Primary Lung Research Articles

A confounding bronchopulmonary situs abnormality after bilateral lung transplantation

A 36-year-old female with a past medical history of primary ciliary dyskinesia and bilateral lung transplantation was noted to have a rare and confounding postsurgical anatomy acquired as a result of transplantation. Bronchoscopy and computed tomography showed isomeric main bronchi with a tri-lobed right lung, a bi-lobed left lung and dextrocardia. This rare phenomenon can be observed in lung transplant recipients with situs ambiguous morphology of their native lungs, who receive donor lungs with normal situs solitus morphology. To the best of our knowledge, ours is the first reported case of such a composite bronchopulmonary situs abnormality. Careful review of bronchial anatomy should be done with the help of CT imaging prior to undertaking any bronchial interventions in these subset of patients with bronchial isomerism and bilateral lung transplantation.

USP15 negatively regulates lung cancer progression through the TRAF6-BECN1 signaling axis for autophagy induction

TNF receptor-associated factor 6 (TRAF6)-BECN1 signaling axis plays a pivotal role in autophagy induction through ubiquitination of BECN1, thereby inducing lung cancer migration and invasion in response to toll-like receptor 4 (TLR4) stimulation. Herein, we provide novel molecular and cellular mechanisms involved in the negative effect of ubiquitin-specific peptidase 15 (USP15) on lung cancer progression. Clinical data of the TCGA and primary non-small cell lung cancer (NSCLC) patients (n = 41) revealed that the expression of USP15 was significantly downregulated in lung cancer patients. Importantly, USP15-knockout (USP15KO) A549 and USP15KO H1299 lung cancer cells generated with CRISPR-Cas9 gene-editing technology showed increases in cancer migration and invasion with enhanced autophagy induction in response to TLR4 stimulation. In addition, biochemical studies revealed that USP15 interacted with BECN1, but not with TRAF6, and induced deubiquitination of BECN1, thereby attenuating autophagy induction. Notably, in primary NSCLC patients (n = 4) with low expression of USP15, 10 genes (CCNE1, MMP9, SFN, UBE2C, CCR2, FAM83A, ETV4, MYO7A, MMP11, and GSDMB) known to promote lung cancer progression were significantly upregulated, whereas 10 tumor suppressor genes (FMO2, ZBTB16, FCN3, TCF21, SFTPA1B, HPGD, SOSTDC1, TMEM100, GDF10, and WIF1) were downregulated, providing clinical relevance of the functional role of USP15 in lung cancer progression. Taken together, our data demonstrate that USP15 can negatively regulate the TRAF6-BECN1 signaling axis for autophagy induction. Thus, USP15 is implicated in lung cancer progression.

Surgical Therapy of Malignant Lung and Chest Wall Tumours in Children

Primary lung and chest wall tumours as well as lung metastases are rare diseases in children. As part of multimodal cancer treatment, thoracic surgery can significantly improve survival in children suffering from paediatric solid tumours. The aim of the review article is to summarise the indications and the current surgical treatment options for malignant chest wall and lung tumours as well as to shed light on the current role of pulmonary metastasectomy in children.

UK 2022 Consensus on Normal Tissue Dose-Volume Constraints for Oligometastatic, Primary Lung and Hepatocellular Carcinoma Stereotactic Ablative Radiotherapy

The use of stereotactic ablative radiotherapy (SABR) in the UK has expanded over the past decade, in part as the result of several UK clinical trials and a recent NHS England Commissioning through Evaluation programme. A UK SABR Consortium consensus for normal tissue constraints for SABR was published in 2017, based on the existing literature at the time. The published literature regarding SABR has increased in volume over the past 5 years and multiple UK centres are currently working to develop new SABR services. A review and update of the previous consensus is therefore appropriate and timely. It is hoped that this document will provide a useful resource to facilitate safe and consistent SABR practice.

Loss of p19Arf promotes fibroblast survival during leucine deprivation

ABSTRACTFibroblasts are quiescent and tumor suppressive in nature but become activated in wound healing and cancer. The response of fibroblasts to cellular stress has not been extensively investigated, however the p53 tumor suppressor has been shown to be activated in fibroblasts during nutrient deprivation. Since the p19 Alternative reading frame (p19Arf) tumor suppressor is a key regulator of p53 activation during oncogenic stress, we investigated the role of p19Arf in fibroblasts during nutrient deprivation. Here, we show that prolonged leucine deprivation results in increased expression and nuclear localization of p19Arf, triggering apoptosis in primary murine adult lung fibroblasts (ALFs). In contrast, the absence of p19Arf during long-term leucine deprivation resulted in increased ALF proliferation, migration and survival through upregulation of the Integrated Stress Response pathway and increased autophagic flux. Our data implicates a new role for p19Arf in response to nutrient deprivation. This article has an associated First Person interview with the first author of the paper.

Concomitant novel ALK-SSH2, EML4-ALK and ARID2-ALK, EML4-ALK\xa0double-fusion variants and confer sensitivity to crizotinib in two lung adenocarcinoma patients, respectively

IntroductionAnaplastic lymphoma kinase (ALK) gene rearrangements, have been identified in approximately 2-7% of patients with lung adenocarcinoma (LUAD). However, co-occurrence of double ALK fusions in one patient was rare. Herein, we reported two Chinese female LUAD patients with confirmed double ALK fusion variants by next generation sequencing.Case presentationCase 1, a 38-year-old female was diagnosed as peripheral LUAD in left upper lobe with synchronous multiple intrapulmonary metastases (pT2N0M1b, stage IVa). And case 2, a 58-year-old female had left lower lobe primary LUAD and synchronous multiple lung metastases (pT4N2M1b, stage IVa). In both patients, tumor cells displayed strong expression of ALK protein. Genetic profiling by next generation sequencing showed both patients concurrently harbored two types of ALK rearrangements. Case 1 had an unreported ALK-SSH2/EML4-ALK double fusions, and case 2 had an another novel ARID2-ALK/EML4‐ALK double fusions. Both of these patients responded to ALK inhibitor crizotinib.ConclusionsOur study reported two novel ALK fusion partners never reported, which expands the knowledge of ALK fusion spectrum and provides insight into therapeutic options for patients with double ALK fusions.

A medium composition containing normal resting glucose that supports differentiation of primary human airway cells

Primary cells isolated from the human respiratory tract are the state-of-the-art for in vitro airway epithelial cell research. Airway cell isolates require media that support expansion of cells in a basal state to maintain the capacity for differentiation as well as proper cellular function. By contrast, airway cell differentiation at an air–liquid interface (ALI) requires a distinct medium formulation that typically contains high levels of glucose. Here, we expanded and differentiated human basal cells isolated from the nasal and conducting airway to a mature mucociliary epithelial cell layer at ALI using a medium formulation containing normal resting glucose levels. Of note, bronchial epithelial cells expanded and differentiated in normal resting glucose medium showed insulin-stimulated glucose uptake which was inhibited by high glucose concentrations. Normal glucose containing ALI also enabled differentiation of nasal and tracheal cells that showed comparable electrophysiological profiles when assessed for cystic fibrosis transmembrane conductance regulator (CFTR) function and that remained responsive for up to 7 weeks in culture. These data demonstrate that normal glucose containing medium supports differentiation of primary nasal and lung epithelial cells at ALI, is well suited for metabolic studies, and avoids pitfalls associated with exposure to high glucose.

Systemic Injection of Oncolytic Vaccinia Virus Suppresses Primary Tumor Growth and Lung Metastasis in Metastatic Renal Cell Carcinoma by Remodeling Tumor Microenvironment.

Immune checkpoint inhibitors and tyrosine kinase inhibitors are the first-line treatment for metastatic renal cell carcinoma (mRCC), but their benefits are limited to specific patient subsets. Here, we aimed to evaluate the therapeutic efficacy of JX-594 (pexastimogene devacirepvec, Pexa-vec) monotherapy by systemic injection in comparison with sunitinib monotherapy in metastatic orthotopic RCC murine models. Two highly metastatic orthotopic RCC models were developed to compare the treatment efficacy in the International Metastatic RCC Database Consortium favorable-risk and intermediate- or poor-risk groups. JX-594 was systemically injected through the peritoneum, whereas sunitinib was orally administered. Post-treatment, tumor microenvironment (TME) remodeling was determined using immunofluorescence analysis. Systemic JX-594 monotherapy injection demonstrated therapeutic benefit in both early- and advanced-stage mRCC models. Sunitinib monotherapy significantly reduced the primary tumor burden and number of lung metastases in the early-stage, but not in the advanced-stage mRCC model. Systemic JX-594 delivery remodeled the primary TME and lung metastatic sites by increasing tumor-infiltrating CD4/8+ T cells and dendritic cells. Systemic JX-594 monotherapy demonstrated significantly better therapeutic outcomes compared with sunitinib monotherapy in both early- and advanced-stage mRCCs by converting cold tumors into hot tumors. Sunitinib monotherapy effectively suppressed primary tumor growth and lung metastasis in early-stage mRCC.

Tumor mass in the lung with superior vena cava syndrome

Group of symptoms due to vena cava superior obstruction is named superior vena cava syndrome. A 65-year-old female, long-standing smoker was presented with a two-week history of dry cough and facial swelling. The patient noticed a palpable mass on the right side of the neck. Computer tomography scan with contrast showed extensive, irregular, non-homogenous consolidation in the right upper lobe, involving the right hilus, surrounding the aortic arch, supra aortic branches and pleural effusion at the right side of the body. Also, ultrasound examination of supra clavicular space showed enlarged pathologic hypoehogenic lymph node without an echogenic hilum. Ultrasound guided fine needle biopsy of lymph node was performed, and cytopathology findings showed metastatic lesion from primary microcellular lung cancer, IIIC stadium, cT4N3M0. Venous angioplasty was performed showing stenosis in the superior vena cava. After balloon dilatation, the stent was placed at the site of stenosis. The patient received chemio- and radiotherapy and survival time was seven months. Superior vena cava syndrome is an urgent clinical condition, and lung cancer is the leading cause of this syndrome. Computer tomography imaging findings and endovascular stent placement are important for detection and management of the superior vena cava thrombosis.

Abstract P012: Investigation of interleukin-34 dependent regulation of renal carcinoma tumor microenvironment

Abstract In 2020, Renal Carcinoma (RC) accounted for around 179,000 worldwide deaths and its mortality is predicted to double in the next 20 years. The major issue for RC patients is the absence of an efficient therapeutic option, especially for metastatic forms of the disease where the 5-years survival rate is close to 10%. The therapy of RC mainly targets the angiogenic and immunosuppressive tumor microenvironment (TME), but it is rarely curative and drug resistance is almost inevitable. Lack of validated biomarkers and scarce knowledge of the biological processes occurring during RC progression are main reasons of therapy failure. In our unpublished work, using a syngeneic murine model of RC, we identified interleukin-34 (IL34) as potential biomarker of RC progression. In particular, we observed that increased IL34 expression was associated with enhanced cancer cell aggressiveness and reduced survival both in mice and in RC patients from two different cohorts (i.e. KIRC-TCGA, and UroCCR local cohort). IL34 exerts pleiotropic functions in different biological processes, including immunity regulation, cell proliferation and monocytes survival and differentiation into macrophages. The expression of IL34 in the TME is heterogeneous between cancer types, and high IL34 levels can represent either a poor (i.e. in brain and lung cancers) or a favorable (i.e. in neck and breast cancers) prognostic factor. Regarding to RC, IL34 role in the TME still remains elusive and has never been described. For this reason, using the KIRC-TCGA database, we performed Gene Ontology enrichment analysis using a list of IL34 co-expressed genes to predict potential IL34 regulatory functions in the TME of RC patients. This analysis revealed that such genes are involved in different immune system related processes, including positive regulation of leukocyte activation, IL-10 production and adaptive immune response. Subsequently, using IL34-overexpressing murine renal carcinoma RENCA cells implanted in BALB/c mice, we investigated the IL34-dependent alteration of the tumor immune microenvironment. In particular, we observed that, both in generated primary tumors and lung metastases, IL34 increased the density of tumor associated macrophages (TAM), which expressed M2-type markers (e.g. Cd206 and Cd163). Furthermore, in these samples, qPCR analysis showed an increase of interleukin-10 gene expression suggesting that IL34 could induce an immunosuppressive microenvironment. Conversely, when we blocked IL34 activity in lung metastases using an inhibitor of CSF1R, the main receptor of IL34, we observed a significant reduction in TAM accumulation and Il10 expression. The major aim of this project is to investigate whether IL34 can sustain immunosuppression and, consequently, chemoresistance by accumulating TAM in the TME. Furthermore, the IL34-dependent regulation of other immune cell populations (e.g. T-reg or myeloid-derived suppressor cells) is under investigation. The study of IL34 role in the TME of RC can be fundamental to improve the current therapy. Citation Format: Andrea Emanuelli, Wilfried Souleyreau, Lindsay Cooley, Tiffanie Chouleur, Marie-Alix Derieppe, Jean-Christophe Bernhard, Andreas Bikfalvi. Investigation of interleukin-34 dependent regulation of renal carcinoma tumor microenvironment [abstract]. In: Abstracts: AACR Virtual Special Conference: Tumor Immunology and Immunotherapy; 2021 Oct 5-6. Philadelphia (PA): AACR; Cancer Immunol Res 2022;10(1 Suppl):Abstract nr P012.

Evaluation of the immunomodulatory activity of thalidomide on tumor-associated macrophages in the 4T1 murine metastatic breast cancer model

ABSTRACT The present work evaluated the immunomodulatory effect of thalidomide (Thal) at different doses on tumor-associated macrophages (TAMs) using a mouse model of human breast cancer. Mice were inoculated with 4T1 cells in the left flank and treated with Thal once a day at concentrations of 50, 100, and 150mg/kg body weight from the 5th day until the 28th day of tumor inoculation. The tumors were sized, proliferation index and TAMs count were evaluated in primary tumors and metastatic lungs. In addition, the metastasis rate was evaluated in the lungs. Thal at 150mg/kg significantly decreased tumor growth, proliferation index, and TAMs infiltration in primary tumors. Conversely, a higher number of TAMs and lower proliferation index were observed in metastatic lungs in mice treated with 150mg/kg of Thal. Furthermore, Thal at 150mg/kg significantly decreased the metastatic nodules in the lungs. Our findings demonstrated that Thal treatment considerably decreased the primary tumor and lung metastasis in mice associated with different TAM infiltration effects in these sites.

Extracellular Matrix Oxidised by the Granulocyte Oxidants Hypochlorous and Hypobromous Acid Reduces Lung Fibroblast Adhesion and Proliferation In Vitro.

Chronic airway inflammation and oxidative stress play crucial roles in the pathogenesis of chronic inflammatory lung diseases, with airway inflammation being a key driving mechanism of oxidative stress in the lungs. Inflammatory responses in the lungs activate neutrophils and/or eosinophils, leading to the generation of hypohalous acids (HOX). These HOX oxidants can damage the extracellular matrix (ECM) structure and may influence cell–ECM interactions. The ECM of the lung provides structural, mechanical, and biochemical support for cells and determines the airway structure. One of the critical cells in chronic respiratory disease is the fibroblast. Thus, we hypothesised that primary human lung fibroblasts (PHLF) exposed to an oxidised cell-derived ECM will result in functional changes to the PHLF. Here, we show that PHLF adhesion, proliferation, and inflammatory cytokine secretion is affected by exposure to HOX-induced oxidisation of the cell-derived ECM. Furthermore, we investigated the impact on fibroblast function from the presence of haloamines in the ECM. Haloamines are chemical by-products of HOX and, like the HOX, haloamines can also modify the ECM. In conclusion, this study revealed that oxidising the cell-derived ECM might contribute to functional changes in PHLF, a key mechanism behind the pathogenesis of inflammatory lung diseases.

Lung ultrasound to detect cardiopulmonary interactions in acutely ill children.

Our prospective observational study is the first study that evaluates the lung ultrasound (LUS) findings of cardiopulmonary interactions in acutely ill children with elevated pro-brain natriuretic peptide (BNP) levels, with the aim of establishing the specific LUS pattern in this category of patients without primary lung diseases. We prospectively analyzed epidemiological, clinical, laboratory, instrumental, and lung ultrasound parameters in acutely ill children aged 1 month to 18 years admitted to the Department of Pediatrics between March 2020 to August 2020. Among the acutely ill patients evaluated, only patients with pro-BNP > 300 pg/ml and who underwent LUS before the start of any treatment were included. They were stratified into three subcategories based on the diagnosis (A) cardiac disease, (B) systemic inflammatory disease/sepsis without functional and/or organic alterations of the myocardium, and (C) systemic inflammatory disease/sepsis and cardiac disease, and were classified into two groups based on the level of pro-BNP. We also enrolled patients belonging to two other categories (patients with primary infectious lung disease and completely healthy patients) analyzing their epidemiological, clinical, laboratory, instrumental parameters, and lung ultrasound findings and comparing them with those of acutely ill children. We found that LUS findings in these acutely ill children are different from the ultrasound pattern of other categories of children and in particular (1) children with acute lower respiratory tract infections and (2) healthy infants. The finding in a child of a sonographic interstitial syndrome with multiple, bright, long, separate, and nonconfluent B-lines/long vertical artifacts deriving from a normal and regular pleural line, in the absence of subpleural consolidations, is strongly predictive of cardiogenic pulmonary edema or pulmonary congestion in the course of systemic inflammatory disease/sepsis.

STEM-02. THERAPEUTIC INTERVENTION OF LUNG-, BREAST-, AND MELANOMA-BRAIN METASTASIS

Abstract BACKGROUND The incidence of brain metastases (BM) is tenfold higher than that of primary brain tumours. BM predominantly originate from primary lung, breast, and melanoma tumours with a 90% mortality rate within one year of diagnosis, posing a large unmet clinical need to identify novel therapies against BM.This unmet clinical need is largely attributed to a small population of cancer stem cells (CSCs), termed BM-initiating cells (BMICs), that are able to escape a primary tumour, drive metastasis and facilitate the formation of a secondary tumour in the brain. METHODS Using a large in-house biobank of patient-derived BMIC lines, the Singh Lab has generated murine orthotopic patient-derived xenograft models of BM and captured a “premetastatic” population of BMICs that have just seeded the brains of mice before forming clinically detectable tumours: a cell population that is impossible to detect in human patients but represents a therapeutic window wherein metastasizing cells can be targeted and eradicated before establishing clinically detectable tumours. RESULTS RNA sequencing of pre-metastatic BMICs from all three primary tumour models with subsequent Connectivity Map analysis identified a lead compound that exhibits selective anti-BM activity in vitro. Preliminary in vivo work has shown that this lead compound reduces the tumor burden of treated mice compared to vehicle control while providing a significant survival advantage. Ongoing mechanistic investigations aim to delineate the protein target of this compound in the context of the observed selective anti-BMIC phenotype. CONCLUSION Identification of novel small molecules that target premetastatic BM cells could prevent the formation of BM and dramatically improve the prognosis of at-risk cancer patients.

Indwelling Pleural Catheters for Malignant Pleural Effusion: A Time for Action.

Malignant pleural effusion (MPE) resulting from metastatic spread to the pleura frequently occurs in patients with primary lung, breast, hematological, gastrointestinal, and gynecological cancers. These effusions tend to reaccumulate quickly, and the patient requires increasingly frequent thoracentesis. An indwelling pleural catheter allows for dramatic improvement in quality of life as the patient has the power to ease her/his own suffering by draining the effusion at home when shortness of breath and/or chest pain intensifies. Patients with MPE need home healthcare support to address symptom management related to complications of advanced metastatic cancer and antineoplasm treatment regimens. The financial obstacles for the home healthcare agency are explored by using agency supply costs, per visit costs, and the patient-driven groupings reimbursement mode grouper to estimate reimbursement. Care for a home healthcare patient with MPE costs Medicare approximately $64.50 per day, markedly less than costs for hospitalization and outpatient thoracentesis. Unfortunately, agencies must absorb the cost of vacuum drainage bottles. Whereas a small positive balance of $291 was estimated for the first 30-day posthospital episode, losses were estimated at $1,185 to $1,633 for subsequent 30-day episodes. Absorbing these costs has become extremely difficult as home healthcare agencies are experiencing unprecedented COVID-19 infection control and staffing-related costs.

P8‐149: Lung volume reduction surgery with opportunistic bilateral upper lobe resections for primary synchronous lung cancers: A case report

P8‐149: Lung volume reduction surgery with opportunistic bilateral upper lobe resections for primary synchronous lung cancers: A case report

Prolonged Time of Lung Collapse Associated With Decreased Recovery of Functional Lung Following Palliative Radiotherapy

<h3>Purpose/Objective(s)</h3> Bronchial obstruction leading to lung collapse from primary lung or metastatic tumors is a common urgent consult to radiation oncology. Palliative chest radiotherapy (RT) can reduce the risk of progression of endobronchial or extrabronchial disease can be utilized alone or in combination with bronchial stenting to re-open existing collapsed lung. The ability to re-open collapsed lung following RT is likely multi-factorial with time since lung collapse long thought as an important predictor of reversibility. In this study, we sought to quantify the time-dependency of recovery of functional lung volume in patients with partial or complete lung collapse using a CT-based imaging metric highly correlated with lung function. <h3>Materials/Methods</h3> Patients with primary lung or metastatic tumors who received palliative chest RT due to segmental, lobar or whole lung collapse who additionally had follow-up CT imaging of the chest were identified from the institutional electronic health record. Total lung volumes on simulation and follow-up chest CTs were manually segmented using a commercially available software. To evaluate functional lung volume, a subthreshold function was applied to the image sets to determine volume of lung with attenuation of -950 to -701 HU. An estimate of time since initiation of lung collapse was determined by review of clinical records and imaging. <h3>Results</h3> A total of 25 evaluable patients were identified with non-small cell lung cancer (NSCLC) being the predominant histology observed (19/25, 76%). The median time of collapse before initiation of RT was 11 days (range = 3-57). The median dose received was 20 Gy in 5 fractions (range = 8 Gy/1 fx to 30 Gy/10 fx). The mean change in total lung volume was 1090 cc with mean change in functional lung volume of 1006 cc. Overall, a 92% increase in functional lung volume was observed following chest RT in this cohort. A linear trend toward decreasing recovery of functional lung was observed with more prolonged lung collapse (<i>P</i> = 0.074). Patients with estimated time of lung collapse of ≤14 days had higher mean recovery of functional lung (113%) compared with those with lung collapse > 14 days (55%) (<i>P</i> = 0.040). <h3>Conclusion</h3> Early initiation of palliative RT following lung collapse may lead to greater recovery of functional lung volume, which may confer a survival benefit/decrease hospitalization rates/improve fitness for systemic therapy. Improvements in targeted therapies are leading to more durable systemic responses potentially increasing the importance of timely chest RT for patients with existing or pending lung collapse as a bridge during acute thoracic events.

External Validation of Pulmonary Toxicity Risk Model for Ultracentral Lung Tumors

Pulmonary toxicity attributed to the proximal bronchial tree (PBT) is dose-limiting in stereotactic body radiation therapy (SBRT) for central lung tumors. The toxicity is of particular concern in ultracentral lesions, which are defined as the gross tumor volume abutting the PBT, esophagus, or other mediastinal structures. In this work we tested published pulmonary toxicity models associated with dose to the airway structures after SBRT for ultracentral tumors in an independent institutional cohort of patients.The PubMed database was scrutinized for toxicity models evaluating pulmonary and airway toxicity for SBRT or hypofractionated radiation treatment for central tumors in the lung. The following search term criteria were used: (central) AND (lung tumor) AND (normal tissue complication probability) AND (radiation). Identified models were explored in all patients with ultracentral lung tumors treated between 2008 and 2017 at one large center (N = 88). This cohort included 60% primary lung and 40% metastatic patients that had been treated to 45 Gy in 5 fractions (fx), 50 Gy in 5 fx, 60 Gy in 8 fx, or 60 Gy in 15 fx. 16% of the patients received anti-VEGF therapy, which as previously shown, was associated with higher incidence of grade 5 hemorrhage.A total of six NTCP models were identified from work by Tekatli et al 2018. Of these, three models were for ≥grade 3 and three for grade 5 toxicity and included bronchial max dose, V60, V100, and V130. Clinical pulmonary toxicity consisted of radiation pneumonitis, atelectasis due to main stem bronchus occlusion, and/or hemoptysis. The pulmonary toxicity rate was 15% and 8% for ≥grade 3 toxicity and grade 5 toxicity, respectively, in the original study. Within the independent cohort, the corresponding values were 18% and 10%. Two maximum dose models were shown to be valid in our institutional dataset; other models failed this validation test. The model was made more robust by expanding the max dose region of the bronchial volume by focusing on the max dose to 0.1 cm3, 1 cm3 and 3 cm3. The max dose (0.1 cm3) model had improved performance with increased steepness. Generally, models from literature underestimated our institutional complication rates.Pulmonary toxicity models for central tumors were identified from one study and explored within an independent cohort. The models derived from primarily central lung tumors systematically underestimated the pulmonary toxicity rate in the solely ultracentral tumor cohort, possibly also due to anti-VEGF therapy used in the independent cohort. A modified model from the best-performing max dose model was designed, and this model could be utilized for rationally constructed airways constraints in ultracentral patients treated with SBRT or hypofractionation.I. Chen: None. M. Thor: None. A.J. Wu: Research Grant; CivaTech Oncology, Inc. Honoraria; 1199SEIU. Consultant; AstraZeneca, MORE Health. Advisory Board; Simphotek, Inc. Travel Expenses; AlphaTau Medical. Stock; Simphotek, Inc. A. Iyer: None. A. Apte: None. A. Rimner: Research Grant; Varian Medical Systems, Boehringer Ingelheim, Astra Zeneca, Pfizer, Merck. Consultant; MoreHealth. Advisory Board; Boehringer Ingelheim, Astra Zeneca, Merck; International Thymic Malignancies Interest Group, International Mesothelioma Interest Group. D.R. Gomez: Research Grant; Merck, AstraZeneca. Honoraria; BMS, Varian, Research to Practice. Speaker's Bureau; Merck. Advisory Board; AstraZeneca, Olympus. J.O. Deasy: Research Grant; Varian Corp., NIH, Breast Cancer Research Foundation. Stock; Paige.AI; AAPM.A. Jackson: None.

Study on Serum miR-204 Expression Levels in Patients with Severe Pneumonia and Patients with Primary Bronchial Lung Cancer and Its Diagnostic Value

Objective. To analyze the expression and clinical significance of miR-204 in the serum of patients with severe pneumonia (SP) and primary bronchial lung cancer (LC). Methods. 65 SP patients and 43 primary bronchial LC patients who were treated in the hospital from January 2017 to December 2018 were randomly selected as the SP group and LC group. At the same time, healthy patients from the physical examination department of the hospital were selected. 65 cases were the control group. QRT-PCR detected serum miR-204 expression and compared the differences between groups. The pathological data of patients were collected, and the relationship between serum miR-204 and the patient’s pathological data was compared; the area under the ROC curve and Kaplan–Meier curve were used to evaluate the diagnostic value of serum miR-204 for the two conditions and to explore the relationship between serum miR-204 and prognosis. Results. The serum miR-204 of the SP group was (0.43 ± 0.09), the serum miR-204 of the LC group was (0.40 ± 0.10), the serum miR-204 of the control group was (1.00 ± 0.09), and the miR-204 level of was significantly higher than that of the control group, and the difference between the groups was statistically significant ( P &lt; 0.05). There was no significant difference in serum miR-204 levels between the SP group and the LC group ( P &gt; 0.05). Serum miR-204 levels in SP patients with cumulative organs ≥3 were higher than those with cumulative organs &lt;3, and the difference was statistically significant ( P &lt; 0.001). In the LC group, in patients with stage III to IV and low and undifferentiated patients, the level of miR-204 was higher than that of stage I∼II and high and moderately differentiated patients, and the difference was statistically significant ( P &lt; 0.001). The level of miR-204 in the two groups of patients (0.89 ± 0.10, 0.83 ± 0.13) who died of illness was significantly higher than that of the surviving patients (1.00 ± 0.11, 1.00 ± 0.10), and the difference was statistically significant ( P &lt; 0.05); the survival rate of patients with high expression of miR-204 was higher than that of patients with low expression. The AUC of serum miR-204 level to SP and LC was 0.766 and 0.818, respectively. Conclusion. The level of miR-204 in the serum of SP patients and patients with primary bronchial LC was significantly lower than that of healthy people, and patients who died were lower than those who survived; the miR-204 in serum has a good diagnostic value for SP and LC and is related to the survival and prognosis of patients.

S3611 Double Trouble: Primary Lung and Colon Cancer in a Patient With Crohn’s Disease

Introduction: This vignette highlights the development of localized rectal adenocarcinoma and concomitant metastatic large cell neuroendocrine tumor of the lung in a patient with longstanding Crohn’s disease (CD) on Vedolizumab (VDZ). Case Description/Methods: A 61 year old male with a 2 year history of severe, uncontrolled colonic inflammatory CD presented to the ED with weakness, loss of appetite, and a 30lb weight loss over a 1 month period. He had been on VDZ 300mg every 8 weeks for 1 year. A CT chest showed a new 2cm pulmonary nodule with increasing mediastinal and perihilar lymphadenopathy. Bronchoscopy and endobronchial ultrasound were performed for lymph node sampling and revealed a large cell neuroendocrine tumor, which was later found to be metastatic to the brain. The patient was discharged with plans to optimize the VDZ therapy and start cancer treatment. Anticipating the use of immunotherapy, a colonoscopy was performed and revealed active inflammation in the sigmoid colon. Incidentally, an 18mm Is (sessile) polyp was found in the rectum and removed by piecemeal snare polypectomy. Pathology was consistent with invasive colonic adenocarcinoma. A colonoscopy one year earlier had been negative for malignancy. After a careful discussion in the GI tumor board, the decision was made to treat the lung cancer first. Unfortunately, the patient developed sepsis after his first chemotherapy dose and passed away. Discussion: This case illustrates the challenges with CD therapy during active malignancy. CD patients are at increased risk for both colonic adenocarcinoma and pulmonary malignancy. There have been isolated cases linking CD to premalignant diffuse idiopathic pulmonary neuroendocrine cell hyperplasia, suggesting a possible correlation between CD and the highly aggressive large cell neuroendocrine tumor of the lung seen, though data is limited. VDZ has been associated with 24%-31% clinical remission of CD after induction. It was shown to be well tolerated and had a low risk of malignancy in patients with and without a history of prior malignancy. Data is limited on the use of VDZ concurrently with active chemotherapy, though it is presumed have a favorable safety profile given the gut-selective nature of the drug. The development of malignancies in this case is thought to be possibly related to CD and likely unrelated to VDZ. With limited data available, a multidisciplinary discussion between oncology and GI is ideal to develop a tailored treatment plan for CD patients with active malignancy.