Large Cell Carcinoma Research Articles

The anticancer effects of cyanidin 3-O-glucoside combined with 5-fluorouracil on lung large-cell carcinoma in nude mice

The haskap (Lonicera caerulea L., Caprifoliaceae) berry has been widely used in traditional medicine in Kuril Islands, Russia, Japan, and China. Cyanidin-3-O-glucoside (C3G) is the most abundant anthocyanin in haskap berries, and C3G induces antiproliferative pharmacological activity in various cancer cells. However, no study has investigated its anti-lung large-cell carcinoma (LCC) pharmacological role. Therefore, this study determined whether C3G alone or C3G combined with 5-fluorouracil (5-FU) inhibits human lung LCC. We determined the tumor growth, apoptosis, inflammation, and metastasis in the H661 lung LCC lines xenografted into BALB/c nude mice. The mice were administered saline (control), 5-FU, C3G, or both C3G and 5-FU. Relative to the control mice, those treated with C3G alone or both C3G and 5-FU exhibited impaired tumor growth; increased tumor apoptosis; decreased inflammatory cytokine levels (e.g., IL-1β, TNF-α, C-reactive protein, and IL-6); decreased inflammation-related factors, including cyclooxygenase-2 protein and nuclear factor-κB (NF-κB) mRNA; increased inhibition of NF-κB kinase α mRNA; and downregulated metastasis-related factors, such as transforming growth factor-β, CD44, epidermal growth factor receptor, and vascular endothelial growth factor. In addition, C3G alone or combined with 5-FU affected the expression of the tumor microenvironment-related factors Ki67, CD45, PDL1, and CD73. Compared with the mice treated with 5-FU or C3G alone, those treated with both C3G and 5-FU exhibited significantly impaired tumor growth, decreased tumor sizes, and increased tumor inhibition. This in vivo study demonstrated that C3G alone or combined with 5-FU may impair the growth of lung LCC and inhibit tumorigenesis. The findings indicate that C3G alone or C3G combined with 5-FU may be beneficial for treating human lung LCC.

Distinct Roles of Adenosine Deaminase Isoenzymes ADA1 and ADA2: A Pan-Cancer Analysis.

ObjectiveAdenosine deaminase (ADA) plays an important role in immune response, which includes two isoenzymes: ADA1 and ADA2. This study aims to explore the roles of ADA1 and ADA2 in cancers.MethodsHuman Protein Atlas (HPA) and Gene Expression Profiling Interactive Analysis (GEPIA2) databases were used to analyze the mRNA expression of ADA1 and ADA2 in human normal cells and tumor tissues. The enzyme assay was used to detect the ADA1 and ADA2 activities in serum from cancer patients. The Kaplan–Meier (KM) plotter was used to analyze the prognostic value of ADA1 and ADA2. TIMER2.0 was used to explore how ADA1 and ADA2 correlate with immune infiltration and immune checkpoints. cBioPortal database was used to investigate the mutations of ADA1 and ADA2. LinkedOmics was used to screen the ADA1 and ADA2 expression-related genes.ResultsADA1 was significantly increased in several tumor tissues, including cholangiocarcinoma (CHOL), lymphoid neoplasm diffuse large B-cell lymphoma (DLBC), head and neck squamous cell carcinoma (HNSC), kidney renal clear cell carcinoma (KIRC), ovarian serous cystadenocarcinoma (OV), pancreatic adenocarcinoma (PAAD), thymoma (THYM), and uterine carcinosarcoma (UCS). ADA2 expression was significantly increased in esophageal carcinoma (ESCA), glioblastoma multiforme (GBM), acute myeloid leukemia (LAML), OV, PAAD, skin cutaneous melanoma (SKCM), and stomach adenocarcinoma (STAD). There were no significant changes in serum ADA1 activities in most cancers, while serum ADA2 activities were increased in most cancers. For prognosis, high ADA1 expression was associated with the poor survival in several cancers, including esophageal squamous cell carcinoma (ESCC), HNSC, KIRC, kidney renal papillary cell carcinoma (KIRP), liver hepatocellular carcinoma (LIHC), lung adenocarcinoma (LUAD), and uterine corpus endometrial carcinoma (UCEC). However, high ADA2 expression showed a favorable prognosis in breast invasive carcinoma (BRCA), cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC), HNSC, KIRC, KIRP, LUAD, OV, PAAD, sarcoma, and THYM. ADA1 showed a moderate positive correlation with multiple infiltrating immune cells in most cancers. ADA2 was positively correlated with B cells, CD8 T cells, monocytes/macrophages, and dendritic cells (DCs) and was strongly negatively correlated with myeloid-derived suppressor cells. Function analysis showed that ADA1 expression-related genes were mainly enriched in cell division biological progression. However, ADA2-related genes were mainly associated with immune response.ConclusionAs isoenzymes, ADA1 and ADA2 showed opposite prognostic values and different correlative patterns with immune infiltrating. These data demonstrated the distinct roles of ADA1 and ADA2 in cancer. ADA2 might act as a protective factor in cancer.

Marine toxin (+)‐chaetocin‐induced apoptosis of lung large cell carcinoma cell lines through cell cycle arrest via CDKN1A expression and replicative stress

AbstractLung large cell carcinoma is a common type of lung cancer with poor prognosis. Although targeted drugs have achieved enormous success in treating non‐small‐cell lung carcinoma (NSCLC), new chemotherapy is needed since the emerged drug resistance always hinders curative effects. The fungal toxin (+)‐chaetocin demonstrated strong antineoplastic activities against the tested lung large cell carcinoma cell lines H460 and H661 at submicromolar concentrations. Further research demonstrated that (+)‐chaetocin effectively induced H460 apoptosis at 10–30 nM concentrations, while cell death occurred at 60 nM concentrations due to DNA duplication errors. Cell cycle and transcriptional analyses proved that cell cycle arrest via CDKN1A expression and the comprehensive replicative stress of (+)‐chaetocin are key factors in the (+)‐chaetocin working mechanisms.

Identification of condition-specific regulatory mechanisms in normal and cancerous human lung tissue.

BackgroundLung cancer is the leading cause of cancer death in both men and women. The most common lung cancer subtype is non-small cell lung carcinoma (NSCLC) comprising about 85% of all cases. NSCLC can be further divided into three subtypes: adenocarcinoma (LUAD), squamous cell carcinoma (LUSC), and large cell lung carcinoma. Specific genetic mutations and epigenetic aberrations play an important role in the developmental transition to a specific tumor subtype. The elucidation of normal lung versus lung tumor gene expression patterns and regulatory targets yields biomarker systems that discriminate lung phenotypes (i.e., biomarkers) and provide a foundation for the discovery of normal and aberrant gene regulatory mechanisms.ResultsWe built condition-specific gene co-expression networks (csGCNs) for normal lung, LUAD, and LUSC conditions. Then, we integrated normal lung tissue-specific gene regulatory networks (tsGRNs) to elucidate control-target biomarker systems for normal and cancerous lung tissue. We characterized co-expressed gene edges, possibly under common regulatory control, for relevance in lung cancer.ConclusionsOur approach demonstrates the ability to elucidate csGCN:tsGRN merged biomarker systems based on gene expression correlation and regulation. The biomarker systems we describe can be used to classify and further describe lung specimens. Our approach is generalizable and can be used to discover and interpret complex gene expression patterns for any condition or species.Supplementary InformationThe online version contains available at 10.1186/s12864-022-08591-9.

Abstract #1183557: Parathyroid Hormone-Related Protein Causing Hypercalcemia in a Patient with Large Cell Lung Cancer

Secretion of parathyroid hormone-related protein (PTHrP) accounts for up to 80% of cases with hypercalcemia of malignancy. It is most commonly associated with lung cancer, with a reported incidence up to 12.5% in those at advanced stages. While elevated PTHrP levels have been reported with all histologic types of lung cancer, it is rare in large cell carcinoma, with only 3 previously reported cases.

Pulmonary Oligometastasis From the Kidney Masquerading as Primary Carcinoma of the Lung

Abstract A biopsy of a solitary lung mass was diagnosed as a primary large cell carcinoma, favoring adenocarcinoma, based on positive epithelial markers, solid growth pattern, absence of squamous or endocrine differentiation, and relatively abundant eosinophilic cytoplasm. The immunohistochemical evaluation was initially confounded by misleading positive results for CD68 and calretinin. The diagnosis was changed to metastatic renal cell carcinoma, when further history and immunohistochemical stains were performed. This report underscores the utility of history and imaging findings in differentiating primary versus metastatic lung tumors and the need for judicious use of immunohistochemical stains. The differential diagnosis of carcinomas of the lung with solid growth pattern is discussed.

Epigenetic Alterations and Inflammation as Emerging Use for the Advancement of Treatment in Non-Small Cell Lung Cancer.

Lung cancer remains one of the most common malignancies in the world. Nowadays, the most common lung cancer is non-small cell lung cancer (NSCLC), namely, adenocarcinoma, squamous cell carcinoma, and large cell lung carcinoma. Epigenetic alterations that refer to DNA methylation, histone modifications, and noncoding RNA expression, are now suggested to drive the genesis and development of NSCLC. Additionally, inflammation-related tumorigenesis also plays a vital role in cancer research and efforts have been attempted to reverse such condition. During the occurrence and development of inflammatory diseases, the immune component of inflammation may cause epigenetic changes, but it is not always certain whether the immune component itself or the stimulated host cells cause epigenetic changes. Moreover, the links between epigenetic alterations and cancer-related inflammation and their influences on the human cancer are not clear so far. Therefore, the connection between epigenetic drivers, inflammation, and NSCLC will be summarized. Investigation on such topic is most likely to shed light on the molecular and immunological mechanisms of epigenetic and inflammatory factors and promote the application of epigenetics in the innovative diagnostic and therapeutic strategies for NSCLC.

Immune Checkpoint Marker of Programmed Death Ligand-1 (PD-L1) Expression in Surgical Lung Cancer Specimens

Background: Currently immune checkpoint pathways of PD1-PD-L1 is being used to treat lung cancer and PD-L1 served as predictive biomarker. Investigations of PD-L1 expression as a target immunotherapy in lung cancer specimens in Indonesia is needed. This study aimed to evaluate PD-L1 expression in resected lung cancer specimens using immunohistochemistry techniques. Methods: Thirty surgically resected sample from lung cancer patients were obtained. The whole specimens were stained by using immunohistochemistry techniques automatically in BOND-MAX Autostainner (Leica, Germany). PD-L1 polyclonal antibody (Genetex) at 1:1500 dilution was applied to immunohistochemistry staining procedure. Clinicopathological characteristic were acquired from the hospital registry database.Result: A total of 30 surgical specimens were assessed from lung cancer patients. Twenty-four (80%) of them were Adenocarcinoma (AC), 1 (3, 33%) Adenosquamous carcinoma, 2 (6, 67%) were Squamous Cell Carcinoma (SSC), 1 (3, 33%) were Large Cell Carcinoma, 1 (3, 33%) were Neuroendocrine Carcinoma, 1 (3, 33%) were Adenoid Cyctic Carcinoma. The expression of PDL-1 positive reactivity was 16 of 30 (53.3%) specimens and we categorized into strong positivity (>50%), medium (= 50%) and low positivity (<50) from 21 specimens, 0 specimens and 7 specimens respectively.Conclusion: PD-L1 expression could be detected in lung cancer specimen using polyclonal antibody.

Variation in targetable genomic alterations in non-small cell lung cancer by genetic ancestry, sex, smoking history, and histology

BackgroundGenomic alterations in 8 genes are now the targets of FDA-approved therapeutics in non-small cell lung cancer (NSCLC), but their distribution according to genetic ancestry, sex, histology, and smoking is not well established.MethodsUsing multi-institutional genetic testing data from GENIE, we characterize the distribution of targetable genomic alterations in 8 genes among 8675 patients with NSCLC (discovery cohort: DFCI, N = 3115; validation cohort: Duke, Memorial Sloan Kettering Cancer Center, Vanderbilt, N = 5560). For the discovery cohort, we impute genetic ancestry from tumor-only sequencing and identify differences in the frequency of targetable alterations across ancestral groups, smoking pack-years, and histologic subtypes.ResultsWe identified variation in the prevalence of KRASG12C, sensitizing EGFR mutations, MET alterations, ALK, and ROS1 fusions according to the number of smoking pack-years. A novel method for computing continental (African, Asian, European) and Ashkenazi Jewish ancestries from panel sequencing enables quantitative analysis of the correlation between ancestry and mutation rates. This analysis identifies a correlation between Asian ancestry and EGFR mutations and an anti-correlation between Asian ancestry and KRASG12C mutation. It uncovers 2.7-fold enrichment for MET exon 14 skipping mutations and amplifications in patients of Ashkenazi Jewish ancestry. Among never/light smokers, targetable alterations in LUAD are significantly enriched in those with Asian (80%) versus African (49%) and European (55%) ancestry. Finally, we show that 5% of patients with squamous cell carcinoma (LUSC) and 17% of patients with large cell carcinoma (LCLC) harbor targetable alterations.ConclusionsAmong patients with NSCLC, there was significant variability in the prevalence of targetable genomic alterations according to genetic ancestry, histology, and smoking. Patients with LUSC and LCLC have 5% rates of targetable alterations supporting consideration for sequencing in those subtypes.

Aberrant Expression of Cardiac Troponin-T in Lung Cancer Tissues in Association With Pathological Severity.

BackgroundCardiac troponin-T (TNNT2) is exclusively present in cardiac muscle. Measurement of TNNT2 is used for diagnosing acute coronary syndrome. However, its expression may not be limited in myocardium. This study aimed at evaluating the expression of TNNT2 in neoplastic tissues.Methods and ResultsWe used paraffin-embedded blocks of 68 patients with lung cancer (age, 68 ± 11 years old; early-stage, 33; advance-stage, 35) at Miyazaki University Hospital, Japan between January 1, 2017, and March 31, 2019. We stained the slide sections with primary monoclonal antibody against TNNT2 protein, and assessed the frequency of positive staining, and its association with pathological severity. In addition, we examined whether TNNT2 gene is detected in lung cancer tissues of four patients using reverse transcription-polymerase chain reaction. Immunoreactivity for TNNT2 protein was present in the cytoplasm and nucleus of lung cancer cells. The frequency was 37% (25 of 68) in all patients and was irrespective of histologic type (six of 13, squamous cell carcinoma; 18 of 50, adenocarcinoma; 0 of 4, neuroendocrine cell carcinoma; 1 of 1, large cell carcinoma). The prevalence increased with pathological staging [9% (3 of 33) at early-stage (Stage 0–I); 63% (22 of 35) at advance-stage (Stage II–IV and recurrence)]. In addition, frequency of positive staining for TNNT2 increased with pleural (χ2 = 5.877, P = 0.015) and vascular (χ2 = 2.449, P = 0.118) invasions but decreased with lymphatic invasion (χ2 = 3.288, P = 0.070) in specimens performed surgical resection. Furthermore, TNNT2 mRNA was detected in the resected squamous cell carcinoma and adenocarcinoma tissues.ConclusionsOur data suggest the aberrant expression of TNNT2 in lung cancer and its prevalence increases with pathological severity.

Essential Oils and Extracts of Juniperus macrocarpa Sm. and Juniperus oxycedrus L.: Comparative Phytochemical Composition and Anti-Proliferative and Antioxidant Activities.

In this work, we conducted a comparative phytochemical, chemotaxonomic, and biological study of essential oils (EOs) and extracts (ethyl acetate and methanol) obtained from the leaves of Juniperus macrocarpa and J. oxycedrus. The dominant compounds of J. macrocarpa EO, analysed by gas chromatography (GC) and gas chromatography-mass spectrometry (GC-MS), are α-pinene, sabinene, manoyl oxide, and germacrene D, whereas α-pinene, limonene, (Z,E)-farnesol, β-pinene, and γ-cadinene are the most representative volatiles of J. oxycedrus EOs. A multivariate analysis of EOs, included a selection of literature data comparing our samples to samples of J. oxycedrus/macrocarpa/deltoides from the Mediterranean area, was performed. As evident by high-performance liquid chromatography (HPLC) analyses, apigenin, (−)-epicatechin, and luteolin were abundant in J. oxycedrus extracts, while gallic acid, kaempferol-3-O-glucoside, and protocatechuic acid were the dominant constituents of J. macrocarpa extracts. EOs and extracts have been investigated for their potential antioxidant properties and anti-proliferative activity against lung adenocarcinoma (A549), breast cancer (MCF-7 and MDA-MB-231), and lung large cell carcinoma (COR-L23) human cell lines. The methanol and ethyl acetate extracts of J. oxycedrus exerted the most valuable antioxidant activity and exhibited the most promising activity against the COR-L23 cell line with an IC50 of 26.0 and 39.1 μg/mL, respectively, lower than that obtained with the positive control (IC50 of 45.5 μg/mL). To the best of our knowledge, this is the first report highlighting the anti-proliferative activity of J. oxycedrus and J. macrocarpa extracts against this lung cancer cell line. Our results indicate that J. oxycedrus may be considered a source of natural compounds with antioxidant and anti-proliferative effects that could be suitable for future applications.

IMMUNOHISTOCHEMISTRY BASED CHARACTERIZATION OF NON- SMALL CELL LUNG CARCINOMA IN A TERTIARY CARE CENTRE OF EASTERN INDIA.

NTRODUCTION- Lung malignancies are the leading cause of cancer-related mortality in industrialized countries. Lung malignancies are traditionally classied as Non-Small Cell Lung Carcinoma(NSCLC) and Small Cell Lung Carcinoma. The NSCLCs are the most common type and is further subclassied into adenocarcinoma, squamous cell carcinoma, and large cell carcinoma. This is aMATERIAL AND METHODS- cross-sectional study done between 2019 and 2021 at the tertiary cancer centre at Jharkhand. A total of 100 diagnosed cases of Non-small cell lung cancer by histopathological examination of lung biopsy are included in this study. Followed by immunohistochemistry with p63, TTF-1, Napsin A, and CK 5/6. Out of 100 cases, 60 cases were of adenocarcinoma and 40 cases of squamous cell carcinoma. Among those 60 cases ofRESULTS- adenocarcinoma, NapsinAwas positive in 85% cases and TTF-1 was positive in 93% cases, CK5/6 and p63 positivity was seen in 7 % and 8% cases respectively. Out of 40 cases of squamous cell carcinoma, 92% cases were immunoreactive for CK5/6 while p63 was positive in 85% cases, 25% cases were also positive for TTF-1. In our study, Napsin A was more specic than TTF-1 regarding the diagnosis of lungDISCUSSION- adenocarcinoma, and CK5/6, having more specicity than p63, showed signicant immunoreactivity with regards to lung squamous cell carcinoma.

Molecular target therapeutics of EGF-TKI and downstream signaling pathways in non-small cell lung cancers.

Lung carcinoma (LC) is the third most common cancer diagnosis and accounted for the most cancer-related mortality worldwide in 2018. Based on the type of cells from which it originates, LC is commonly classified into non-small cell lung cancers (NSCLC) and small cell lung cancers (SCLC). NSCLC account for the majority of LC and can be further categories into adenocarcinoma, large cell carcinoma, and squamous cell carcinoma. Accurate classification of LC is critical for its adequate treatment and therapeutic outcome. Since NSCLC express more epidermal growth factor receptor (EGFR) with activation mutations, targeted therapy EGFR-tyrosine kinase inhibitors (TKIs) have been considered as primary option of NSCLC patients with activation EGFR mutation. In this review, we present the genetic alterations, reported mutations in EGFR, and TKIs treatment in NSCLC patients with an emphasis on the downstream signaling pathways in NSCLC progression. Among the signaling pathways identified, mitogen activation protein kinase (MAPK), known also as extracellular signal-regulated protein kinase (Erk) pathway, is the most investigated among the related pathways. EGFR activation leads to the autophosphorylation of its kinase domain and subsequent activation of Ras, phosphorylation of Raf and MEK1/2, and the activation of ERK1/2. Phosphatidylinositol 3-kinase (PI3K)/Akt is another signal pathway that regulates cell cycle and has been linked to NSCLC progression. Currently, three generations of EGFR TKIs have been developed as a first-line treatment of NSCLC patients with EGFR activation and mutation in which these treatment options will be further discussed in this review. The Supplementary Appendix for this article is available at http://links.lww.com/JCMA/A138.

Research of histopathology and immunohistochemistry classification in lung cancer patients

Background: Lung cancer is the most common cancer and one of the leading causes of cancer-related deaths worldwide. In Vietnam, there have been many research associated with lung cancer, focusing mainly on the aspects of epidemiology, histopathological diagnosis and treatment therapy. The research of the expression of immunohistochemical markers to determine the immunophenotype of tumor cells in lung cancer and their relationship to histopathology and stage of the disease has not been systematically studied. Objectives: (1) To determine the expression of IHC markers in lung cancer, histopathology classification during immunohistochemistry evaluation, (2) to investigate the supplementary values of immunohistochemical test and immunophenotypes of common types of lung cancer. Materials and methods: 104 samples of patients who came for lung cancer examination and treatment at Hue Central Hospital and Hue University of Medicine and Pharmacy Hospital from October 2019 to July 2021, using cross-sectional descriptive study methods. Results: Histopathologically, the most common types were adenocarcinoma 36.5%, followed by squamous cell carcinoma (34.6%), small cell carcinoma (17.3%), and squamous cell carcinoma (17.3%), large cells carcinoma (2.9%), others (8.7%). after Immunohistochemical staining indicates that the most popular types were adenocarcinoma (48.1%), squamous cell carcinoma (24.0%), small cell carcinoma (15.4%), large cell carcinoma (3.8%), adeno-squamous cell carcinoma (1.0%) and other types (7.7%). Conclusions: Immunohistochemistry helps to determine the immunophenotype, which will contribute to the routine histopathological diagnosis of HE staining of lung cancer types, supporting targeted treatment for patients. Keywords: Lung cancer, Histopathology, Immunohistochemistry, Immunophenotype

Comprehensive Characterization of Human Lung Large Cell Carcinoma Identifies Transcriptomic Signatures with Potential Implications in Response to Immunotherapy.

Lung cancer is the leading cause of cancer mortality worldwide, with non-small cell lung cancer (NSCLC) being the most prevalent histology. While immunotherapy with checkpoint inhibitors has shown outstanding results in NSCLC, the precise identification of responders remains a major challenge. Most studies attempting to overcome this handicap have focused on adenocarcinomas or squamous cell carcinomas. Among NSCLC subtypes, the molecular and immune characteristics of lung large cell carcinoma (LCC), which represents 10% of NSCLC cases, are not well defined. We hypothesized that specific molecular aberrations may impact the immune microenvironment in LCC and, consequently, the response to immunotherapy. To that end, it is particularly relevant to thoroughly describe the molecular genotype–immunophenotype association in LCC–to identify robust predictive biomarkers and improve potential benefits from immunotherapy. We established a cohort of 18 early-stage, clinically annotated, LCC cases. Their molecular and immune features were comprehensively characterized by genomic and immune-targeted sequencing panels along with immunohistochemistry of immune cell populations. Unbiased clustering defined two novel subgroups of LCC. Pro-immunogenic tumors accumulated certain molecular alterations, showed higher immune infiltration and upregulated genes involved in potentiating immune responses when compared to pro-tumorigenic samples, which favored tumoral progression. This classification identified a set of biomarkers that could potentially predict response to immunotherapy. These results could improve patient selection and expand potential benefits from immunotherapy.

In vitro Anticancer and Antioxidant Activity of Partially Purified Poly-saccharides from Marine Bivalves Against Human Lung Cancer Cell Lines (A549 and NCI-H460)

Marine-derived bioactive polysaccharide have aroused extensive attention because of their potential nutritional and therapeutic benefits. Polysaccharides from marine molluscs have high potential as promising candidates for drug development. In this study, partially purified polysaccharide from various bivalve species were investigated for its bioactivity. Enzyme assisted extraction technique was applied for polysaccharide extraction from marine bivalves. Five papain released crude polysaccharide extracts were prepared from four clams (Donax variabilis, Donax incarnatus, Donax cuneatus, Sunetta scripta) and one mussel (Perna viridis). Initially, all five species were subjected to biochemical and proximate analyses. Five distinct partially purified polysaccharide extracts were tested in vitro for antioxidant and anticancer properties. The cytotoxicity and cell viability of five marine bivalve extracts was investigated in normal (Vero) and two lung cancer cell lines (lung adenocarcinoma (A549) and lung large cell carcinoma (NCI-H460)). In the performed antioxidant assays, almost all the polysaccharide extracts showed strong antioxidant activity in a dose dependent manner. Likewise, all the five polysaccharide extracts showed significant inhibitory effects on growth of human lung cancer cells. In particular, polysaccharide from clam Donax variabilis showed high activity in the growth inhibition of both non-small cell lung cancers. This research can be considered as the foundation for the development of a new marine-derived drug whose biological activity can be assessed by further purification and characterization of the active bio-compound.

THE PROGNOSIS OF THE DIFFERENT ESOPHAGEAL NEUROENDOCRINE CARCINOMA SUBTYPES: A POPULATION-BASED STUDY.

Neuroendocrine neoplasms are extremely rare and account for 0.4% to 2% of all malignant esophageal neoplasms. The burden of the neuroendocrine histological type on the patients' prognosis and survival is poorly debated. This study aimed to compare the survival rates of primary neuroendocrine neoplasms compared with adenocarcinoma and squamous cell carcinoma of the esophagus. This is a retrospective cohort from the Surveillance, Epidemiology, and End Results Program database. Overall survival and cancer-specific survival were evaluated with Kaplan-Meier curves and logrank tests. Proportional Cox regression models were used to evaluate variables related to overall survival. After eligibility criteria, 66,528 patients were selected. The mean follow-up was 22.6 months (SD 35.6). Adenocarcinoma was predominant (62%), followed by squamous cell carcinoma (36%). Large cell carcinoma, small cell carcinoma, and mixed adenoneuroendocrine carcinoma each account for less than 1% each. On the long-term overall survival analysis, esophageal adenocarcinoma showed a better prognosis than all the other histologic types (P-value for logrank test <0.001). With adenocarcinoma as a reference, HR was 1.32 for large cell carcinoma (95%CI 1.2 to 1.45) and 1.37 for small cell carcinoma (95%CI 1.23 to 1.53). The HR was 1.22 for squamous cell carcinoma (95%CI: 1.2 to 1.24); and 1.3 for adenoneuroendocrine carcinoma (95%CI 1.01 to 1.66). For multivariate Cox regression analysis, besides age and stage, the neuroendocrine subtypes large cell carcinoma and small cell carcinoma were considered independent prognostic variables. In the esophagus, large cell carcinoma and small cell carcinoma show poorer long-term survival rates than squamous cell carcinoma and adenocarcinoma.

Thorahcic SMARCA4-deficient undifferentiated tumors with ganglioneuroma and enchondroma: implications for SLC7A11 and ARID1A expression: a case report

BackgroundSWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin, subfamily A, member 4-deficient thoracic sarcoma (SMARCA4-DTS) is a rare disease that has recently been described as an entity. It is characterized by an aggressive clinical course and specific genetic alterations. As an immunohistological feature, the tumors are deficient in SMARCA4 and SMARCA2 and express sex-determining region Y (SRY)-box 2 (SOX2). Occasionally, there are cases that are less frequent and difficult to distinguish from SMARCA4-deficient non-small cell lung carcinoma (SMARCA4-dNSCLC). Therefore, the 5th edition of the World Health Organization (WHO) classification describes thoracic SMARCA 4-deficient undifferentiated tumors (SMARCA4-UT). In contrast, Carney’s triad is a syndrome that combines three rare soft tissue tumors: gastric leiomyosarcoma, pulmonary chondroma, and extra-adrenal paraganglioma. Protein kinase cAMP-dependent type I regulatory subunit alpha (PRKAR1A) has been proposed as the causative gene. Both diseases are valuable cases; moreover, there have been no previous reports of their coexistence.Case presentationA 43-year-old man visited our hospital because of respiratory distress. Computed tomography revealed a large mass measuring 55 mm in the upper lobe of the right lung and front mediastinum, with metastases in the surrounding lymph nodes. Needle biopsy was performed for diagnosis, and histological examination of the samples revealed monotonous epithelioid-like cells with loose binding and sheet-form proliferation. The tumor cells had distinct nuclei with some rhabdoid-like cells. Immunohistochemical analysis revealed that the tumor cells were positive for AE1AE3, SOX2, CD34, and p53 and negative for SMARCA4 and SMARCA2. The patient died 6 months after admission, without any treatment. Autopsy revealed ganglioneuroma and enchondroma suggestive of an incomplete Carney complex.ConclusionSMARCA4-UT is a rare and recently established disease. While it is difficult to diagnose, it is necessary to distinguish undifferentiated carcinoma, large cell carcinoma, Ewing sarcoma, and epithelioid sarcoma when diagnosing tumors involving the mediastinum. Moreover, cases of SMARCA4-UT with ganglioneuroma and enchondroma are very rare. We discuss and report a case of SMARCA4-UT in which we also examined ARID1A and SLC7A11expression.

Pulmonary large cell carcinoma with neuroendocrine morphology shows genetic similarity to large cell neuroendocrine carcinoma

BackgroundLarge cell neuroendocrine carcinoma (LCNEC) is a high-grade malignant pulmonary neuroendocrine tumour. The distinction of pulmonary large cell carcinoma (LCC) and LCNEC is based on the presence of neuroendocrine morphology and the expression of at least one neuroendocrine marker in at least 10% of tumour cells in the latter. According to the current classification, LCC with neuroendocrine morphology and without neuroendocrine marker expression is classified as LCC. This subgroup we have named LCNEC-null and aimed to analyze its characteristics.Methods31 surgical samples resected in West China Hospital of Sichuan University between 2017 to 2021 were collected, including 7 traditional LCCs, 11 LCNEC-nulls and 13 LCNECs. Each case was conducted to immunohistochemistry and 425-panel-NGS.ResultsCompared to other LCCs, detailed analysis of LCNEC-nulls revealed biological features similar to those of LCNECs, especially for immunohistochemistry and molecular analysis: 1. diffusive, coarse granular and high expression of Pan-CK; 2. rare PD-L1 expression; 3. High rate of p53 expression and Rb deficiency 4. abundant genetic alterations are similar to LCNEC. All characteristics above deviated from traditional LCC, indicating they have the same origin as LCNEC. Furthermore, LCNEC could be genetically divided into two subtypes when we reclassified LCNEC-null as LCNEC, and the mutational type and prognosis differed significantly.ConclusionsWe consider that LCNEC-null should be reclassified as LCNEC based on analysis above. In addition, two genetic types of LCNEC with different prognosis also indicate two mechanism of tumour formation.

Salvage surgery following immuno-chemo-radiotherapy for advanced non-small cell lung cancer

BackgroundSalvage surgery following definitive radiotherapy or systemic treatment has become a feasible treatment option in selected patients with advanced initially unresectable non-small cell lung cancer. Recent clinical trials of neoadjuvant treatment have showed that surgery following immuno-chemotherapy is safely performed. Here, we present the first case of salvage surgery following immuno-chemotherapy with concurrent definitive radiotherapy for advanced lung large cell carcinoma.Case presentationA 44-year male was admitted to our hospital for salvage surgery. Ten months prior to this administration, he had been diagnosed with unresectable large cell carcinoma with malignant pericardial effusion (clinical stage IVA/T3N2M1A; no driver-gene alteration) originating from the right upper lobe (RUL). Due to rapid intrabronchial tumor growth causing severe dyspnea, emergency bronchial stenting in the right main bronchus using an expandable metallic stent had been performed. Thereafter, he had received immuno-chemotherapy with concurrent definitive radiotherapy. Despite dramatic radiographic response, he had suffered from persistent and refractory Pseudomonas aeruginosa lung infection associated with bronchial stent placement. As pericardial effusion had disappeared and no distant metastasis had developed, he was diagnosed with a potentially curable disease and was referred to our hospital. An extended sleeve resection was successfully performed, and pathological sections revealed that pathologic complete response was achieved with immuno-chemo-radiotherapy. The patient received no subsequent treatment, and is alive without tumor recurrence at 8 months after surgery.ConclusionsSalvage surgery following immuno-chemotherapy with concurrent definitive radiotherapy for advanced non-small cell lung cancer may be feasible in selected patients, and may be considered as a treatment option to control local disease.