Asymptomatic Esophageal Necrosis in a Patient with Recent COVID-19: The First Case Diagnosed through Autopsy.

Acute esophageal necrosis is a rare condition, characterized by a distinctive endoscopic/necropsic image-circumferential black area of the esophagus. This paper presents a case of a 78-year-old patient with recent history of a severe form of COVID-19 (2 months previously), with multiple comorbidities, which presents sudden death in hospital. Anatomic-pathological autopsy showed extensive esophageal necrosis, pulmonary thromboses, and coronarian and aortic atherosclerosis. The histopathological examination revealed necrosis of the esophageal mucosa and phlegmonous inflammation extended to the mediastinum, chronic pneumonia with pulmonary fibrosis, viral myocarditis, papillary muscle necrosis, and pericoronary neuritis. Thromboses and necroses were identified also in the liver, pancreas, and adrenal glands. Post-COVID-19 thromboses can manifest late, affecting various vascular territories, including esophageal ones. Their clinical picture may be diminished or absent in elderly and/or diabetic patients.

Multiple Faces of the Glioblastoma Microenvironment.

The tumor microenvironment is a highly dynamic accumulation of resident and infiltrating tumor cells, responsible for growth and invasion. The authors focused on the leading-edge concepts regarding the glioblastoma microenvironment. Due to the fact that the modern trend in the research and treatment of glioblastoma is represented by multiple approaches that target not only the primary tumor but also the neighboring tissue, the study of the microenvironment in the peritumoral tissue is an appealing direction for current and future therapies.

COVID-19 and Pneumocystis jirovecii Pulmonary Coinfection-The First Case Confirmed through Autopsy.

Background: Establishing the diagnosis of COVID-19 and Pneumocystisjirovecii pulmonary coinfection is difficult due to clinical and radiological similarities that exist between the two disorders. For the moment, fungal coinfections are underestimated in COVID-19 patients. Case presentation: We report the case of a 52-year-old male patient, who presented to the emergency department for severe dyspnea and died 17 h later. The RT-PCR test performed at his admission was negative for SARS-CoV-2. Retesting of lung fragments collected during autopsy revealed a positive result for SARS-CoV-2. Histopathological examination showed preexisting lesions, due to comorbidities, as well as recent lesions: massive lung thromboses, alveolar exudate rich in foam cells, suprapleural and intra-alveolar Pneumocystisjirovecii cystic forms, and bilateral adrenal hemorrhage. Conclusion: COVID-19 and P.jirovecii coinfection should be considered, particularly in critically ill patients, and we recommend the systematic search for P. jirovecii in respiratory samples.

Physalis alkekengi L. Extract Reduces the Oxidative Stress, Inflammation and Apoptosis in Endothelial Vascular Cells Exposed to Hyperglycemia.

To find new natural remedies in diabetes, this study investigated the biological activity of two extracts obtained from the fruits (PhyF) and herba (PhyH) of Physalis alkekengi var. franchetii L. on human umbilical vein endothelial cells (HUVECs) exposed to normo- and hyperglycemic conditions. The biological effect was quantified by malondialdehyde, IL-31 and IL-33 levels in correlation with physico-chemical characterization and antioxidant activity. Additionally, from PhyP extract, the caspase-3, IL-6, IL-10, tumor necrosis factor (TNF)-α and nuclear transcription factor NFkB expressions were evaluated. HPLC analysis revealed a significant number of phenolic compounds, especially in PhyF extract, with a good antioxidant activity as highlighted by TEAC, CUPRAC or DPPH methods. On HUVECS cells, the extracts were not toxic even at high concentrations. Particularly PhyF extract, diminished lipid peroxidation and inhibited the IL-31 and IL-33 secretions induced by hyperglycemia. The inhibitory effect on proinflammatory cytokines was noticed after both doses of PhyF extract in parallel with the upregulation of anti-inflammatory cytokine IL-10. Moreover, PhyF, especially in a low dose, reduced caspase-3 active form. These experimental findings suggest that Physalis fruits extract exerted beneficial effects in hyperglycemia by inhibition of oxidative stress, inflammation and apoptosis being a good adjuvant option in diabetes.

Hypoxia: Overview on Hypoxia-Mediated Mechanisms with a Focus on the Role of HIF Genes.

Hypoxia represents a frequent player in a number of malignancies, contributing to the development of the neoplastic disease. This review will discuss the means by which hypoxia powers the mechanisms behind cancer progression, with a majority of examples from lung cancer, the leading malignancy in terms of incidence and mortality rates (the frequent reference toward lung cancer is also for simplification purposes and follow up of the global mechanism in the context of a disease). The effects induced by low oxygen levels are orchestrated by hypoxia-inducible factors (HIFs) which regulate the expression of numerous genes involved in cancer progression. Hypoxia induces epithelial-to-mesenchymal transition (EMT) and metastasis through a complex machinery, by mediating various pathways such as TGF-ß, PI3k/Akt, Wnt, and Jagged/Notch. Concomitantly, hypoxic environment has a vast implication in angiogenesis by stimulating vessel growth through the HIF-1α/VEGF axis. Low levels of oxygen can also promote the process through several other secondary factors, including ANGPT2, FGF, and HGF. Metabolic adaptations caused by hypoxia include the Warburg effect-a metabolic switch to glycolysis-and GLUT1 overexpression. The switch is achieved by directly increasing the expression of numerous glycolytic enzymes that are isoforms of those found in non-malignant cells.

Repositioning metformin in cancer: genetics, drug targets, and new ways of delivery.

After sitting many years on the shelves of drug stores as a harmless antidiabetic drug, metformin comes back in the spotlight of the scientific community as a surprisingly effective antineoplastic drug. Metformin targets multiple pathways that play pivotal roles in cancer progression, impacting various cellular processes, such as proliferation, cell death, metabolism, and even the cancer stemness features. The biomolecular characteristics of tumors, such as appropriate expression of organic cation transporters or genetic alterations including p53, K-ras, LKB1, and PI3K may impact metformin's anticancer efficiency. This could indicate a need for tumor genetic profiling in order to identify patients most likely to benefit from metformin treatment. Considering that the majority of experimental models suggest that higher, supra-clinical doses of metformin should be used in order to obtain an antineoplastic effect, new ways of drug delivery could be developed, such as metformin-loaded nanoparticles or incorporation of metformin into microparticles used in transarterial chemoembolization, with the aim of obtaining higher intratumoral drug concentrations and a targeted therapy which will ultimately maximize metformin's efficacy.

The role of depression and neuroimmune axis in the prognosis of cancer patients.

New exciting research in psycho-oncology has shed light on the mechanisms by which biobehavioral signaling in cancer interplays with the neuroimmune axis, as well as on the progression and mortality of cancer patients. Cancer and cancer therapy can collectively result in inflammation and cytokine production, which have been associated with occurrence of depression. Conversely, depression supports a chronic activated hypothalamopituitary-adrenal axis (HPA) and further determines cortisol and adrenal disturbances, as well as immune dysfunction and increased cytokine production. Through these processes, depression is associated with a worse cancer outcome. New treatment strategies which counter the aberrant pathways between depression and cancer, such as drugs that target cytokines, pro-inflammatory signaling, neuroendocrine, metabolic pathways and sympathetic activation, might disrupt important vehicles for cancer progression. In this review, we emphasize the major pathways that link inflammation, depression and immunity, in order to highlight potential therapeutic strategies which may become of paramount importance to those depressed individuals with cancer that have a higher risk for developing a more aggressive disease.

Metformin plus sorafenib highly impacts temozolomide resistant glioblastoma stem-like cells.

PURPOSE: Glioblastoma stem cells (GSCs), responsible for the dismal disease prognosis after conventional treatments, are driven by overactive signaling pathways, such as PI3K/ AKT/mTOR and RAS/RAF/MAPK. The objective of our study was to target in vitro-GSCs by combining metformin (Met) as a mTOR inhibitor, with sorafenib (Soraf) as a RAF inhibitor. METHODS: GSCs cultured under basal conditions were treated with Met, temozolomide (TMZ), Soraf, Met+TMZ and Met+Soraf; as untreated arm served as control. At 4 hrs of drug exposure, we measured the level of reactive oxygen species (ROS) by 2',7'-dichlorofluorescein diacetate (DCFDA) assay, apoptosis by prodium iodide (PI)-V Annexin staining and efflux pump activity by using the fluorescent dye rhodamine 123. At 24 hrs, we measured cell proliferation by 3-(4,5-dimethylthiazolyl-2)-2,5-diphenyltetrazolium bromide (MTT) assay, apoptosis and malondialdehyde (MDA) levels. MTT results were compared with corresponding measurements on cultures of non-stem glioblastoma cells and osteoblasts. RESULTS: Met+Soraf exerted the highest antiproliferative effects in GSCs and non-stem glioblastoma cells (p<0.001). Both Met and Soraf monotherapy exhibited a selective cytotoxic effect on GSCs (p<0.001), while no effect was detected on non-stem glioblastoma cells (p>0.05). Soraf, but not Met, impacted the proliferation of normal cells. Soraf displayed synergism with Met in producing high levels of ROS, decreasing efflux pump activity and generating the highest apoptotic rates when compared to either drug alone (p<0.001). CONCLUSION: GSCs were highly sensitive to the combination of Met and Soraf which reduced cell proliferation, increased oxidative stress, inhibited efflux pump activity and ultimately killed GSCs. We strongly believe that these results warrant further in vivo exploration.

The Management of Obstructive Sleep Apnea Patients during the COVID-19 Pandemic as a Public Health Problem-Interactions with Sleep Efficacy and Mental Health.

With the onset of the COVID-19 outbreak, it was stipulated that patients with obstructive sleep apnea (OSA) may have a greater risk of morbidity and mortality and may even experience changes in their mental health. The aim of the current study is to evaluate how patients managed their disease (sleep apnea) during the COVID-19 pandemic, to determine if continuous positive airway pressure (CPAP) usage changed after the beginning of the pandemic, to compare the stress level with the baseline, and to observe if any modifications are related to their individual characteristics. The present studies highlight the level of anxiety, which was high among patients with OSA during the COVID-19 pandemic (p < 0.05), with its influence on weight control (62.5% of patients with high levels of stress gained weight) and sleep schedule (82.6% reported a change in sleep schedule). Patients with severe OSA and high levels of stress increased their CPAP usage (354.5 min/night vs. 399.5 min/night during the pandemic, p < 0.05). To conclude, in OSA patients, the presence of the pandemic led to a greater level of anxiety, changes in sleep schedule and weight gain because of job loss, isolation, and emotional changes, influencing mental health. A possible solution, telemedicine, could become a cornerstone in the management of these patients.

Dendrimers: Advancements and Potential Applications in Cancer Diagnosis and Treatment-An Overview.

Cancer is a leading cause of death worldwide, and the main treatment methods for this condition are surgery, chemotherapy, and radiotherapy. These treatment methods are invasive and can cause severe adverse reactions among organisms, so nanomaterials are increasingly used as structures for anticancer therapies. Dendrimers are a type of nanomaterial with unique properties, and their production can be controlled to obtain compounds with the desired characteristics. These polymeric molecules are used in cancer diagnosis and treatment through the targeted distribution of some pharmacological substances. Dendrimers have the ability to fulfill several objectives in anticancer therapy simultaneously, such as targeting tumor cells so that healthy tissue is not affected, controlling the release of anticancer agents in the tumor microenvironment, and combining anticancer strategies based on the administration of anticancer molecules to potentiate their effect through photothermal therapy or photodynamic therapy. The purpose of this review is to summarize and highlight the possible uses of dendrimers regarding the diagnosis and treatment of oncological conditions.

Histopathological Lung Findings in COVID-19 B.1.617.2 SARS-CoV-2 Delta Variant.

BACKGROUND: The Delta variant (Pango lineage B.1.617.2) is one of the most significant and aggressive variants of SARS-CoV-2. To the best of our knowledge, this is the first paper specifically studying pulmonary morphopathology in COVID-19 caused by the B.1.617.2 Delta variant. METHODS: The study included 10 deceased patients (40-83 years) with the COVID-19 Delta variant. The necrotic lung fragments were obtained either by biopsy (six cases) or autopsy (four cases). Tissue samples were subjected to virology analysis for identification of the SARS-CoV-2 variant, histopathology, and immunohistochemistry (anti-SARS coronavirus mouse anti-virus antibody). RESULTS: Virology analysis identified B.1.617.2 through genetic sequencing in eight cases, and in two cases, specific mutations of B.1.617.2 were identified. Macroscopically, in all autopsied cases, the lung had a particular appearance, purple in color, with increased consistency on palpation and abolished crepitations. Histopathologically, the most frequently observed lesions were acute pulmonary edema (70%) and diffuse alveolar damage at different stages. The immunohistochemical examination was positive for proteins of SARS-CoV-2 in 60% of cases on alveolocytes and in endothelial cells. CONCLUSIONS: The histopathological lung findings in the B.1.617.2 Delta variant are similar to those previously described in COVID-19. Spike protein-binding antibodies were identified immunohistochemically both on alveolocytes and in the endothelial cells, showing the potential of indirect damage from thrombosis.

Antidiabetic Treatment before Hospitalization and Admission Parameters in Patients with Type 2 Diabetes, Obesity, and SARS-CoV-2 Viral Infection.

BACKGROUND: SARS-CoV-2 viral infection is a current and important topic for patients with comorbidities of type 2 diabetes and obesity, associated with increased risk of mortality and morbidity. This study aims to analyze, compare and describe admission parameters in patients with type 2 diabetes, obesity, and SARS-CoV-2 infection based on whether they received insulin therapy before hospital admission. METHODS: Our study enrolled patients diagnosed with type 2 diabetes, obesity, and SARS-CoV-2 viral infection, 81 patients without insulin treatment before hospital admission, and 81 patients with insulin at "Gavril Curteanu" Municipal Clinical Hospital of Oradea, Romania, between August 2020 and March 2022. RT-PCR/rapid antigen tests were used for detecting SARS-CoV-2 viral infection. RESULTS: The severe form of COVID-19 was found in 66% of all patients (65% in the group without insulin and 67% in the group with insulin). Oxygen saturation at the time of hospital admission was greater or equal to 90% in 62% of all patients. The most associated comorbidities we founded in this study were: hypertension in 75% of all patients (grade two hypertension 63% in the group without insulin and 64% in the group with insulin), ischemic heart disease in 35% of patients (25% in the group without insulin and 44% in the group with insulin, n = 0.008), heart failure in 9.3% of all patients (8.6% in the group without insulin and 10% in the group with insulin). CRP and procalcitonin are increased in both groups at hospital admission, with a slightly higher trend in the group with insulin therapy before hospital admission. We found that 56% of patients in the group with insulin treatment were with uncontrolled diabetes on admission. Only 10% of patients required a change in antidiabetic treatment with insulin therapy at discharge. In our study, 89% of all patients did not require short-term home oxygen therapy at discharge. CONCLUSIONS: Antidiabetic therapy taken before hospital admission did not protect patients against cytokine storm in COVID-19, but is very important in the pathophysiological stage of comorbidities. Paraclinical parameters at hospitalization showed differences in correlation with oral antidiabetic treatment like metformin or insulin therapy. Changing the antidiabetic treatment for a small percentage of patients in the group who had not been receiving insulin therapy before discharge was necessary. It is necessary for future studies to see all changes involved in antidiabetic treatment in patients with diabetes type 2 and obesity after SARS-CoV2 viral infection and its long-term evolution.

Targeted EGFR Nanotherapy in Non-Small Cell Lung Cancer.

Non-small cell lung cancer (NSCLC) remains a leading cause of cancer-related mortality worldwide. Despite advances in treatment, the prognosis remains poor, highlighting the need for novel therapeutic strategies. The present review explores the potential of targeted epidermal growth factor receptor (EGFR) nanotherapy as an alternative treatment for NSCLC, showing that EGFR-targeted nanoparticles are efficiently taken up by NSCLC cells, leading to a significant reduction in tumor growth in mouse models. Consequently, we suggest that targeted EGFR nanotherapy could be an innovative treatment strategy for NSCLC; however, further studies are needed to optimize the nanoparticles and evaluate their safety and efficacy in clinical settings and human trials.

Quantitative MRI of Pancreatic Cystic Lesions: A New Diagnostic Approach.

The commonly used magnetic resonance (MRI) criteria can be insufficient for discriminating mucinous from non-mucinous pancreatic cystic lesions (PCLs). The histological differences between PCLs' fluid composition may be reflected in MRI images, but cannot be assessed by visual evaluation alone. We investigate whether additional MRI quantitative parameters such as signal intensity measurements (SIMs) and radiomics texture analysis (TA) can aid the differentiation between mucinous and non-mucinous PCLs. Fifty-nine PCLs (mucinous, n = 24; non-mucinous, n = 35) are retrospectively included. The SIMs were performed by two radiologists on T2 and diffusion-weighted images (T2WI and DWI) and apparent diffusion coefficient (ADC) maps. A total of 550 radiomic features were extracted from the T2WI and ADC maps of every lesion. The SIMs and TA features were compared between entities using univariate, receiver-operating, and multivariate analysis. The SIM analysis showed no statistically significant differences between the two groups (p = 0.69, 0.21-0.43, and 0.98 for T2, DWI, and ADC, respectively). Mucinous and non-mucinous PLCs were successfully discriminated by both T2-based (83.2-100% sensitivity and 69.3-96.2% specificity) and ADC-based (40-85% sensitivity and 60-96.67% specificity) radiomic features. SIMs cannot reliably discriminate between PCLs. Radiomics have the potential to augment the common MRI diagnosis of PLCs by providing quantitative and reproducible imaging features, but validation is required by further studies.

Obesity Impact on SARS-CoV-2 Infection: Pros and Cons "Obesity Paradox"-A Systematic Review.

BACKGROUND: During the last years, the COVID-19 pandemic meets the pandemic generated by obesity, raising many questions regarding the outcomes of those with severe forms of infection. METHODS: The present systematic review summarises and analyses the data providing evidence for or against the "obesity-paradox" in COVID-19 patients. After applying the inclusion and exclusion criteria, 23 studies were included. We also analysed the presumably underlying basic mechanisms. RESULTS: The patients with a body mass index (BMI) of 30-40 kg/m2 presented severe symptoms that led to intensive care unit (ICU) admission but not increased death rate. Those with a higher degree of obesity, with a BMI higher than 40 kg/m2, led to a rise in the death rate, particularly in young patients. Obesity was associated with a higher rate of ICU admission but was not determined as an independent predictor of increased mortality. In contrast, some studies suggest a strong association between obesity or morbid obesity and the risk of death. CONCLUSIONS: The existence of "obesity-paradox" cannot be stated; our study presents obesity as a critical risk factor in the evolution of COVID-19.

Glioblastoma Microenvironment and Cellular Interactions.

The central nervous system (CNS) represents a complex network of different cells, such as neurons, glial cells, and blood vessels. In tumor pathology, glial cells result in the highest number of cancers, and glioblastoma (GB) is considered the most lethal tumor in this region. The development of GB leads to the infiltration of healthy tissue through the interaction between all the elements of the brain network. This results in a GB microenvironment, a complex peritumoral hallo composed of tumor cells and several non-tumor cells (e.g., nervous cells, stem cells, fibroblasts, vascular and immune cells), which might be the principal factor for the ineffective treatment due to the fact that the microenvironment modulates the biologic status of the tumor with the increase in its evasion capacity. Crosstalk between glioma cells and the brain microenvironment finally inhibits the beneficial action of molecular pathways, favoring the development and invasion of the tumor and its increasing resistance to treatment. A deeper understanding of cell-cell interactions in the tumor microenvironment (TME) and with the tumor cells could be the basis for a more efficient therapy.

Early development of human ganglionic eminences assessed in vitro by using 7.04 Tesla micro-MRI - a pilot study.

BACKGROUND AND AIMS: Ganglionic eminences are temporary structures which appear during the 5th week post-fertilization on the floor of telencephalic vesicles and disappear until the 35th week of gestation. The aim of this descriptive study of morphological research is to depict the ganglionic eminences within the embryonic and early fetal brains by using micro-MRI. METHODS: Six human embryos and fetuses ranging from 21 mm crown-rump length CRL (9 gestational week GW) to 85 mm CRL (14 GW) were examined in vitro by micro-MRI. The investigation was performed with a Bruker BioSpec 70/16USR scanner (Bruker BioSpin MRI GmbH, Ettlingen, Germany) operating at 7.04 Tesla. RESULTS: We describe the morphological characteristics of the ganglionic eminences at different gestational ages. The acquisition parameters were modified for each subject in order to obtain an increased spatial resolution. The remarkable spatial resolution of 27 µm/voxel allows visualization of millimetric structures of the developing brain on high quality micro-MR images. CONCLUSION: In our study we give the description of the ganglionic eminences within the embryonic and early fetal brains by using micro-MRI, which, to the best of our knowledge, have not been previously documented in literature. Micro-MRI provides accurate images, which are comparable with the histological slices.

Postpartum assessment of fetal inflammatory response syndrome in a preterm population with premature rupture of membranes: A Romanian study.

Fetal inflammatory response syndrome is associated with increased neonatal morbidity and mortality. The aim of the present study was to evaluate the dynamics of the plasmatic value of pro-inflammatory cytokines: tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and neutrophil activating peptide 78 (ENA-78) and the anti-inflammatory cytokine IL-10 in the first and third day of life and the correlation with neonatal morbidities and mortality. The current research was designed as a prospective case control study included 80 neonates hospitalized at the 3rd level Neonatal Intensive Care Unit (NICU), 1st Gynecology Clinic, County Emergency Hospital, Cluj-Napoca, Romania. For each patient, the following parameters were noted: pH at first hour of life, oxygen saturation, fraction of inspired oxygen (FiO2) and duration of premature rupture of the membranes (PROM). Measurements of cytokines were determined from venous blood in the first and third day of life. The values of all cytokines were higher in the newborns from mothers with PROM. The value of IL-6 in the study group was higher compared to the controls during the first day of life and met the highest value in necrotizing enterocolitis (NEC). ENA-78 was higher in the study group (P=0.037) and decreased during the first 3 days of life. The highest value of ENA-78 was found in the neonates with cerebral hemorrhage. IL-10 also had values with a significant difference in the first day of life between both groups (P=0.02). IL-10 had the highest value in sepsis cases. In conclusion, among the inflammatory parameters that were evaluated, the dynamics of ENA-78 and IL-10 were found to influence the neonatal prognosis of newborns with PROM. The decrease in ENA-78 and IL-10 during the third day of life could suggest the evolution towards the ending of the inflammatory process and an increase in the survival rate was noted.

Ultrasonography in the Differentiation of Endometriomas from Hemorrhagic Ovarian Cysts: The Role of Texture Analysis.

The ultrasonographic (US) features of endometriomas and hemorrhagic ovarian cysts (HOCs) are often overlapping. With the emergence of new computer-aided diagnosis techniques, this is the first study to investigate whether texture analysis (TA) could improve the discrimination between the two lesions in comparison with classic US evaluation. Fifty-six ovarian cysts (endometriomas, 30; HOCs, 26) were retrospectively included. Four classic US features of endometriomas (low-level internal echoes, perceptible walls, no solid components, and less than five locules) and 275 texture parameters were assessed for every lesion, and the ability to identify endometriomas was evaluated through univariate, multivariate, and receiver operating characteristics analyses. The sensitivity (Se) and specificity (Sp) were calculated with 95% confidence intervals (CIs). The texture model, consisting of seven independent predictors (five variations of difference of variance, image contrast, and the 10th percentile; 100% Se and 100% Sp), was able to outperform the ultrasound model composed of three independent features (low-level internal echoes, perceptible walls, and less than five locules; 74.19% Se and 84.62% Sp) in the diagnosis of endometriomas. The TA showed statistically significant differences between the groups and high diagnostic value, but it remains unclear if the textures reflect the intrinsic histological characteristics of the two lesions.

Epithelial-Mesenchymal Transition Gene Signature Related to Prognostic in Colon Adenocarcinoma.

Colon adenocarcinoma (COAD) remains an important cause of cancer-related mortality worldwide. Epithelial-mesenchymal transition (EMT) is a key mechanism, promoting not only the invasive or metastatic phenotype but also resistance to therapy. Using bioinformatics approaches, we studied the alteration on EMT related genes and its implication on COAD prognostic based on public datasets. For the EMT mechanisms, two overexpressed genes were identified (NOX4 and IGF2BP3), as well as five downregulated genes (BMP5, DACT3, EEF1A2, GCNT2 and SFRP1) that were related to prognosis in COAD. A qRT-PCR validation step was conducted in a COAD patient cohort comprising of 29 tumor tissues and 29 normal adjacent tissues, endorsing the expression level for BMP5, as well as for two of the miRNAs targeting key EMT related genes, revealing upregulation of miR-27a-5p and miR-146a-5p. The EMT signature can be used to develop a panel of biomarkers for recurrence prediction in COAD patients, which may contribute to the improvement of risk stratification for the patients.