Histological Subtypes Of Lung Cancer Research Articles

Adrenergic microenvironment driven by cancer-associated Schwann cells contributes to chemoresistance in patients with lung cancer.

Doublecortin (DCX)-positive neural progenitor-like cells are purported components of the cancer microenvironment. The number of DCX-positive cells in tissues reportedly correlates with cancer progression; however, little is known about the mechanism by which these cells affect cancer progression. Here we demonstrated that DCX-positive cells, which are found in all major histological subtypes of lung cancer, are cancer-associated Schwann cells (CAS) and contribute to the chemoresistance of lung cancer cells by establishing an adrenergic microenvironment. Mechanistically, the activation of the Hippo transducer YAP/TAZ was involved in the acquisition of new traits of CAS and DCX positivity. We further revealed that CAS express catecholamine-synthesizing enzymes and synthesize adrenaline, which potentiates the chemoresistance of lung cancer cells through the activation of YAP/TAZ. Our findings shed light on CAS, which drive the formation of an adrenergic microenvironment by the reciprocal regulation of YAP/TAZ in lung cancer tissues.

Abstract LB151: Association of radiotherapy with the risk of subtype-specific lung cancer among breast cancer survivors in the United States

Abstract Background Breast cancer survivors face an elevated risk of subsequent primary lung cancer (SPLC), especially those who received radiotherapy. Nevertheless, the association of radiotherapy for breast cancer and the risk of subtype-specific lung cancer is unknown. Methods Females diagnosed with first primary breast cancer at ages 20-84 years from 1992-2020 were identified from 12 Surveillance, Epidemiology, and End Results registries. Follow-up began at 2 months from breast cancer diagnosis and ended at subsequent lung cancer diagnosis, last known vital status, death, or December 31, 2020. Standardized incidence ratios (SIRs) and excess absolute risks (EARs, per 10,000 women) were calculated for each histological subtype of lung cancer (adenocarcinoma, squamous cell carcinoma, small cell carcinoma, large cell carcinoma, and others) using expected rates of each subtype in the SEER population. Subgroup analyses were conducted by treatment for breast cancer (radiotherapy yes or no/unknown), overall and stratified by the relative position (ipsilateral and contralateral) of the breast and SPLC. Results Of all 550,007 breast cancer survivors (>50 years old, 74%; non-Hispanic Whites, 67%; localized, 51%), 8,014 SPLCs were diagnosed during a mean follow-up of 9.7 years. 52.6% of the participants received radiotherapy treatment. Compared with the general population, breast cancer survivors had a statistically significantly higher risk of lung cancer with subtype-specific SIR being greatest for adenocarcinoma (Observed N=4337; SIR=1.20, 95% Confidence Interval [CI]=1.16-1.24; EAR=1.35), followed by squamous cell carcinoma (Observed N=1368; SIR=1.11, 95% CI=1.05-1.17; EAR=0.26) and small cell carcinoma (Observed N=1026; SIR=1.08, 95% CI=1.02-1.15; EAR=0.14). When stratified by radiotherapy receipt, the increased risk associated with adenocarcinoma did not vary across strata. In contrast, the increased risk for squamous and transitional cell carcinoma and small cell carcinoma were confined to those who received radiotherapy (SIR=1.16, 95% CI=1.08-1.24 vs SIR=1.06, 95% CI=0.98-1.15 for squamous and transitional cell carcinoma; SIR=1.15, 95% CI=1.06-1.25 vs SIR= 1.00, 95% CI=0.91-1.09 for small cell carcinoma). Further analysis by laterality showed that associations of treatment receipt with increased risk of lung cancer were confined to ipsilateral SPLC for these two subtypes. Conclusion Different subtypes of lung cancer may have distinct associations with prior radiation treatment in individuals who have survived breast cancer. The findings have implications for evaluating risks and implementing surveillance for subsequent primary lung cancer in the growing population of breast cancer survivors. Citation Format: Chenxi Jiang, Rachel A. Freedman, Ahmedin Jemal, Hyuna Sung. Association of radiotherapy with the risk of subtype-specific lung cancer among breast cancer survivors in the United States [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 LB151.

Systematic proteome-wide Mendelian randomization using the human plasma proteome to identify therapeutic targets for lung adenocarcinoma

BackgroundLung adenocarcinoma (LUAD) is the predominant histological subtype of lung cancer and the leading cause of cancer-related mortality. Identifying effective drug targets is crucial for advancing LUAD treatment strategies.MethodsThis study employed proteome-wide Mendelian randomization (MR) and colocalization analyses. We collected data on 1394 plasma proteins from a protein quantitative trait loci (pQTL) study involving 4907 individuals. Genetic associations with LUAD were derived from the Transdisciplinary Research in Cancer of the Lung (TRICL) study, including 11,245 cases and 54,619 controls. We integrated pQTL and LUAD genome-wide association studies (GWASs) data to identify candidate proteins. MR utilizes single nucleotide polymorphisms (SNPs) as genetic instruments to estimate the causal effect of exposure on outcome, while Bayesian colocalization analysis determines the probability of shared causal genetic variants between traits. Our study applied these methods to assess causality between plasma proteins and LUAD. Furthermore, we employed a two-step MR to quantify the proportion of risk factors mediated by proteins on LUAD. Finally, protein–protein interaction (PPI) analysis elucidated potential links between proteins and current LUAD medications.ResultsWe identified nine plasma proteins significantly associated with LUAD. Increased levels of ALAD, FLT1, ICAM5, and VWC2 exhibited protective effects, with odds ratios of 0.79 (95% CI 0.72–0.87), 0.39 (95% CI 0.28–0.55), 0.91 (95% CI 0.72–0.87), and 0.85 (95% CI 0.79–0.92), respectively. Conversely, MDGA2 (OR, 1.13; 95% CI 1.08–1.19), NTM (OR, 1.12; 95% CI 1.09–1.16), PMM2 (OR, 1.35; 95% CI 1.18–1.53), RNASET2 (OR, 1.15; 95% CI 1.08–1.21), and TFPI (OR, 4.58; 95% CI 3.02–6.94) increased LUAD risk. Notably, none of the nine proteins showed evidence of reverse causality. Bayesian colocalization indicated that RNASET2, TFPI, and VWC2 shared the same variant with LUAD. Furthermore, NTM and FLT1 demonstrated interactions with targets of current LUAD medications. Additionally, FLT1 and TFPI are currently under evaluation as therapeutic targets, while NTM, RNASET2, and VWC2 are potentially druggable. These findings shed light on LUAD pathogenesis, highlighting the tumor-promoting effects of RNASET2, TFPI, and NTM, along with the protective effects of VWC2 and FLT1, providing a significant biological foundation for future LUAD therapeutic targets.ConclusionsOur proteome-wide MR analysis highlighted RNASET2, TFPI, VWC2, NTM, and FLT1 as potential drug targets for further clinical investigation in LUAD. However, the specific mechanisms by which these proteins influence LUAD remain elusive. Targeting these proteins in drug development holds the potential for successful clinical trials, providing a pathway to prioritize and reduce costs in LUAD therapeutics.

IBPGNET: lung adenocarcinoma recurrence prediction based on neural network interpretability.

Lung adenocarcinoma (LUAD) is the most common histologic subtype of lung cancer. Early-stage patients have a 30-50% probability of metastatic recurrence after surgical treatment. Here, we propose a new computational framework, Interpretable Biological Pathway Graph Neural Networks (IBPGNET), based on pathway hierarchy relationships to predict LUAD recurrence and explore the internal regulatory mechanisms of LUAD. IBPGNET can integrate different omics data efficiently and provide global interpretability. In addition, our experimental results show that IBPGNET outperforms other classification methods in 5-fold cross-validation. IBPGNET identified PSMC1 and PSMD11 as genes associated with LUAD recurrence, and their expression levels were significantly higher in LUAD cells than in normal cells. The knockdown of PSMC1 and PSMD11 in LUAD cells increased their sensitivity to afatinib and decreased cell migration, invasion and proliferation. In addition, the cells showed significantly lower EGFR expression, indicating that PSMC1 and PSMD11 may mediate therapeutic sensitivity through EGFR expression.

Evaluation of the clinical significance of long non-coding RNA MALAT1 genetic variants in human lung adenocarcinoma.

Lung adenocarcinoma (LUAD) is the most frequent histological subtype of lung cancer, which is the most common malignant tumor and the main cause of cancer-related mortality globally. Recent reports revealed that long non-coding RNA (lncRNA) of metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) plays a crucial role in tumorigenesis and metastasis development in lung cancer. However, the contribution of MALAT1 genetic variants to the development of LUAD is unclear, especially in epidermal growth factor receptor (EGFR) mutation status. In this study, 272 LADC patients with different EGFR status were recruited to dissect the allelic discrimination of the MALAT1 polymorphisms at rs3200401, rs619586, and rs1194338. The findings of the study showed that MALAT1 polymorphisms rs3200401, rs619586, and rs1194338 were not associated to LUAD susceptibility; however, rs3200401 polymorphisms was significantly correlated to EGFR wild-type status and tumor stages in LUAD patients in dominant model (p=0.016). Further analyses using the datasets from The Cancer Genome Atlas (TCGA) revealed that lower MALAT1 mRNA levels were associated with the advanced stage, and lymph node metastasis in LADC patients. In conclusion, our results showed that MALAT1 rs3200401 polymorphisms dramatically raised the probability of LUAD development.

The Clinical Value of Pre-Diagnostic Thrombocytosis for the Detection of Lung Cancer in Primary Care.

Thrombocytosis is a risk marker for lung cancer in primary care. We investigated whether thrombocytosis presents pre-diagnostically for all the histological subtypes of lung cancer and its association with the stage at diagnosis. A matched cohort study used English electronic primary care data linked to the national cancer registry. Patients diagnosed with lung cancer aged ≥40 years with no prior history of malignancy were matched by age, sex, and general practice to five controls without lung cancer. Multivariable logistic regression models quantified the incidence of pre-diagnostic thrombocytosis and advanced-stage diagnoses, adjusting for COPD diagnosis, smoking status, and anti-platelet drug prescriptions. A total of 9504 cases were matched to 45,647 controls, consisting of 3260 (34%) adenocarcinomas (ADC), 2020 (21%) squamous cell carcinomas (SCC), 70 (<1%) large-cell carcinomas (LCC), and 1089 (12%) small-cell lung cancers (SCLC). The patients with lung cancer were 8.9 (95% CI 8.0-9.9) times more likely to exhibit pre-diagnostic thrombocytosis than the controls. The odds ratios were highest for the comparison between SCC and ADC (1.8, 95% CI 1.5-2.1). Thrombocytosis is associated with advanced-stage ADC and SCC but presented equally for early- and advanced-stage SCLC. Pre-diagnostic thrombocytosis may aid in the detection of all the histological subtypes in primary care.

Potential association of HSPD1 with dysregulations in ribosome biogenesis and immune cell infiltration in lung adenocarcinoma: An integrated bioinformatic approach.

Lung adenocarcinoma (LUAD) is a major histological subtype of lung cancer with a high mortality rate worldwide. Heat shock protein family D member 1 (HSPD1, also known as HSP60) is reported to be increased in tumor tissues of lung cancer patients compared with healthy control tissues. We aimed to investigate the roles of HSPD1 in prognosis, carcinogenesis, and immune infiltration in LUAD using an integrative bioinformatic analysis. HSPD1 expression in LUAD was investigated in several transcriptome-based and protein databases. Survival analysis was performed using the KM plotter and OSluca databases, while prognostic significance was independently confirmed through univariate and multivariate analyses. Integrative gene interaction network and enrichment analyses of HSPD1-correlated genes were performed to investigate the roles of HSPD1 in LUAD carcinogenesis. TIMER and TISIDB were used to analyze correlation between HSPD1 expression and immune cell infiltration. The mRNA and protein expressions of HSPD1 were higher in LUAD compared with normal tissues. High HSPD1 expression was associated with male gender and LUAD with advanced stages. High HSPD1 expression was an independent prognostic factor associated with poor survival in LUAD patients. HSPD1-correlated genes with prognostic impact were mainly involved in aberrant ribosome biogenesis, while LUAD patients with high HSPD1 expression had low tumor infiltrations of activated and immature B cells and CD4+ T cells. HSPD1 may play a role in the regulation of ribosome biogenesis and B cell-mediated immunity in LUAD. It could serve as a predictive biomarker for prognosis and immunotherapy response in LUAD.

INTEGRAL‐ILCCO cohort data analysis revealed the association of clonal haematopoiesis with an increased risk of lung cancer

AbstractTo investigate the association between clonal haematopoiesis (CH) and lung cancer risk, we identified CH mutations in 1 059 lung cancer cases and 899 controls using the blood whole‐exome sequencing data generated from the Integrative Analysis of Lung Cancer Etiology and Risk project of the International Lung Cancer Consortium (INTEGRAL‐ILCCO). Based on the variant allele frequency (VAF) of these mutations, we stratified CH carriers into two groups, low VAF (1%–10%) and high VAF (≥10%), respectively. We observed a significant association between the presence of CH mutations and the risk of lung cancer after adjusting for known risk factors (odd ratio, OR = 1.37, 95% confidence interval, CI = 1.02–1.85). Such an association was largely driven by CH mutations with high‐VAF, the OR for high‐VAF CH and low‐VAF CH were 2.54 (1.38–4.93) and 1.14 (0.82–1.6), respectively. Trend analysis indicated a significant dose–response relationship (P trend = 0.004). This association between high‐VAF CH and lung cancer risk remained consistent when subjects were stratified by risk factors or lung cancer histological subtypes. A combination of results from INTEGRAL‐ILCCO, UKBB, and MGBB cohorts resulted in a meta‐analysed OR of 1.36 (95% CI = 1.14–1.62) for all CH carriers and of 1.76 (95% CI = 1.34–2.31) for high‐VAF CH carriers, respectively. In conclusion, our analysis revealed a significant association between CH and increased risk of lung cancer as supported by three independent cohorts.

Progress in the treatment of lung adenocarcinoma by integrated traditional Chinese and Western medicine.

Non-small cell lung cancer (NSCLC) overwhelmingly represents the predominant histological subtype of lung cancer, with lung adenocarcinoma emerging as the most prevalent form. Conventional Western medical treatments encompass a spectrum of modalities, including surgical interventions, cytotoxic chemotherapy, radiotherapy, targeted pharmacotherapy, and immunotherapy. In contrast, Traditional Chinese Medicine (TCM) methodologies encompass traditional Chinese medicine treatments, acupuncture therapies, and tuina treatments. While conventional Western medicine has made remarkable strides in the treatment of lung cancer, it is important to acknowledge the limitations inherent in singular treatment approaches. Consequently, the quest for a more comprehensive and integrative therapeutic paradigm becomes imperative. A deficiency of evaluation criteria specific to lung adenocarcinoma treatment in the realm of TCM represents an outstanding challenge in need of resolution. Nonetheless, in the backdrop of the continuous evolution of lung adenocarcinoma treatment modalities, the amalgamation of Chinese and Western medical approaches for treating this condition has exhibited a promising trajectory. It not only contributes to mitigating toxicity and augmenting efficacy but also serves to reduce a spectrum of postoperative complications, thereby enhancing the quality of patients' survival and extending life expectancy. This article furnishes a comprehensive survey of the research advancements in the integration of Chinese and Western medical approaches for treating lung adenocarcinoma. It elucidates the merits and demerits of individual and combined therapeutic strategies, surmounts current limitations, underscores the virtues of amalgamating Chinese and Western medical paradigms, and offers a more holistic, integrated, and efficacious treatment blueprint.

Lung cancer and HIV

People, living with HIV, have a greater chance of malignancies especially with the success of antiretroviral therapy, and Non-AIDS-defining cancers have become the most common cause of death after AIDS and the most common of them is the lung cancer in developed countries.&#x0D; The main purpose of this article is to research nosological characteristics of lung cancer in the context of HIV infection, HIV-associated risk factors during ART and compare with global trends of this problem.&#x0D; Retrospectively were analyzed the medical documentation of 98 patients with lung cancer and HIV-infection, who were in database and received specialized treatment in St. Petersburg from 2008 to 2018 years. There are several important questions regarding to lung cancer with HIV-infection. HIV-infected lung cancer patients are younger than HIV-negative, have a more advanced disease and that is more difficult to treat. The increased risk of lung cancer in HIV-positive population is multifactorial.&#x0D; The population was dominated by patients of young (18-44 years old) and middle (45-59 years old) ages, 45.9% and 42.9%, respectively, and 11.2% of elderly patients (60-74 years old), p0.001, which satisfies the global data of earlier incidence of lung cancer in people living with HIV.&#x0D; Adenocarcinomas were more common histological subtype of lung cancer as in the general population (p0.001).&#x0D; There was no static significance between high viral load and lung cancer, which can indicate the absence of a direct mechanism of HIV-carcinogenesis (90.8% of patients with low and medium viral load, p0.001).Nevertheless, the prevalence of 4-stage of HIV infection among lung cancer patients (p0.001) indicates a history of inflammatory diseases, including pulmonary diseases, as a result of induced immunosuppression due to CD8+T-lymphocyte dysfunction and the formation of a micro-tumor environment, which can be a prognostic unfavorable factor in the occurrence of lung cancer in this group of patients , as well as indirect mechanism of viral carcinogenesis.&#x0D; The presence of elderly patients (11.2%, MAX -71 years) indirectly indicates an increasing of period of life expectancy among this category of patients in Russia, making this area of research more actual.

Abstract C093: Increasing racial diversity of lung adenocarcinoma cell lines to mitigate lung cancer health disparities

Abstract Lung cancer is the leading cause of cancer death in the United States and worldwide, and a significant source of cancer health disparities. Black/African American (B/AA) men exhibit the highest rate of lung cancer death compared to any other racial group. Compared to White men, B/AA men have a 12% higher lung cancer incidence rate and a 15% higher lung cancer death rate. One essential tool in the study of lung cancer is the use of lung cancer cell lines, which can be applied to molecular studies of lung cancer development and progression and pre-clinical drug testing. To minimize disparities in lung cancer research, it is important that cell lines representing different lung cancer histological subtypes, carrying different cancer driver genes, and representing different races and ethnicities be available. This is particularly relevant for lung cancer cell lines from B/AA men. We reviewed the availability of lung cancer cell lines and observed a considerable imbalance in the representation of cell lines from different population groups. We identified over 800 lung cancer cell lines, with the majority of lung cancer cell lines derived from White and Asian patients, and only 31 lung cancer cell lines from B/AA patients. In addition, we did not find any cell lines from Hispanic/Latin(x) (H/L), American Indian/American Native (AI/AN), or Native Hawaiian or other Pacific Islander (NHOPI) patients. Focusing on lung adenocarcinoma, the most common type of lung cancer, we aim to increase the representation of B/AA cell lines by creating new cell lines from B/AA lung cancer patients, as well as by generating isogenic cell line variants from existing lung cancer cell lines, such as NCI-H23. NCI-H23 was derived from a Black male patient with a KRAS G12C heterozygous mutation. We use CRISPR/Cas9-based genome editing to replace the KRAS G12C mutation with other KRAS mutations found in B/AA patients, including KRAS G12V, KRAS G12A, and KRAS G13C. The lack of an appropriately diverse collection of lung cancer cell lines significantly limits racially and ethnically inclusive lung cancer research. This hinders the ability to develop inclusive models, screen comprehensively for therapeutic compounds, and pre-clinically test new drugs. Ultimately, this leads to an under-development of therapies that can increase the survival of minority and underserved patients. The noted lack of cell lines from underrepresented groups should mobilize researchers and clinicians to establish additional cell lines and ensure appropriate representation of all population groups in this critical pre-clinical research resource. Citation Format: Christopher Leon, Matthew Gladstone, Chunli Yan, Diana I. Romero, Yong Huang, Kweku Ofosu-Asante, Nazarius S. Lamango, Ite A. Offringa. Increasing racial diversity of lung adenocarcinoma cell lines to mitigate lung cancer health disparities [abstract]. In: Proceedings of the 16th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2023 Sep 29-Oct 2;Orlando, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2023;32(12 Suppl):Abstract nr C093.

Lessons and opportunities from improved understanding of global lung cancer histological subtypes

Lessons and opportunities from improved understanding of global lung cancer histological subtypes

Pathomic Features Reveal Immune and Molecular Evolution From Lung Preneoplasia to Invasive Adenocarcinoma

Recent statistics on lung cancer, including the steady decline of advanced diseases and the dramatically increasing detection of early-stage diseases and indeterminate pulmonary nodules, mark the significance of a comprehensive understanding of early lung carcinogenesis. Lung adenocarcinoma (ADC) is the most common histologic subtype of lung cancer, and atypical adenomatous hyperplasia is the only recognized preneoplasia to ADC, which may progress to adenocarcinoma in situ (AIS) and minimally invasive adenocarcinoma (MIA) and eventually to invasive ADC. Although molecular evolution during early lung carcinogenesis has been explored in recent years, the progress has been significantly hindered, largely due to insufficient materials from ADC precursors. Here, we employed state-of-the-art deep learning and artificial intelligence techniques to robustly segment and recognize cells on routinely used hematoxylin and eosin histopathology images and extracted 9 biology-relevant pathomic features to decode lung preneoplasia evolution. We analyzed 3 distinct cohorts (Japan, China, and United States) covering 98 patients, 162 slides, and 669 regions of interest, including 143 normal, 129 atypical adenomatous hyperplasia, 94 AIS, 98 MIA, and 205 ADC. Extracted pathomic features revealed progressive increase of atypical epithelial cells and progressive decrease of lymphocytic cells from normal to AAH, AIS, MIA, and ADC, consistent with the results from tissue-consuming and expensive molecular/immune profiling. Furthermore, pathomics analysis manifested progressively increasing cellular intratumor heterogeneity along with the evolution from normal lung to invasive ADC. These findings demonstrated the feasibility and substantial potential of pathomics in studying lung cancer carcinogenesis directly from the low-cost routine hematoxylin and eosin staining.

Differences in serum cytokine levels distinguish between clinically noninvasive lung adenocarcinoma and invasive lung adenocarcinoma: A cross-sectional study.

Lung cancer incidence and mortality remain high and are now the leading cause of cancer-related death. Lung adenocarcinoma (LUAD) is one of the main histological subtypes of lung cancer. Previous studies have shown the role of inflammation in the development of lung cancer, but the relationship between cytokines and LUAD is still unclear. To further differentiate and explore the association of cytokines with the risk of non-invasive and invasive LUAD, we studied and assessed serum cytokine levels in patients with two types of LUAD. A cohort study of 90 non-invasive LUAD and 90 invasive LUAD was retrospectively included, and the clinical characteristics were recorded in detail. The differences in the levels of 12 serum cytokines (IFN-α, IFN-γ, IL-10, IL-12P70, IL-17A, IL-1β, IL-2, IL-4, IL-5, IL-6, IL-8, and TNF-α) between the two groups of patients with LUAD were analyzed and evaluated. And we evaluated the clinical value of cytokine differential diagnosis of invasive LUAD based on receiver operating characteristics (ROC) curves. The mean age of the patients was 56.6 years, and the proportions of males and females were 38.9% and 61.1%, respectively. IFN-α, IL-1β, IL-2, IL-6, TNF-α, IL-4, and IL-8 were significantly increased in patients with invasive LUAD compared with the non-invasive LUAD group. Further research found that smoking is an important factor, with changes in the four cytokines IL-1β, IL-6, IL-8, and TNF-α being significantly higher in the smoking group of patients with invasive LUAD. It can be seen from the area under the curve that IL-1β and IL-2 have a significant differential diagnosis. We observed differences in preoperative serum cytokine levels between patients with invasive and non-invasive LUAD, which may serve as potential serum biomarkers for clinical differential diagnosis and disease progression assessment.

A survey of flexible bronchoscopy practice at Kenyatta National Hospital, Kenya

Objectives: Flexible bronchoscopy (FB) is an essential diagnostic and therapeutic tool for managing respiratory diseases, and an audit of its practice is important; it enhances standardization of practice and improves outcomes and patient safety. This study aimed to describe the FB practice at Kenyatta National Hospital (KNH) regarding indications, peri-procedure practice, gross and histologic findings, and safety. Materials and Methods: This study was a quantitative and retrospective chart review of files of 282 patients who underwent flexible bronchoscopies over 5 years in KNH. Results: We reviewed 282 flexible bronchoscopies done between January 2016 and December 2020. There was a significant documentation gap (22%); 54 out of the 282 cases audited had incomplete documentation. The male-to-female ratio was 1:1, with a median age of 51 years. Most (58.2%) of the patients were residents of counties outside Nairobi. Despite a lack of evidence for routine evaluation, we noted significant rates (75.9%) of routine laboratory evaluations (International normalized ratio (INR), platelet count). The most common indication of bronchoscopy was the evaluation of a lung mass (100) 35.7%, pulmonary infiltrate 53 (18.9%), and assessment for interstitial lung disease 39 (13.9%). The most common gross bronchoscopic findings were visible tumors at 38.5% (107) and normal endoscopic findings at 29.5% (82). The practice was safe, with a complication rate of 3.2%. The most common diagnostic outcome was lung cancer (40.1%), with adenocarcinoma being the most common (45.1%) histologic subtype. The diagnostic yield for malignancy where there was a visible tumor was 87.2%. Conclusion: Our study showed that FB practice at KNH is safe and provides a good diagnostic yield, but a significant documentation gap and record keeping exist. Adenocarcinoma was the most predominant lung cancer histologic subtype among the mostly non-smoker population.

Claudin expression in pulmonary adenoid cystic carcinoma and mucoepidermoid carcinoma.

Background: Although the expression of tight junction protein claudins (CLDNs) is well known in common histological subtypes of lung cancer, it has not been investigated in rare lung cancers. The aim of our study was to examine the expression of different CLDNs in pulmonary salivary gland tumors. Methods: 35 rare lung cancers including pathologically confirmed 12 adenoid cystic carcinomas (ACCs) and 23 mucoepidermoid carcinomas (MECs) were collected retrospectively. Immunohistochemical (IHC) staining was performed on formalin fixed paraffin embedded (FFPE) tumor tissues, and CLDN1, -2, -3, -4, -5, -7, and -18 protein expressions were analyzed. The levels of immunopositivity were determined with H-score. Certain pathological characteristics of ACC and MEC samples (tumor grade, presence of necrosis, presence of blood vessel infiltration, and degree of lymphoid infiltration) were also analyzed. Results: CLDN overexpression was observed in both tumor types, especially in CLDN2, -7, and -18 IHC. Markedly different patterns of CLDN expression were found for ACC and MEC tumors, especially for CLDN1, -2, -4, and -7, although none of these trends remained significant after correction for multiple testing. Positive correlations between expressions of CLDN2 and -5, CLDN3 and -4, and CLDN5 and -18 were also demonstrated. Tumors of never-smokers presented lower levels of CLDN18 than tumors of current smokers (p-value: 0.003). Conclusion: This is the first study to comprehensively describe the expression of different CLDNs in lung ACC and MEC. Overexpression of certain CLDNs may pave the way for targeted anti-claudin therapy in these rare histological subtypes of lung cancer.

Dissecting the alternation landscape of mitochondrial metabolism-related genes in lung adenocarcinoma and their latent mechanisms.

Lung adenocarcinoma (LUAD) is the most common histological subtype of lung cancer with high incidence and unsatisfactory prognosis. The majority of LUAD patients eventually succumb to local and/or distinct metastatic recurrence. Genomic research of LUAD has broadened our understanding of this disease's biology and improved target therapies. However, the alternation landscape and characteristics of mitochondrial metabolism-related genes (MMRGs) in LUAD progression remain poorly understood. We performed a comprehensive analysis to identify the function and mechanism of MMRGs in LUAD based on the TCGA and GEO databases, which might offer therapeutic values for clinical researchers. Then, we figured out three hub prognosis-associated MMRGs (also termed as PMMRGs: ACOT11, ALDH2, and TXNRD1) that were engaged in the evolution of LUAD. To investigate the correlation between clinicopathological characteristics and MMRGs, we divided LUAD samples into two clusters (C1 and C2) based on key MMRGs. In addition, important pathways and the immune infiltration landscape affected by LUAD clusters were also delineated. Further, we nominated potential regulatory mechanisms underlying the MMRGs in LUAD development and progression. In conclusion, our integrative analysis enables a more comprehensive understanding of the mutation landscape of MMRGs in LUAD and provides an opportunity for more precise treatment.

Automated Classification of Lung Cancer Subtypes Using Deep Learning and CT-Scan Based Radiomic Analysis

Artificial intelligence and emerging data science techniques are being leveraged to interpret medical image scans. Traditional image analysis relies on visual interpretation by a trained radiologist, which is time-consuming and can, to some degree, be subjective. The development of reliable, automated diagnostic tools is a key goal of radiomics, a fast-growing research field which combines medical imaging with personalized medicine. Radiomic studies have demonstrated potential for accurate lung cancer diagnoses and prognostications. The practice of delineating the tumor region of interest, known as segmentation, is a key bottleneck in the development of generalized classification models. In this study, the incremental multiple resolution residual network (iMRRN), a publicly available and trained deep learning segmentation model, was applied to automatically segment CT images collected from 355 lung cancer patients included in the dataset “Lung-PET-CT-Dx”, obtained from The Cancer Imaging Archive (TCIA), an open-access source for radiological images. We report a failure rate of 4.35% when using the iMRRN to segment tumor lesions within plain CT images in the lung cancer CT dataset. Seven classification algorithms were trained on the extracted radiomic features and tested for their ability to classify different lung cancer subtypes. Over-sampling was used to handle unbalanced data. Chi-square tests revealed the higher order texture features to be the most predictive when classifying lung cancers by subtype. The support vector machine showed the highest accuracy, 92.7% (0.97 AUC), when classifying three histological subtypes of lung cancer: adenocarcinoma, small cell carcinoma, and squamous cell carcinoma. The results demonstrate the potential of AI-based computer-aided diagnostic tools to automatically diagnose subtypes of lung cancer by coupling deep learning image segmentation with supervised classification. Our study demonstrated the integrated application of existing AI techniques in the non-invasive and effective diagnosis of lung cancer subtypes, and also shed light on several practical issues concerning the application of AI in biomedicine.

The changing landscape of small-cell lung cancer.

e20634 Background: Small-cell lung cancer (SCLC) is an aggressive histologic subtype of lung cancer with distinct biology and clinical course. The aim of this study is to investigate the trends in demographics and outcomes. Methods: We queried the Surveillance, Epidemiology, and End Results (SEER) database to assess the incidence, demographics, and survival for SCLC using SEER 8 (8 registries), which include data from 1975 to 2019. The pattern of metastases was evaluated using SEER 17 from 2010 to 2019. Jointpoint analysis was used to calculate the trends in annual percentage change according to year of diagnosis. Results: There were 530,198 patients with lung cancer, including 73,362 (13.8%) patients with SCLC in the SEER 8. The percentage of SCLC among all lung tumors progressively increased from 13.3% in 1975 to a peak of 17.5% in 1986, followed by steadily decrease since 1990, reaching 11.1% in 2019. The incidence per 100,000 population increased from 9.5 in 1975 to 15.3 in 1986 followed by a gradual decline to 6.5 in 2019. Among patients with SCLC included in SEER 8, demographic changes from 1975-1979 to 2015-2019 included increased median age at diagnosis from 63 years to 69 and increased percentage of women from 31.4% to 51.2%. The percentage of patients with stage IV increased from 56.9% to 63.8% from 1995-1999 to 2000-2004, and to 69.5% in 2010-2014 without further increase. Among the 55,035 patients with SCLC in SEER 17 from 2010 to 2019, the most common sites of metastasis at diagnosis were mediastinal lymph nodes (69.9%) liver (30.5%), bone (22.8%), and brain (15.8%). The median, 1-year, and 5-year overall survival increased from 6 months, 23%, and 3.6% respectively in 1975-1979 to 7 months, 30.8%, and 6.8% respectively in 2010-2019 (P &lt; 001). Conclusions: The incidence of SCLC in the United States reached a peak in 1985 to 1989 followed by a gradual decline. Demographic changes included an increased median age at diagnosis and the percentage of women, which surpassed men in the last study period. There was also an increase in the percentage of stage IV. The improvement in 5-year OS has been statistically significant but clinically modest.

Use of immune checkpoint gene (ICG) signatures to identify selective enrichment of FGL1 and CEACAM1 in histologic subtypes of lung cancer.

e20527 Background: Immune checkpoint blockade has changed the management paradigm for lung cancer. Identification of vulnerable subsets using reliable predictive biomarkers is an area of unmet need. We systematically compared the pattern of expression of validated mediators of adaptive and innate immune response in clinical and histologic subsets of lung cancer using publicly available datasets. Methods: Gene expression data for lung adenocarcinoma (LUAD, N = 501) and and lung squamous cell carcinoma (LUSC, N = 491) was obtained from The Cancer Genome Atlas. We compared the expression of ICGs between LUSC and LUAD using DESeq2 and estimated the proportion of different immune cells in the tumor microenvironment by CIBERSORT. An expanded panel of ICG signatures from MSigDB was compared between LUSC and LUAD using gene set variation analysis (GSVA). Weighted gene co-expression network analysis (WGCNA) identified modules of immune checkpoint inhibitor genes with significant correlation with histology, which were further investigated for biologic pathway involvement and survival analysis using Ingenuity Pathway Analysis and Gene Expression Profiling Interactive Analysis (GEPIA2), respectively. Results: Majority of the ICGs had a higher expression in LUAD than LUSC with the strongest differential expression recorded for FGL1 (LogFC = 6.2, FDR = 1.2E-239) and CEACAM1 (LogFC = 1.4, FDR = 2E-71). Treg cells and monocytes were higher in LUAD while NK cells and macrophages were higher in LUSC. There was no difference in CD8(+) T cell population by histology. Genesets related to PD1 signaling from MSigDB had significantly higher GSVA scores in LUAD than LUSC. WGCNA identified 2 modules containing immune checkpoint genes – one module containing 15 of the 23 ICGs involved in allograft rejection, interferon gamma response, interferon alpha response, IL6-signaling, IL2-signaling and TNF-alpha signaling showed moderate correlation with LUAD (module-trait correlation = 0.3, P = 8e-26). A second module with 4 ICGs ( FGL1, LGALS3, CEACAM1, PVRL2) enriched in pathways related to carbohydrate and lipid metabolism (galactose degradation, gamma-linolenate biosynthesis) showed very strong correlation with LUAD (module-trait correlation = 0.85, P = 5e-278). Additional comparison by gender and smoking status along with external validation using independent dataset is ongoing. Conclusions: ICG expression profile differs between LUAD and LUSC with a stronger expression profile in LUAD than LUSC.