bateman, Thomas P. Conrads, Clifton L. Dalgard, Hai Hu, Teri J. Franks, Jianfang Liu, Daoud Meerzaman, Emanuel F. Petricoin, Qingrong Chen, Chunhua Yan, Xijun Zhang, Clesson E. Turner, The APOLLO Research Network, Craig D. Shriver, Christopher A. Moskaluk, Robert F. Browning, Matthew D. Wilkerson. Comprehensive proteogenomic analysis and classification of lung adenocarcinoma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5893.

The introduction of the flexible bronchoscope in the late 1960s increased the popularity of the bronchoscopic technique and demonstrated that transbronchial biopsy (TBBX) with the flexible instrument could be obtained with minimal mortality and morbidity. The radiographic finding of diffuse lung disease on imaging may be an indication for transbronchial lung biopsy but as with any diagnostic procedure, clinical correlation and consideration of other less invasive diagnostic tests should be made before performing an invasive procedure. There are a few absolute contraindications to TBBX through the flexible bronchoscope, including patient inability to cooperate with the procedure, unstable cardiovascular status, severe hypoxemia despite support, status asthmaticus, and lack of adequately trained personnel and equipment to properly perform the procedure. New techniques and adjuncts designed to enhance the yield and safety of bronchoscopic biopsy include electromagnetic navigation and cone beam computed tomography to improve accuracy, but the technique with the most emerging data is cryobiopsy.

Background: Lung cancer remains the leading cause of cancer deaths in the United States, and lung cancer screening has been shown to decrease this mortality. Adherence to lung cancer screening is paramount to realize the mortality benefit, and reported adherence rates vary widely. Few reports address non-adherence to screening, and our study sought to understand the non-compliant patients in our military population. Methods: This Institutional Review Board approved retrospective review of patients enrolled in our screening program from 2013-2019 identified patients who failed to obtain a subsequent Low Dose CT scan (LDCT) within 15 months of their prior scan. Attempts were made to contact these patients and elucidate motivations for non-adherence via telephone. Results: Of the 242 patients enrolled, 183 (76%) patients were adherent to the protocol. Significant predictors of non-adherence versus adherence were younger age (P=0.008), female sex (P=0.005), and enlisted officer rank (P=0.03). There was no difference with regards to race, smoking status, pack-years, negative screens, lung-RADS level, or nodule size. 31 (52%) non-adherent patients were contacted, and 24 (77%) reported their reason for non-adherence was lack of follow-up for a LDCT. Twenty (64%) were interested in re-enrollment. Of the total screening cohort, 15 interventions were performed, with lung cancer identified in 5 (2%)-a 67% false positive rate. One stage IV lung cancer was found in a non-adherent patient who re-enrolled. Conclusions: Lack of perceived contact for follow-up was expressed as the primary reason for non-compliance in our screening program. Compliance is critical to the efficacy of any screening modality, and adherence rates to lung cancer screening may be increased through improved contact with patients via multiple avenues (i.e., phone, email, and letter). There is benefit in contacting non-adherent patients as high rates of re-enrollment are possible.

BACKGROUNDThe aim of this study was to determine if transfusion with RBCs is associated with a rise in mean pulmonary artery pressure (MPAP) and whether such a rise is influenced by the duration of RBC storage.STUDY DESIGN AND METHODSA retrospective chart review of intensive care unit patients with pulmonary artery catheters was conducted at two military medical centers.RESULTSRBC transfusion is associated with a sustained (≥4 hours) statistically significant 2‐ to 3‐mm Hg rise in MPAP relative to both pretransfusion levels (p < 0.05) and compared to asanguinous fluid infusions (p < 0.05). The magnitude of the rise (all infusions, RBCs, and asanguinous) correlates positively with in‐hospital mortality (p < 0.01) and hospital length of stay (p < 0.01). The duration of RBC storage was not statistically correlated with the magnitude of rise in the population studied. Mean infusion volume was greater for RBC (vs. asanguinous) infusions, but volume adjustment of MPAP values did not alter the pattern or statistical significance of the results.CONCLUSIONSAnalysis of retrospectively collected data suggests that transfusion of RBC‐containing fluids results in a sustained elevation of MPAP. In the patient population studied, the duration of RBC storage did not correlate with the magnitude of MPAP rise. Future prospective studies of transfusion effects should consider including assessment of MPAP and subpopulation analyses.

Background: Current bronchoscopic methods to diagnose Peripheral Pulmonary Nodule (PPN) have a low yield and high false negative rate. Probe-based Confocal Laser Endomicroscopy (pCLE) enables in-vivo real-time visualization of alveolar microstructure during navigational bronchoscopy. Objectives: This primary objective was to identify and to validate pCLE criteria for the diagnosis of malignant PPN. Methods: Patients with suspicious PPN were recruited prospectively in a multicenter trial. Navigational bronchoscopy was performed to guide the pCLE probe and video images were recorded prior to transbronchial biopsy (TBB). Seven pCLE criteria were identified by expert pulmonologists and validated in a blinded fashion with a standard TBB histopathology. A linear regression combining pCLE criteria with the pre-test nodule malignancy calculation (PNMC) score based on CT, demographics and clinical data was performed. Results: 70 patients (73 PPN) were enrolled in six centers. pCLE criteria were conclusive in 72% of the cases compared to TBB. Complete loss of tissue architecture was identified as the most accurate and reproducible pCLE criterion predicting malignancy. Combining pCLE findings to PNMC significantly improved the sensitivity from 0.67 to 0.92, the negative predictive value from 0.65 to 0.88, the accuracy from 0.68 to 0.82 and the area under the receiver operating curve from 0.74 to 0.87. There were three technical failures (4.3%) and three small pneumothoraces (4.3%) not attributed to pCLE. Conclusions: pCLE criteria could improve the performance of the pre-test probability of PPN malignancy.

SESSION TITLE: Lung Cancer SESSION TYPE: Fellow Case Report Posters PRESENTED ON: 10/09/2018 01:15 PM - 02:15 PM INTRODUCTION: Small cell lung cancer (SCLC) is a poorly differentiated neuroendocrine tumor that represents about 15% of all lung cancers. It is distinguished from NSCLC by its rapid doubling time, high growth fraction, and the early development of metastases. SCLC typically arises in the central airways, infiltrating the submucosa, and gradually narrowing the bronchial lumen through extrinsic or endobronchial spread. The most common presentation of SCLC is usually in the central region of the lungs and mediastinum often presenting with a large hilar mass or bulky mediastinal adenopathy. Approximately 70% of patients present with overt metastatic disease; SCLC has a particular propensity to spread to liver, adrenals, bone, bone marrow, and brain. Potential clinical consequences include cough, dyspnea, weight loss, and debility.We report a case of a patient with a complex small pleural effusion and ipsilateral pleural based pulmonary nodules without mediastinal lymphadenopathy. After serial unsuccessful diagnostic attempts at thoracentesis, diagnosis was achieved with pleuroscopic biopsy revealing advanced peripheral SCLC. CASE PRESENTATION: An 81-year-old ex-smoker female presented with several months of progressive cough, dyspnea, and weight loss. She had right-sided pleural effusion and pleural-based nodules very suspicious for malignancy. PET showed hyper-metabolic activity around pleura, as well as mild bilateral lymphadenopathy. We were unable to make a diagnosis through thoracentesis and analysis of the pleural fluid. A medical pleuroscopy was performed as a safe alternative option that has a higher diagnostic yield than a thoracentesis and less invasive than surgical VATS for possible metastatic disease. Ultimately, pleuroscopy confirmed SCLC which was an extensive stage disease. With consideration of the patient's comorbid illness and side effects of chemotherapy, the patient declined any treatments. DISCUSSION: Predominantly peripheral presentation of SCLC is extremely uncommon. Pleural fluid analysis from thoracentesis is often not able to establish a diagnosis especially in a complicated pleural effusion with loculations. Diagnosis and staging of this extensive disease with small peripheral pulmonary nodules and a small complicated effusion with moderate sedation and a single 1 cm trocar incision required by pleuroscopy allowed for a timely diagnosis in this rare presentation of SCLC. CONCLUSIONS: Peripheral SCLC is rare. We report a rare presentation of a peripheral SCLC where we were able to establish the diagnosis via pleuroscopy after thoracentesis failed to achieve a diagnosis. Although thoracentesis is the preferred first minimally invasive diagnostic test in pleural effusions, in rapidly progressive malignancies such as SCLC, pleuroscpic biopsy is a safe and effective minimally invasive technique for staging and diagnosis even in complicated patients with complex pleural disease. Reference #1: Junker K, Wiethege T, Müller KM. Pathology of small-cell lung cancer. J Cancer Res Clin Oncol 2000; 126:361 Reference #2: Guinee DG Jr, Fishback NF, Koss MN, et al. The spectrum of immunohistochemical staining of small-cell lung carcinoma in specimens from transbronchial and open-lung biopsies. Am J Clin Pathol 1994; 102:406. Reference #3: Travis, WD.. The concept of pulmonary neuroendocrine tumours.. In: Pathology & Genetics: Tumours of the Lung, Pleura, Thymus, and Heart., Travis, WD, Brambilla, E, Muller-Hermelink, HK, Harris, CC. (Eds), IARC Press, Lyon 2004. p.19. DISCLOSURES: No relevant relationships by Haydar Al-Eid, source=Web Response No relevant relationships by Robert Browning, source=Web Response No relevant relationships by Sean McKay, source=Web Response

We use pulmonary interventional procedures for the diagnosis of pulmonary diseases either for benign or malignant lesions. Flexible bronchoscopy with or without radial endobronchial ultrasound, convex-probe endobronchial ultrasound and electromagnetic navigation are procedures performed in centers with experience in diagnostic pulmonary medicine. The method of sedation and ventilation is very important in order to avoid or handle with success complications. Proper respiration during pulmonary (or other interventional) procedures is a key factor. Apart from the proper sedation method we have to choose the proper ventilation method which decides respiratory movement. Superimposed high-frequency jet ventilation (SHFJV) is supposed to be safe and effective in clinical practice. Although this perception is commonly accepted, there is no study proving its safety on the basic of reliable data. We analyzed the data of 100 patients in different interventional settings (bronchoscopy with or without navigational approach, left atrial appendage closure (LAAC) or intracardiac catheterization) using nasal SHFJV. Mainly analyzed were capillary ABG-Data at the beginning and end of the intervention under sedation. The aim was to analyze if a risk scenario for the patient by using the nasal SHFJV can be derived by measuring the changes of pCO2, pO2, cBase Excess, cHCO3 and PH. Due to our data we conclude that this method of ventilation can be easily and safely used in interventional medicine for patients with all kind of comorbidities such as; chronic respiratory disease, lung cancer, interstitial lung disease, structural heart disease and heart failure.