Genomic characterization and immunotherapy for microsatellite instability-high in cholangiocarcinoma.

BACKGROUND: Microsatellite instability-high (MSI-H) is a unique genomic status in many cancers. However, its role in the genomic features and immunotherapy in cholangiocarcinoma (CCA) is unclear. This study aimed to systematically investigate the genomic characterization and immunotherapy efficacy of MSI-H patients with CCA. METHODS: We enrolled 887 patients with CCA in this study. Tumor samples were collected for next-generation sequencing. Differences in genomic alterations between the MSI-H and microsatellite stability (MSS) groups were analyzed. We also investigated the survival of PD-1 inhibitor-based immunotherapy between two groups of 139 patients with advanced CCA. RESULTS: Differential genetic alterations between the MSI-H and MSS groups included mutations in ARID1A, ACVR2A, TGFBR2, KMT2D, RNF43, and PBRM1 which were enriched in MSI-H groups. Patients with an MSI-H status have a significantly higher tumor mutation burden (TMB) (median 41.7 vs. 3.1 muts/Mb, P < 0.001) and more positive programmed death ligand 1 (PD-L1) expression (37.5% vs. 11.9%, P < 0.001) than those with an MSS status. Among patients receiving PD-1 inhibitor-based therapy, those with MSI-H had a longer median overall survival (OS, hazard ratio (HR) = 0.17, P = 0.001) and progression-free survival (PFS, HR = 0.14, P < 0.001) than patients with MSS. Integrating MSI-H and PD-L1 expression status (combined positive score ≥ 5) could distinguish the efficacy of immunotherapy. CONCLUSIONS: MSI-H status was associated with a higher TMB value and more positive PD-L1 expression in CCA tumors. Moreover, in patients with advanced CCA who received PD-1 inhibitor-based immunotherapy, MSI-H and positive PD-L1 expression were associated with improved both OS and PFS. TRIAL REGISTRATION: This study was registered on ClinicalTrials.gov on 07/01/2017 (NCT03892577).

Knockdown of NCAPD3 inhibits the tumorigenesis of non-small cell lung cancer by regulation of the PI3K/Akt pathway.

BACKGROUND: Accumulating evidence indicates that aberrant non-SMC condensin II complex subunit D3 (NCAPD3) is associated with carcinogenesis of various cancers. Nevertheless, the biological role of NCAPD3 in the pathogenesis of non-small cell lung cancer (NSCLC) remains unclear. METHODS: Immunohistochemistry and Western blot were performed to assess NCAPD3 expression in NSCLC tissues and cell lines. The ability of cell proliferation, invasion, and migration was evaluated by CCK-8 assays, EdU assays, Transwell assays, and scratch wound healing assays. Flow cytometry was performed to verify the cell cycle and apoptosis. RNA-sequence and rescue experiment were performed to reveal the underlying mechanisms. RESULTS: The results showed that the expression of NCAPD3 was significantly elevated in NSCLC tissues. High NCAPD3 expression in NSCLC patients was substantially associated with a worse prognosis. Functionally, knockdown of NCAPD3 resulted in cell apoptosis and cell cycle arrest in NSCLC cells as well as a significant inhibition of proliferation, invasion, and migration. Furthermore, RNA-sequencing analysis suggested that NCAPD3 contributes to NSCLC carcinogenesis by regulating PI3K/Akt/FOXO4 pathway. Insulin-like growth factors-1 (IGF-1), an activator of PI3K/Akt signaling pathway, could reverse NCAPD3 silence-mediated proliferation inhibition and apoptosis in NSCLC cells. CONCLUSION: NCAPD3 suppresses apoptosis and promotes cell proliferation via the PI3K/Akt/FOXO4 signaling pathway, suggesting a potential use for NCAPD3 inhibitors as NSCLC therapeutics.

Association of interleukin-6, ferritin, and lactate dehydrogenase with venous thromboembolism in COVID-19: a systematic review and meta-analysis.

BACKGROUND: Coronavirus disease 2019 (COVID-19) is frequntly accompanied by venous thromboembolism (VTE), and its mechanism may be related to the abnormal inflammation and immune status of COVID-19 patients. It has been proved that interleukin-6 (IL-6), ferritin and lactate dehydrogenase (LDH) may play an important role in the occurrence of VTE in COVID-19 infection. But whether they can server as predictors for VTE in COVID-19 is still unclear. In this study, we performed a systematic review and meta-analysis to compare IL-6, ferritin and LDH in VTE and non-VTE COVID-19 patients in order to shed light on the prevention and treatment of VTE. METHODS: Related literatures were searched in PubMed, Embase, Web of Science, Google Scholar, China National Knowledge Infrastructure (CNKI), WANGFANG. COVID-19 patients were divided into VTE group and non-VTE group. Meta-analysis was then conducted to compare levels of IL-6, ferritin and LDH between the two groups. RESULTS: We finally included and analyzed 17 literatures from January 2019 to October 2022. There was a total of 7,035 COVID-19 patients, with a weighted mean age of 60.01 years. Males accounted for 62.64% and 61.34% patients were in intensive care unit (ICU). Weighted mean difference (WMD) of IL-6, ferritin and LDH was 31.15 (95% CI: 9.82, 52.49), 257.02 (95% CI: 51.70, 462.33) and 41.79 (95% CI: -19.38, 102.96), respectively. The above results indicated that than compared with non-VTE group, VTE group had significantly higher levels of IL-6 and ferritin but similar LDH. CONCLUSION: This systematic review and meta-analysis pointed out that elevated levels of IL-6 and ferritin were significantly possitive associated with VTE, thus could be used as biological predictive indicators of VTE among COVID-19 patients. However, no association was found between level of LDH and VTE. Therefore, close monitoring of changes in IL-6 and ferritin concentrations is of great value in assisting clinicans to rapidly identify thrombotic complications among COVID-19 patients, hence facilitating the timely effective managment. Further studies are required in terms of the clinical role of cytokines in the occurrence of VTE among COVID-19 infection, with more reliable systematic controls and interventional trials.

[Application of electrical impedance tomography imaging technology combined with generative adversarial network in pulmonary ventilation monitoring].

Electrical impedance tomography (EIT) plays a crucial role in the monitoring of pulmonary ventilation and regional pulmonary function test. However, the inherent ill-posed nature of EIT algorithms results in significant deviations in the reconstructed conductivity obtained from voltage data contaminated with noise, making it challenging to obtain accurate distribution images of conductivity change as well as clear boundary contours. In order to enhance the image quality of EIT in lung ventilation monitoring, a novel approach integrating the EIT with deep learning algorithm was proposed. Firstly, an optimized operator was introduced to enhance the Kalman filter algorithm, and Tikhonov regularization was incorporated into the state-space expression of the algorithm to obtain the initial lung image reconstructed. Following that, the imaging outcomes were fed into a generative adversarial network model in order to reconstruct accurate lung contours. The simulation experiment results indicate that the proposed method produces pulmonary images with clear boundaries, demonstrating increased robustness against noise interference. This methodology effectively achieves a satisfactory level of visualization and holds potential significance as a reference for the diagnostic purposes of imaging modalities such as computed tomography.

Single-cell RNA sequencing in cancer research: discovering novel biomarkers and therapeutic targets for immune checkpoint blockade.

Immune checkpoint blockade (ICB) has become a promising strategy in treating advanced cancers, providing significant survival benefits for patients with various cancer types. However, among the vast population of cancer patients, only a small fraction are able to respond to and derive benefits from ICB therapy. Numerous factors contribute to the diminished efficacy of ICB, with the complex tumor microenvironment (TME) playing an important role. Therefore, comprehensively understanding the intricate composition of the TME is critical for elucidating the mechanisms that underlie distinct responses to ICB in patients. Single-cell RNA sequencing (scRNA-seq) is a novel technique that reveals gene expression profiles of individual cells, facilitating the investigation of TME heterogeneity at a high resolution and the identification of key cell subsets participating in the response to ICB. This review emphasizes the importance of scRNA-seq in studying ICB and summarizes recent findings in the discovery of biomarkers that predict ICB response and novel potential therapeutic targets for immunotherapy. These findings suggest future directions for the clinical implementation of cancer immunotherapy, facilitating further advancements in precision medicine.

Isolated crater-like tumour in a renal transplant recipient.

Compared with asymptomatic pulmonary cryptococcosis, secondary cutaneous cryptococcosis may be the first clinical manifestation of disseminated infection but it can be difficult to diagnose clinically. The clinical manifestation of cutaneous cryptococcosis is not pathognomonic, varying from nodules to ulcers and plaques, and frequently mimics other pathologies. This case highlights that an isolated tumour can be an initial manifestation of systemic cryptococcosis in a kidney transplant patient.

ARHGAP10 inhibits the epithelial-mesenchymal transition of non-small cell lung cancer by inactivating PI3K/Akt/GSK3ß signaling pathway.

BACKGROUND: Rho GTPase activating protein 10 (ARHGAP10) has been implicated as an essential element in multiple cellular process, including cell migration, adhesion and actin cytoskeleton dynamic reorganization. However, the correlation of ARHGAP10 expression with epithelial-mesenchymal transition (EMT) in lung cancer cells is unclear and remains to be elucidated. Herein, we investigated the relationship between the trait of ARHGAP10 and non-small cell lung cancer (NSCLC) pathological process. METHODS: Immunohistochemistry was conducted to evaluate the expression of ARHGAP10 in NSCLC tissues. CCK-8 assays, Transwell assays, scratch assays were applied to assess cell proliferation, invasion and migration. The expression levels of EMT biomarkers and active molecules involved in PI3K/Akt/GSK3ß signaling pathway were examined through immunofluorescence and Western blot. RESULTS: ARHGAP10 was detected to be lower expression in NSCLC tissues compared with normal tissues from individuals. Moreover, overexpression of ARHGAP10 inhibited migratory and invasive potentials of A549 and NCI-H1299 cells. In addition, ARHGAP10 directly mediated the process of EMT via PI3K/Akt/GSK3ß pathway. Meanwhile, activation of the signaling pathway of insulin-like growth factors-1 (IGF-1) reversed ARHGAP10 overexpression regulated EMT in NSCLC cells. CONCLUSION: ARHGAP10 inhibits the epithelial-mesenchymal transition in NSCLC via PI3K/Akt/GSK3ß signaling pathway, suggesting agonist of ARHGAP10 may be an optional remedy for NSCLC patients than traditional opioids.

Short-chain fatty acid, acylation and cardiovascular diseases.

Cardiovascular diseases (CVDs) are the leading cause of morbidity and mortality worldwide. Metabolic dysfunction is a fundamental core mechanism underlying CVDs. Previous studies generally focused on the roles of long-chain fatty acids (LCFAs) in CVDs. However, a growing body of study has implied that short-chain fatty acids (SCFAs: namely propionate, malonate, butyrate, 2-hydroxyisobutyrate (2-HIBA), ß-hydroxybutyrate, crotonate, succinate, and glutarate) and their cognate acylations (propionylation, malonylation, butyrylation, 2-hydroxyisobutyrylation, ß-hydroxybutyrylation, crotonylation, succinylation, and glutarylation) participate in CVDs. Here, we attempt to provide an overview landscape of the metabolic pattern of SCFAs in CVDs. Especially, we would focus on the SCFAs and newly identified acylations and their roles in CVDs, including atherosclerosis, hypertension, and heart failure.

A Ratiometric Fluorescent Bioprobe Based on Carbon Dots and Acridone Derivate for Signal Amplification Detection Exosomal microRNA.

Recently, sensitive and selective detection of exosomal microRNAs (miRNAs) has been garnering significant attention, because it is related to many complex diseases, including cancer. Herein, we report a ratiometric fluorescent bioprobe based on DNA-labeled carbon dots (DNA-CDs) and 5,7-dinitro-2-sulfo-acridone (DSA) coupling with the target-catalyzing signal amplification for the detection of exosomal miRNA-21. There was high fluorescence resonance energy transfer (FRET) efficiency between carbon dots (CDs) and DSA when the bioprobe was assembled. However, in the presence of the target, with disassembling of the fluorescent bioprobe, the fluorescence intensities of CDs and DSA were changed simultaneously. Because of the ratio of dual fluorescence intensities, this ratiometric fluorescent bioprobe was able to cancel out environmental fluctuations by calculating emission intensity ratio at two different wavelengths, being robust and stable enough for detection of exosomal miRNA-21. In addition, we displayed that a single miRNA-21 can catalyze the disassembly of multiple CDs with DSA theoretically, yielding significant change in the fluorescence ratio for the detection of miRNA-21. With this signal amplification strategy, the limit of detection was as low as 3.0 fM. Furthermore, because of the introduction of lock nucleic acid to mediate the strand displacement reaction, the selectivity of this strategy was improved remarkably, even against single base mismatch sequence. More importantly, our strategy could monitor the dynamic change of exosomal miRNA-21, which maybe becomes a potential tool to distinguish cancer exosomes and nontumorigenic exosomes. In a short, this ratiometric fluorescence bioprobe possessed high stability, sensitivity and selectivity coupling with ease of operation and cost efficiency, leading to great potential for wide application.

Critical limitations of prognostic signatures based on risk scores summarized from gene expression levels: a case study for resected stage I non-small-cell lung cancer.

Most of current gene expression signatures for cancer prognosis are based on risk scores, usually calculated as some summaries of expression levels of the signature genes, whose applications require presetting risk score thresholds and data normalization. In this study, we demonstrate the critical limitations of such type of signatures that the risk scores of samples will change greatly when they are normalized together with different samples, which would induce spurious risk classification and difficulty in clinical settings, and the risk scores of independent samples are incomparable if data normalization is not adopted. To overcome these limitations, we propose a rank-based method to extract a prognostic gene pair signature for overall survival of stage I non-small-cell lung cancer. The prognostic gene pair signature is verified in three integrated data sets detected by different laboratories with different microarray platforms. We conclude that, different from the type of signatures based on risk scores summarized from gene expression levels, the rank-based signatures could be robustly applied at the individualized level to independent clinical samples assessed in different laboratories.

Stem cells with FGF4-bFGF fused gene enhances the expression of bFGF and improves myocardial repair in rats.

The aim of this study was to investigate whether the modification of bone marrow-derived mesenchymal stem cells (BMSCs) with the fused FGF4 (fibroblast growth factor 4)-bFGF (basic fibroblast growth factor) gene could improve the expression and secretion of BFGF, and increase the efficacies in repairing infarcted myocardium. We used In-Fusion technique to construct recombinant lentiviral vectors containing the individual gene of bFGF, enhanced green fluorescent protein (EGFP), or genes of FGF4-bFGF and EGFP, and then transfected these lentiviruses into rat BMSCs. We conducted an in vitro experiment to compare the secretion of bFGF in BMSCs infected by these lentiviruses and also examined their therapeutic effects in the treatment of myocardial infraction in a rodent study. Sixty rats were tested in the following five conditions: Group-SHAM received only sham operation as controls; Group-AMI received only injection of placebo PBS buffer; Group-BMSC, Group-bFGF and Group-FGF4-bFGF received implantation of BMSCs with empty lentivirus, bFGF lentivirus, and FGF4-bFGF lentivirus, respectively. Our results found out that the transplanted FGF4-bFGF BMSCs had the highest survival rate, and also the highest myocardial expression of bFGF and microvascular density as evidenced by Western blotting and immunohistochemistry, respectively. As compared to other groups, the Group-FGF4-BFGF rats had the lowest myocardial fibrotic fraction, and the highest left ventricular ejection fraction. These results suggest that the modification of BMSCs with the FGF4-bFGF fused gene can not only increase the expression of bFGF but also improve its secretion. The FGF4-bFGF BMSCs thus can enhance the survival of the transplanted cells, diminish myocardial fibrosis, promote myocardial angiogenesis, and improve cardiac functions.

Coronary effluent from postconditioned hearts promotes survival of mesenchymal stem cells under hypoxia.

OBJECTIVES: Mesenchymal stem cells are sensitive to hypoxia under myocardial micro-environment of ischemia and reperfusion. Ischemic postconditioning, which is cardioprotective against ischemia-reperfusion injury, enhances in-vivo survival and therapeutic effects of transplanted stem cells. In this study, we investigated the effects of coronary effluent from postconditioned rat hearts on proliferation and survival of mesenchymal stem cells in vitro under hypoxia. DESIGN: Isolated perfused rat hearts were divided into three groups (n = 6): the Sham group--receiving a 90 min perfusion; the Control group--receiving a 30 min global ischemia followed by a 60 min reperfusion; the ischemic postconditioning group--before sustained reperfusion, 3 cycles of 30 s reperfusion and 30 s ischemia were performed. Inflammation-related factors in coronary effluent were assessed by ELISA. Mesenchymal stem cells from bone marrow of Sprague-Dawley rats were cultured with coronary effluent under hypoxia (95% nitrogen, 5% carbon dioxide, and < 1% oxygen) for 6- or 18 h. Cell proliferation was determined by methyl thiazolyl tetrazolium. Survival rate was measured by Annexin V/PI. RESULTS: Compared with ischemia-reperfusion treatment alone, postconditioning treatment increased the level of interleukin-10 and decreased the level of tumor necrosis factor-α and interleukin-1ß in coronary effluent (P < 0.01). Stem cells cultured with postconditioned effluent, compared with those with ischemia-reperfusion effluent, had a higher proliferation (optical density value), more surviving cells, and less necrosis (P < 0.01). CONCLUSIONS: Coronary effluent from postconditioned hearts may promote the proliferation and survival of mesenchymal stem cells under hypoxia, and the suppression of inflammation may be involved in this process.

Role and mechanism of NCAPD3 in promoting malignant behaviors in gastric cancer.

Background: Gastric cancer (GC) is one of the major malignancies threatening human lives and health. Non-SMC condensin II complex subunit D3 (NCAPD3) plays a crucial role in the occurrence of many diseases. However, its role in GC remains unexplored. Materials and Methods: The Cancer Genome Atlas (TCGA) database, clinical samples, and cell lines were used to analyze NCAPD3 expression in GC. NCAPD3 was overexpressed and inhibited by lentiviral vectors and the CRISPR/Cas9 system, respectively. The biological functions of NCAPD3 were investigated in vitro and in vivo. Gene microarray, Gene set enrichment analysis (GSEA) and ingenuity pathway analysis (IPA) were performed to establish the potential mechanisms. Results: NCAPD3 was highly expressed in GC and was associated with a poor prognosis. NCAPD3 upregulation significantly promoted the malignant biological behaviors of gastric cancer cell, while NCAPD3 inhibition exerted a opposite effect. NCAPD3 loss can directly inhibit CCND1 and ESR1 expression to downregulate the expression of downstream targets CDK6 and IRS1 and inhibit the proliferation of gastric cancer cells. Moreover, NCAPD3 loss activates IRF7 and DDIT3 to regulate apoptosis in gastric cancer cells. Conclusion: Our study revealed that NCAPD3 silencing attenuates malignant phenotypes of GC and that it is a potential target for GC treatment.

Endothelial H2S-AMPK dysfunction upregulates the angiocrine factor PAI-1 and contributes to lung fibrosis.

Dysfunction of the vascular angiocrine system is critically involved in regenerative defects and fibrosis of injured organs. Previous studies have identified various angiocrine factors and found that risk factors such as aging and metabolic disorders can disturb the vascular angiocrine system in fibrotic organs. One existing key gap is what sense the fibrotic risk to modulate the vascular angiocrine system in organ fibrosis. Here, using human and mouse data, we discovered that the metabolic pathway hydrogen sulfide (H2S)-AMP-activated protein kinase (AMPK) is a sensor of fibrotic stress and serves as a key mechanism upregulating the angiocrine factor plasminogen activator inhibitor-1 (PAI-1) in endothelial cells to participate in lung fibrosis. Activation of the metabolic sensor AMPK was inhibited in endothelial cells of fibrotic lungs, and AMPK inactivation was correlated with enriched fibrotic signature and reduced lung functions in humans. The inactivation of endothelial AMPK accelerated lung fibrosis in mice, while the activation of endothelial AMPK with metformin alleviated lung fibrosis. In fibrotic lungs, endothelial AMPK inactivation led to YAP activation and overexpression of the angiocrine factor PAI-1, which was positively correlated with the fibrotic signature in human fibrotic lungs and inhibition of PAI-1 with Tiplaxtinin mitigated lung fibrosis. Further study identified that the deficiency of the antioxidative gas metabolite H2S accounted for the inactivation of AMPK and activation of YAP-PAI-1 signaling in endothelial cells of fibrotic lungs. H2S deficiency was involved in human lung fibrosis and H2S supplement reversed mouse lung fibrosis in an endothelial AMPK-dependent manner. These findings provide new insight into the mechanism underlying the deregulation of the vascular angiocrine system in fibrotic organs.

Effect of anticoagulation on the incidence of venous thromboembolism, major bleeding, and mortality among hospitalized COVID-19 patients: an updated meta-analysis.

Objective: Anticoagulation is crucial for patients hospitalized with coronavirus disease 2019 (COVID-19) due to the high risk of venous thromboembolism (VTE). However, the optimal anticoagulation regimen needs further exploration. Therefore, we evaluated the efficacy and safety of diverse anticoagulation dosage dosages for COVID-19. Methods: An updated meta-analysis was performed to assess the effect of thromboprophylaxis (standard, intermediate, and therapeutic dose) on the incidence of VTE, mortality and major bleeding among COVID-19 patients. Literature was searched via PubMed, EMBASE, Web of Science, and China National Knowledge Infrastructure (CNKI) database. The odds ratio (OR) and 95% confidence interval (CI) were calculated for effect estimates. Results: Nineteen studies involving 25,289 participants without VTE history were included. The mean age of patients was 59.3 years old. About 50.96% were admitted to the intensive care unit. In the pooled analysis, both therapeutic-dose and intermediate-dose anticoagulation did not have a significant advantage in reducing VTE risk over standard dosage (OR = 1.09, 95% CI: 0.58-2.02, and OR = 0.89, 95% CI: 0.70-1.12, respectively). Similarly, all-cause mortality was not further decreased in either therapeutic-dose group (OR = 1.12, 95% CI: 0.75-1.67) or intermediate-dose group (OR = 1.34, 95% CI: 0.83-2.17). While the major bleeding risk was significantly elevated in the therapeutic-dose group (OR = 2.59, 95%CI: 1.87-3.57) as compared with the standard-dose regimen. Compared with intermediate dosage, therapeutic anticoagulation did not reduce consequent VTE risk (OR = 0.85, 95% CI: 0.52-1.38) and all-cause mortality (OR = 0.84, 95% CI: 0.60-1.17), but significantly increased major bleeding rate (OR = 2.42, 95% CI: 1.58-3.70). In subgroup analysis of patients older than 65 years, therapeutic anticoagulation significantly lowered the incidence of VTE in comparation comparison with standard thromboprophylaxis, however, at the cost of elevated risk of major bleeding. Conclusion: Our results indicated that for most hospitalized patients with COVID-19, standard-dose prophylactic anticoagulation might be the optimal choice. For elderly patients at low risk of bleeding, therapeutic-dose anticoagulation could further reduce VTE risk and should be considered especially when there were other strong risk factors of VTE during hospital stay. Systematic Review Registration: https://www.crd.york.ac.uk/PROSPERO, identifier, CRD42023388429.

Thyroid Dysfunction in Non-Small Cell Lung Cancer With Immune Checkpoint Inhibitors: A Meta-Analysis.

Immune checkpoint inhibitors (ICIs) have been established as the cornerstone for advanced non-small cell lung cancer, while thyroid adverse events (AEs) associated with ICIs have not been systematically documented. Therefore, we performed a meta-analysis to evaluate the effect of ICI applications on the thyroid of patients with non-small cell lung cancer. We performed a systematic search of PubMed, the Cochrane Library, Web of Science, and Embase for eligible randomized controlled trials up to December 2021. Clinical trials reporting thyroid AEs including hypothyroidism, hyperthyroidism, and thyroiditis were enrolled. The I2  statistic was also calculated to quantify the heterogeneity. Data were evaluated as risk ratio (RR) and corresponding 95%CIs. A total of 10 randomized clinical trials involving 6154 patients were included in this meta-analysis. ICI application was found to have a statistically significant higher risk of all grade hypothyroidism (RR, 7.03; P < 0.0001), hyperthyroidism (RR, 4.88; P < 0.0001), and thyroiditis (RR, 6.58; P = 0.0014) compared with the chemotherapy group. Moreover, we demonstrated that second-line therapy significantly increased the risk of all-grade hypothyroidism (RR, 7.03 [95%CI, 4.69-10.55]) and hyperthyroidism (RR, 4.88 [95%CI, 3.11-7.65]). Our meta-analysis manifested that regimens with ICIs may significantly increase all grades of hypothyroidism, hyperthyroidism, and thyroiditis. ICIs may induce the occurrence and exacerbation of endocrine AEs compared with chemotherapy.

Risk factors and prognostic factors for pulmonary large cell neuroendocrine carcinoma with brain metastasis.

BACKGROUND: As the studies regarding the brain metastasis (BM) of pulmonary large cell neuroendocrine carcinoma (LCNEC) are insufficient, the present research aims to describe the risk factors and prognostic factors that are related to cancer-specific survival (CSS) for LCNEC patients with BM. METHODS: The data of LCNEC patients between January 2010 and October 2018 were obtained from the SEER database. Binary logistic regression analyses were utilized to screen the possible risk factors related to BM. Prognostic factors for LCNEC patients with BM were indentified by Cox regression analyses. Moreover, a nomogram was established to predict the 6-, 12-, and 18-month CSS rates. The concordance index (C-index), receiver operating characteristic (ROC) curves and calibration curves were utilized to assess the discrimination and reliability of the model. Clinical decision curves (DCAs) were used to evaluate the clinical benefits and utility of our model. RESULTS: Totally, 1875 patients were enrolled, with 294 (15.7%) of them having BM at diagnosis. Multivariate logistic regression analyses revealed that patients with age < 65 (odds ratio, OR = 1.564) and N2 staging (OR = 1.775) had a greater chance of developing BM. Age (≥ 65 vs. < 65: hazard ratio, HR = 1.409), T staging (T1 vs. T0: HR = 4.580; T2 vs. T0: HR = 6.008; T3 vs. T0: HR = 7.065; T4 vs. T0: HR = 6.821), N staging (N2 vs. N0: HR = 1.592; N3 vs. N0: HR = 1.654), liver metastasis (HR = 1.410), primary site surgery (HR = 0.581) and chemotherapy (HR = 0.452) were independent prognostic factors for LCNEC patients with BM. A nomogram prediction model was constructed by incorporating these factors. Using the C-index, calibration curves, ROC curves, and DCAs, we found that the clinical prediction model performed well. CONCLUSION: We described the risk factors and prognostic factors that were associated with CSS for LCNEC patients with BM. The related nomogram was established and validated to help clinicians formulate more rational and effective treatment strategies.

Case report: Clinical management of recurrent small cell lung cancer transformation complicated with lung cancer-induced acute pancreatitis after lung adenocarcinoma surgery.

In the diagnosis and treatment of non-small cell lung cancer (NSCLC), the histological type may change from lung adenocarcinoma to lung squamous cell cancer or small cell lung cancer (SCLC). Pancreatic metastasis is extremely rare in advanced lung cancer, and pancreatitis characterized by lung cancer metastasis-induced acute pancreatitis (MIAP) is more rare. This paper reports in detail the clinical diagnosis and treatment of a female patient with lung adenocarcinoma who relapsed after radical surgery and progressed after multiple treatments. A second pathological biopsy revealed SCLC transformation, and the patient developed pancreatic metastasis and lung cancer MIAP during follow-up treatment. This paper mainly suggests that clinicians should pay attention to the possibility of pathological type transformation in the progression of advanced NSCLC, closely observe the dynamic changes of tumor markers and pay attention to the re-biopsy pathological analysis. In addition, it provides clinical experience and scientific reference for the discovery, diagnosis and treatment of transforming SCLC and lung cancer MIAP.