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Pancreatic cancer is one of the deadliest cancers worldwide, mainly due to late diagnosis. Therefore, there is an urgent need for novel diagnostic approaches to identify the disease as early as possible. We have developed a diagnostic assay for pancreatic cancer based on the detection of naturally occurring tumor associated autoantibodies against Mucin-1 (MUC1) using engineered glycopeptides on nanoparticle probes. We used a structure-guided approach to develop unnatural glycopeptides as model antigens for tumor-associated MUC1. We designed a collection of 13 glycopeptides to bind either SM3 or 5E5, two monoclonal antibodies with distinct epitopes known to recognize tumor associated MUC1. Glycopeptide binding to SM3 or 5E5 was confirmed by surface plasmon resonance and rationalized by molecular dynamics simulations. These model antigens were conjugated to gold nanoparticles and used in a dot-blot assay to detect autoantibodies in serum samples from pancreatic cancer patients and healthy volunteers. Nanoparticle probes with glycopeptides displaying the SM3 epitope did not have diagnostic potential. Instead, nanoparticle probes displaying glycopeptides with high affinity for 5E5 could discriminate between cancer patients and healthy controls. Remarkably, the best-discriminating probes show significantly better true and false positive rates than the current clinical biomarkers CA19-9 and carcinoembryonic antigen (CEA)., (© 2024 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH.)

Background: Cancers of ductal origin often express glycoprotein mucin 1 (MUC1), also known as CA15.3, with higher levels leading to poor prognosis. Conversely, anti-MUC1 antibodies develop in some patients, leading to better prognosis. We sought to identify epidemiologic factors associated with CA15.3 antigen or antibody levels., Methods: Levels of CA15.3 antigen and anti-CA15.3 IgG antibodies were measured in archived sera from 2,302 mostly healthy women from the National Health and Nutritional Survey; and epidemiologic predictors of their levels were examined using multivariate and correlational analyses., Results: Among racial groups, Black women had the highest levels of CA15.3 antigen and lowest levels of antibodies. Increasing body mass index and current smoking were associated with low anti-CA15.3 antibody levels. Low CA15.3 antigen levels were seen in oral contraceptive users and high levels in women who were pregnant or lactating at the time of blood collection, with the latter group also having high antibody levels. Past reproductive events associated with high antigen levels included the following: later age at menarche, having given birth, and history of endometriosis. Lower antigen levels were seen with increasing duration of OC use. Anti-CA15.3 antibody levels decreased with an increasing estimated number of ovulatory years., Conclusions: Key determinants of CA.15.3 antigen or antibody levels include the following: race, body mass index, smoking, later menarche, childbirth, number of ovulatory cycles, and endometriosis., Impact: This study supports the premise that known epidemiologic factors affecting risk for or survival after MUC1-expressing cancers may, at least partially, operate through their association with CA15.3 antigen or antibody levels., (©2024 American Association for Cancer Research.)

Background: Anti-synthetase syndrome-associated interstitial lung disease (ASS-ILD) may occur without myositis. Although a recent Japanese guide proposed a watch-and-wait approach for chronic ASS-ILD without obvious progression, the natural history of this subgroup and the appropriateness of the watch-and-wait approach remain unclear. We aimed to describe the natural history of ASS-ILD, that is sufficiently indolent to be a candidate for the watch-and-wait approach., Methods: Among consecutive patients with ASS-ILD, we retrospectively identified those without myositis, acute/subacute onset, and significant lung function impairment, which qualified them as indolent-ASS-ILD cases, and described their natural course. Additionally, we evaluated the risk factors for fibrosis progression on computed tomography (CT) using the Cox proportional hazards model., Results: Among 80 patients with ASS-ILD, we identified 33 with indolent-ASS-ILD, all of whom were initially followed up with a watch-and-wait approach. Among 30 patients with sufficient follow-up data, 27 (90%) showed a stable course without treatment over 24 months. Subsequently, four patients experienced ≥10% relative forced vital capacity (FVC) decline without treatment during a median follow-up duration of 81 months. Seven patients showed fibrosis progression with >10% increase in the total lung area on CT. Higher levels of Krebs von den Lungen-6 (KL-6) and surfactant protein-D (SP-D) were associated with fibrosis progression on CT., Conclusion: Most patients with indolent-ASS-ILD did not experience ≥10% relative FVC decline over five years without treatment. However, fibrosis progression on CT, which seemed to precede significant FVC decline, occurred more frequently, especially in patients with higher KL-6 and SP-D levels., Competing Interests: Declaration of competing interest Mitsuhiro Moda has no conflict of interest; Hiromitsu Sumikawa has no conflict of interest; Ryota Shintani has no conflict of interest; Naoko Takeuchi has no conflict of interest; Tomoko Kagawa has no conflict of interest; Takayuki Takimoto has no conflict of interest; Toru Arai received lecture fees from Boehringer Ingelheim and Shionogi for activities not connected to the submitted work., (Copyright © 2024 The Japanese Respiratory Society. Published by Elsevier B.V. All rights reserved.)

A label-free optical sandwich immunoassay sensor, utilizing weak value amplification and total internal reflection, was devised for real-time, high-sensitivity analysis and detection of low-concentration targets. 3D printed channels and sodium chloride solution were employed to ensure reproducibility, reliability, and stability of the measurements for calibration. The sandwich structure demonstrated enhanced responsiveness in the proposed optical biosensor through a comparative analysis of the direct assay and sandwich assay for detecting alpha-fetoprotein (AFP) at the same concentration. By optimizing the binding sequences of the coating antibody, target, and detection antibody in the sandwich method, a more suitable sandwich sensing approach based on weak value amplification was achieved. With this approach, the limit of detection (LOD) of 6.29 ng/mL (pM level) for AFP in PBS solution was achieved. AFP testing and regeneration experiments in human serum have proved the feasibility of our methods in detecting complex samples and the reusability of sensing chips. Additionally, the method demonstrated excellent selectivity for unpaired antigens. The efficacy of this methodology was evaluated by simultaneously detecting AFP, carcinoembryonic antigen (CEA), and CA15-3 on a singular sensor chip. In conclusion, the label-free sandwich immunoassay sensing scheme holds promise for advancing the proposed optical sensors based on weak value amplification in early diagnosis and prevention applications. Compared to other biomarker detection methods, it will be easier to promote in practical applications., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Small extracellular vesicles (sEVs) reflect the genotype and phenotype of original cells and are biomarkers for early diagnosis and treatment monitoring of tumors. Yet, their small size and low density make them difficult to isolate and detect in body fluid samples. This study proposes a novel acDEP-Exo chip filled with transparent micro-beads, which formed a non-uniform electrical field, and finally achieved rapid, sensitive, and tunable sEVs capture and detection. The method requires only 20-50 μL of sample, achieved a limit of detection (LOD) of 161 particles/μL, and can detect biomarkers within 13 min. We applied the chip to analyze the two markers of sEV's EpCAM and MUC1 in clinical plasma samples from breast cancer (BC) patients and healthy volunteers and found that the combined evaluation of sEV's biomarkers has extremely high sensitivity, specificity and accuracy. The present study introduces an alternative approach to sEVs isolation and detection, has a great potential in real-time sEVs-based liquid biopsy., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Exosomes, as novel biomarker for liquid biopsy, exhibit huge important potential value for cancer diagnosis. However, various proteins show different expression levels on exosomal membrane, and the absolute concentration of exosomes in clinical samples is easily influenced by a number of factors. Here, we developed a CRISPR/Cas12a and aptamer-chemiluminescence based analysis (CACBA) for the relative abundance determination of tumor-related protein positive exosomes in plasma for breast cancer diagnosis. The total concentration of exosomes was determined through captured CD63 using a CRISPR/Cas12a-based method with the LoD of 8.97 × 10 3 particles/μl. Meanwhile, EpCAM and MUC1 positive exosomes were quantitatively detected by aptamer-chemiluminescence (ACL) based method with the LoD of 1.45 × 10 2 and 3.73 × 10 2 particles/μl, respectively. It showed that the percentages of EpCAM and MUC1 positive exosomes offered an excellent capability to differentiate breast cancer patients and healthy donors. The high sensitivity, strong specificity, outstanding anti-interference capability, and steady recovery rate of this approach offered higher accuracy and robustness than the commercialized method in clinical trial. In addition with good stability, easy preparation and low cost, this method not only provides a new approach to rapid analysis of exosome proteins, it may be quickly extended to the diagnoses of various cancers., Competing Interests: Declaration of competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: The serum markers Krebs von den Lungen-6 (KL-6), surfactant protein A (SP-A), and surfactant protein D (SP-D) have been used for the diagnosis, differential diagnosis, and prognosis prediction of interstitial pneumonia. However, the significance of measuring the serum and bronchoalveolar lavage fluid (BALF) KL-6, SP-D, and SP-A levels in predicting the prognosis of chronic fibrosing interstitial pneumonia (CFIP), idiopathic pulmonary fibrosis, and idiopathic nonspecific interstitial pneumonia remains unclear. We aimed to clarify the significance of measuring the serum and BALF KL-6, SP-A, and SP-D levels in predicting the prognosis of patients with CFIP., Methods: Among 173 patients who were diagnosed with CFIP between September 2008 and February 2021, 39 who underwent bronchoalveolar lavage were included in this study. Among these, patients experiencing an annual decrease in forced vital capacity (FVC) of ≥10% or those facing challenges in undergoing follow-up pulmonary function tests owing to significant deterioration in pulmonary function were categorized as the rapidly progress group. Conversely, individuals with an annual decrease in the FVC of <10% were classified into the slowly progress group. The serum and BALF KL-6, SP-D, and SP-A levels, as well as BALF/serum SP-D and SP-A ratios were compared between the two groups., Results: Among the patients with CFIP, the BALF SP-D level (p=0.0111), BALF SP-A level (p<0.0010), BALF/serum SP-D ratio (p=0.0051), and BALF/serum SP-A ratio (p<0.0010) were significantly lower in the rapidly than in the slowly progress group (p<0.0010). The receiver operating characteristics analysis results demonstrated excellent performance for diagnosing patients with CFIP, with the BALF SP-D level (area under the curve [AUC], 0.7424), BALF SP-A level (AUC, 0.8842), BALF/serum SP-D ratio (AUC, 0.7673), and BALF/serum SP-A ratio (AUC, 0.8556). Moreover, the BALF SP-A level showed a notably superior CFIP diagnostic capability. Survival analysis using the Kaplan-Meier method revealed that patients with a BALF SP-A level of <1500 ng/mL and BALF/serum SP-A ratio of <15.0 had poor prognoses., Conclusions: Our results suggest that BALF SP-A measurement may be useful for predicting the prognosis in patients with CFIP., (© 2024. The Author(s).)

Worldwide, female breast cancer (BC) has surpassed lung cancer as the most commonly diagnosed cancer. Early diagnosis of cancer recurrence can provide substantial benefits for BC patients who are at high risk of relapse. We aimed to investigate the role of ALU 247, ALU 115, cfDNA integrity index, CA15-3 and CEA as potential diagnostic markers in BC patients and as markers for early prediction of recurrence. Fifty BC patients (10 patients showed recurrence), 26 BBD patients and 22 healthy controls were included. Real-time q-PCR was used to measure the concentration of ALU 247 and ALU 115 in plasma then cfDNA integrity index was calculated. "ECLIA" was used to measure the concentration of CA15-3 and CEA in serum. Our results showed significant higher levels of ALU 247, ALU 115, CA15-3 and CEA in BC patients in comparison to healthy controls (P=0.02, 0.008, <0.001 and < 0.001 respectively). Also, cfDNA integrity index was higher in BC patients in comparison to healthy controls but statistically insignificance (p = 0.46). In recurrent BC patients; ALU 247, ALU 115, cfDNA integrity index, CA15-3 and CEA levels were higher compared to non-recurrent BC patients but with no statistic significant (p = 0.46, 0.59, 0.09, 0.85 and 0.84 respectively). This may result from the short period of follow up (1-2 years) and the relatively small sample size due to exclusion of patients with chronic diseases or inflammation as well as those who received therapy or post-surgery. By using the ROC curve, the sensitivity of ALU 247, ALU 115, CA15-3 and CEA for discriminating BC patients from BBD patients and healthy controls was 79 %, 79.2 %, 76.0 % and 88.0 % respectively. This study suggested that ALU 247, ALU 115, CA15-3 and CEA could be promising non-invasive markers of BC for diagnosis and early prediction of recurrence after validation in large-scale future studies., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Objective: The aim of this study was to explore the potential values of Krebs von den Lungen-6 (KL-6), neutrophil to lymphocyte ratio (NLR), systemic immune inflammation (SII), platelet to lymphocyte ratio (PLR), monocyte to lymphocyte ratio (MLR) and red blood cell distribution width (RDW) in the diagnosis and evaluation of the severity of connective tissue disease-associated interstitial lung disease (CTD-ILD)., Methods: A total of 140 connective tissue disease (CTD) patients and 85 CTD-ILD patients were recruited for this study at Shanxi Provincial People's Hospital from May 2022 to May 2023. Patients were divided into subgroups based on medication history and CTD subtypes to compare and analyze the clinical data and laboratory parameters of CTD-ILD patients and CTD patients. The receiver operating characteristic curve (ROC) was used to evaluate the diagnostic efficacy of KL-6, NLR, SII, PLR, MLR, and RDW in identifying CTD-ILD patients from CTD patients. A Spearman correlation analysis was conducted to elucidate the correlations between these markers and the lung function parameters of forced vital capacity (FVC, %), forced expired volume in one second (FEV1, %), and diffusing capacity of carbon monoxide (DLCO, %). Finally, binary logistic regression analysis was applied to discern the independent risk factors for CTD-ILD., Results: NLR, SII, MLR, RDW, and KL-6 displayed significant statistical differences in the experimental groups. In both untreated and treated subgroups, KL-6 displayed higher values for CTD-ILD than CTD among all CTD subtypes. In untreated subgroups, there were significant differences in MLR levels between rheumatoid arthritis (RA) and RA-ILD patients and in NLR levels between Sjögren syndrome (SjS) and SjS-ILD patients. There were also significant differences in RDW-SD between the "other CTD" and "other CTD-ILD" groups. In treated subgroups, there were significant differences in both RDW-SD and RDW-CV between RA and RA-ILD patients and in NLR, SII, MLR, PLR, and RDW-SD between "other CTD" and "other CTD-ILD" groups. ROC revealed that KL-6 emerged as the most effective predictor for CTD-ILD in both treated and untreated groups. The multivariate logistic regression analysis results showed that both KL-6 and age were independent risk factors for CTD-ILD. NLR, SII, and PLR were negatively correlated with DLCO (%) in the untreated CTD-ILD group, and KL-6 was negatively correlated with various lung function parameters in both treated and untreated CTD-ILD groups., Conclusion: KL-6 emerged as the most promising biomarker for diagnosing CTD-ILD and assessing its severity. The diagnostic value of KL-6 was unaffected by medication interference and surpassed the value of other parameters, such as NLR, SII, MLR, and RDW. The diagnostic value of RDW-SD was higher than that of RDW-CV in CTD-ILD patients. NLR, SII, MLR, and PLR have potential value in diagnosing the different types of CTD-ILD., Competing Interests: The authors declare that they have no competing interests., (© 2024 Xing and Liang.)

Objectives: Quantitatively assess the severity and predict the mortality of interstitial lung disease (ILD) associated with Rheumatoid arthritis (RA) was a challenge for clinicians. This study aimed to construct a radiomics nomogram based on chest computed tomography (CT) imaging by using the ILD-GAP (gender, age, and pulmonary physiology) index system for clinical management., Methods: Chest CT images of patients with RA-ILD were retrospectively analyzed and staged using the ILD-GAP index system. The balanced dataset was then divided into training and testing cohorts at a 7:3 ratio. A clinical factor model was created using demographic and serum analysis data, and a radiomics signature was developed from radiomics features extracted from the CT images. Combined with the radiomics signature and independent clinical factors, a nomogram model was established based on the Rad-score and clinical factors. The model capabilities were measured by operating characteristic curves, calibration curves and decision curves analyses., Results: A total of 177 patients were divided into two groups (Group I, n = 107; Group II, n = 63). Krebs von den Lungen-6, and nineteen radiomics features were used to build the nomogram, which showed favorable calibration and discrimination in the training cohort [AUC, 0.948 (95% CI: 0.910-0.986)] and the testing validation cohort [AUC, 0.923 (95% CI: 0.853-0.993)]. Decision curve analysis demonstrated that the nomogram performed well in terms of clinical usefulness., Conclusion: The CT-based radiomics nomogram model achieved favorable efficacy in predicting low-risk RA-ILD patients., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Han, Guo, Zhu, Zhang, Qin, Li, Gu and Jin.)

Systemic sclerosis (SSc) is an autoimmune disease characterized by vasculopathy, aberrant immune activation, and extensive tissue fibrosis of the skin and internal organs. Because of the complicated nature of its pathogenesis, the underlying mechanisms of SSc remain incompletely understood. Angiogenic factor with a G-patch domain and a Forkhead-associated domain 1 (AGGF1) is a critical factor in angiogenesis expressed on vascular endothelial cells, associated with inflammatory and fibrotic responses. To elucidate the possible implication of AGGF1 in SSc pathogenesis, we investigated the association between serum AGGF1 levels and clinical manifestations in SSc patients. We conducted a cross-sectional analysis of AGGF1 levels in sera from 60 SSc patients and 19 healthy controls with enzyme-linked immunosorbent assay. Serum AGGF1 levels in SSc patients were significantly higher than those in healthy individuals. In particular, diffuse cutaneous SSc patients with shorter disease duration had higher levels compared to those with longer disease duration and limited cutaneous SSc patients. Patients with higher serum AGGF1 levels had a higher incidence of digital ulcers, higher modified Rodnan Skin Scores (mRSS), elevated serum Krebs von den Lungen-6 (KL-6) levels, C-reactive protein levels, and right ventricular systolic pressures (RVSP) on the echocardiogram, whereas they had reduced percentage of vital capacity (%VC) and percentage of diffusing capacity of the lungs for carbon monoxide (%DLCO) in pulmonary functional tests. In line, serum AGGF1 levels were significantly correlated with mRSS, serum KL-6 and surfactant protein D levels, RVSP, and %DLCO. These results uncovered notable correlations between serum AGGF1 levels and key cutaneous and vascular involvements in SSc, suggesting potential roles of AGGF1 in SSc pathogenesis., (© 2024 Japanese Dermatological Association.)

Background: Interstitial lung disease (ILD) is a common pulmonary manifestation of rheumatoid arthritis (RA) and is associated with a poor prognosis. However, the role of blood biomarkers in RA-associated interstitial lung disease (RA-ILD) is ill-defined. We aim to evaluate the role of YKL-40 and Krebs von den Lungen-6 (KL-6) in the diagnosis and severity evaluation of RA-ILD., Methods: 45 RA-non-ILD patients and 38 RA-ILD patients were included. The clinical data and the levels of YKL-40 and KL-6 were measured and collected for all patients. The risk factors for RA-ILD were analyzed and their correlation with relevant indicators and predictive value for RA-ILD was explored., Results: The levels of YKL-40 and KL-6 in RA-ILD patients were higher than RA-non-ILD patients ( p < .001). Both YKL-40 and KL-6 were correlated with the incidence of RA-ILD. The predictive power of combined KL-6 and YKL-40 for the presence of ILD was 0.789, with a sensitivity and specificity at 73.7% and 73.3%, respectively. In RA-ILD patients, both YKL-40 and KL-6 were positively correlated with the Scleroderma Lung Study (SLS) I score and negatively correlated with pulmonary function., Conclusions: KL-6 and YKL-40 might be a useful biomarker in the diagnosis and severity evaluation of RA-ILD.

Background: The five-year prognosis for patients with late-stage high-grade serous carcinoma (HGSC) remains dismal, underscoring the critical need for identifying early-stage biomarkers. This study explores the potential of extracellular vesicles (EVs) circulating in blood, which are believed to harbor proteomic cargo reflective of the HGSC microenvironment, as a source for biomarker discovery., Results: We conducted a comprehensive proteomic profiling of EVs isolated from blood plasma, ascites, and cell lines of patients, employing both data-dependent (DDA) and data-independent acquisition (DIA) methods to construct a spectral library tailored for targeted proteomics. Our investigation aimed at uncovering novel biomarkers for the early detection of HGSC by comparing the proteomic signatures of EVs from women with HGSC to those with benign gynecological conditions. The initial cohort, comprising 19 donors, utilized DDA proteomics for spectral library development. The subsequent cohort, involving 30 HGSC patients and 30 control subjects, employed DIA proteomics for a similar purpose. Support vector machine (SVM) classification was applied in both cohorts to identify combinatorial biomarkers with high specificity and sensitivity (ROC-AUC > 0.90). Notably, MUC1 emerged as a significant biomarker in both cohorts when used in combination with additional biomarkers. Validation through an ELISA assay on a subset of benign (n = 18), Stage I (n = 9), and stage II (n = 9) plasma samples corroborated the diagnostic utility of MUC1 in the early-stage detection of HGSC., Conclusions: This study highlights the value of EV-based proteomic analysis in the discovery of combinatorial biomarkers for early ovarian cancer detection., (© 2024. The Author(s).)

In this work, a colorimetric aptasensor based on magnetic beads (MBs), gold nanoparticles (AuNPs) and Horseradish Peroxidase (HRP) was prepared for the detection of mucin 1 (MUC1). Complementary DNA of the MUC1 aptamer (Apt) immobilized on the MBs was combined with the prepared AuNPs-Apt-HRP complex (AuNPs@Apt-HRP). In the presence of MUC1, it specifically bound to Apt, resulting in the detachment of gold nanoparticles from the MBs. After magnetic separation, AuNPs@Apt-HRP was separated into the supernatant and reacted with 3,3',5,5'-Tetramethylbenzidine (TMB) to produce color reaction from colorless to blue. The linear range of MUC1 was from 75 to 500 μg/mL (R 2  = 0.9878), and the detection limit was 41.95 μg/mL. The recovery rate of MUC1 in human serum was 99.18 %∼101.15 %. This method is simple and convenient. Moreover, it does not require complex and expensive equipment for detection of MUC1. It provides value for the development of MUC1 colorimetric sensors and a promising strategy for the determination of MUC1 in clinical diagnosis., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Serum KL-6 is elevated in patients with various diseases such as interstitial lung disease(ILD), lung cancer, or breast cancer. However, whether serum KL-6 levels would be increased in patients with gastric cancer remains unclear. In this study, we aimed to reveal the frequency and characteristics of patients with gastric cancer exhibiting high serum KL-6 levels and no ILD. Therefore, we retrospectively reviewed the medical records of patients with gastric cancer and serum KL-6 levels measured prior to nivolumab-containing therapies. No patients had ILD at pretreatment. The median serum KL-6 level at pretreatment was 314 U/mL. Serum KL-6 levels increased above 500 U/mL in 16 of 56 patients at pretreatment. Serum KL-6 levels were higher in smokers and ex-smokers than in never-smokers as well as in patients with multiple metastases than in those with a single metastatic lesion. Moreover, we conducted a representative case presentation. Due to the increasing immune checkpoint inhibitor use in gastric cancer management, awareness concerning potentially increased serum KL-6 levels in patients with gastric cancer without ILD would be useful for physicians due to the more frequent opportunities to measure serum KL-6 levels for early detection and differential diagnosis of ILD.

Aim: To evaluate whether seasonal changes influence fluctuations in serum Krebs von den Lungen-6 (KL-6) levels in systemic sclerosis-related interstitial lung disease (SSc-ILD)., Methods: Summer was defined as the period between July and September, and winter as between December and February. The study was conducted between 2015 and 2016, with a focus on these two seasons. A diagnosis of ILD and ILD progression overtime were evaluated using chest computed tomography. Among patients with SSc-ILD, those with data on serum KL-6 and lactate dehydrogenase (LDH) levels in the 2015 winter, 2015 summer, and 2016 winter seasons were included. Patients with comorbidities that could affect serum KL-6 levels were excluded., Results: Of 60 patients with SSc-ILD, 52 (86.7%) had stable ILD, 5 (8.3%) had worsened ILD, and 3 (5.0%) had improved ILD. Serum KL-6 levels were significantly higher during the winter than those during the summer (2015 winter vs. 2015 summer: 649 U/mL vs. 585 U/mL, p < .0001; 2016 winter vs. 2015 summer: 690 U/mL vs. 585 U/mL, p < .0001). No significant differences were observed between the winters of 2015 and 2016 (649 U/mL vs. 690 U/mL, p = .78). However, serum LDH levels did not exhibit seasonal fluctuations (2015 winter vs. 2015 summer: 203 U/L vs. 199 U/L, p = .3; 2016 winter vs. 2015 summer: 201 U/L vs. 199 U/L, p = .6; 2015 winter vs. 2016 winter: 203 U/L vs. 201 U/L, p = .24)., Conclusion: Seasonal fluctuations in serum KL-6 levels were observed in patients with SSc-ILD., (© 2024 Asia Pacific League of Associations for Rheumatology and John Wiley & Sons Australia, Ltd.)

In forensic cases, detailed identification of pneumonia is important. Our objective was to statistically determine the applicability of three interstitial lung disease (ILD) markers for forensic diagnosis using serum collected from dead bodies with various postmortem intervals (PMIs). We retrospectively analyzed the levels of postmortem serum Krebs von den Lungen-6 (KL-6) and pulmonary surfactant-associated proteins A and D (SP-A and SP-D) using 221 samples obtained during forensic autopsy at our facility from 2019 to 2023. We evaluated the diagnostic efficacy of ILD markers for various pneumonias against the pathological diagnosis, and examined the assessment of the severity of ILD. When comparing the ILD group with bacterial pneumonia (BP) versus the control group, there was a significant increase in KL-6 in the ILD group. When comparing the severe ILD (SILD) group with the mild ILD (MILD) group, there was a significant increase in KL-6 and SP-D in the SILD group. The optimal cutoff values for differentiating SILD were 607.0 U/mL for KL-6, 55.5 ng/mL for SP-A, and 160.0 ng/mL for SP-D, and the sensitivity/specificity (%) of KL-6, SP-A, and SP-D for SILD were 84.1/95.2, 55.6/85.7, and 66.7/74.6, respectively. This is the first study to examine KL-6 in postmortem serum in forensic medicine. By analyzing dead bodies with various PMIs, our results confirmed statistically that postmortem serum KL-6 specifically detects ILD, postmortem serum SP-A has high sensitivity to lung injury, and postmortem serum SP-D is potentially useful in assessing the severity of ILD., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Novel progressive fibrotic phenotype has recently been proposed characterized by progressive and inexorable worsening of the disease. Krebs von den Lungen-6 (KL-6) has been proposed as fibrotic-ILD biomarker. We aimed to assess the role of KL-6 in fibrotic-ILD and the progressive phenotype in accordance with serial serum KL-6., Methods: 107 patients were enrolled in the study (median age,IQR, 65(54-71)y/o) followed at respiratory diseases and rheumatology units of University of Siena. Thirty-five had diagnoses of IPF, 18 sarcoidosis, 10 PLCH, 5 LAM, 24 fibrotic HP(fHP), 13 RA (4/13 RA-ILD) and 22 SSc (18/22 SSc-ILD). Serial serum samples were collected before therapy (t0) and 24 months later (t1) from IPF, SSc- and RA-ILD patients. Twenty-two healthy controls (HC) were enrolled. Serum samples were assayed for KL-6 concentrations (Fujirebio Europe, Gent, Belgium)., Results: Higher KL-6 concentrations were reported in IPF, fHP and SSc-ILD patients than HC (p<0.0001). KL-6 cut-off value of 885 U/mL identified fibrotic-ILD patients. Logistic regression analysis indicated KL-6 (p=0.004) and smoking-habit (p=0.005) affected the ILD diagnosis. The decision tree model showed KL-6>1145 U/mL, DLco≤60.15 %, FVC≤86 % to classify 86 % IPF patients. Inverse correlation between T0-KL-6 and T1-FVC%(r=-0.314, p=0.046) and T1-DLco%(r=-0.327, p=0.038) in the progressive group., Conclusion: KL-6 proved to be a reliable marker for diagnosis and prognosis of fibrotic ILD patients with predictive value in progressive fibrotic patients and a useful marker to identify the new and similar progressive phenotype of IPF and SSc-ILD patients assessing the functional progression in accordance with serial serum KL-6 measurements., Competing Interests: Declaration of Competing Interest The authors have declared that no conflict of interest exists., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Although circulating tumor cells (CTCs) have demonstrated considerable importance in liquid biopsy, their detection is limited by low concentrations and complex sample components. Herein, we developed a homogeneous, simple, and high-sensitivity strategy targeting breast cancer cells. This method was based on a non-immunological stepwise centrifugation preprocessing approach to isolate CTCs from whole blood. Precise quantification is achieved through the specific binding of aptamers to the overexpressed mucin 1 (MUC1) and human epidermal growth factor receptor 2 (HER2) proteins of breast cancer cells. Subsequently, DNAzyme cleavage and parallel catalytic hairpin assembly (CHA) reactions on the cholesterol-stacking DNA machine were initiated, which opened the hairpin structures T-Hg 2+ -T and C-Ag + -C, enabling multiple amplifications. This leads to the fluorescence signal reduction from Hg 2+ -specific carbon dots (CDs) and CdTe quantum dots (QDs) by released ions. This strategy demonstrated a detection performance with a limit of detection (LOD) of 3 cells/mL and a linear range of 5-100 cells/mL. 42 clinical samples have been validated, confirming their consistency with clinical imaging, pathology findings and the folate receptor (FR)-PCR kit results, exhibiting desirable specificity of 100% and sensitivity of 80.6%. These results highlight the promising applicability of our method for diagnosing and monitoring breast cancer., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

The development of an ultrasensitive and precise measurement of a breast cancer biomarker (cancer antigen 15-3; CA15-3) in complex human serum is essential for the early diagnosis of cancer in groups of healthy populations and the treatment of patients. However, currently available testing technologies suffer from insufficient sensitivity toward CA15-3, which severely limits early large-scale screening of breast cancer patients. We report a versatile electrochemical immunoassay method based on atomically cobalt-dispersed nitrogen-doped carbon (Co-NC)-modified disposable screen-printed carbon electrode (SPCE) with alkaline phosphatase (ALP) and its metabolite, ascorbic acid 2-phosphate (AAP), as the electrochemical labeling and redox signaling unit for sensitive detection of low-abundance CA15-3. During electrochemical detection by differential pulse voltammetry (DPV), it was found that the Co-NC-SPCE electrode did not have a current signal response to the AAP substrate; however, it had an extremely favorable response current to ascorbic acid (AA). Based on the above principle, the target CA15-3-triggered immunoassay enriched ALP-catalyzed AAP produces a large amount of AA, resulting in a significant change in the system current signal, thereby realizing the highly sensitive detection of CA15-3. Under the optimal AAP substrate concentration and ALP catalysis time, the Co-NC-SPCE-based electrochemical immunoassay demonstrated a good DPV current for CA15-3 in the assay interval of 1.0 mU/mL to 10,000 mU/mL, with a calculated limit of detection of 0.38 mU/mL. Since Co-NC-SPCE has an excellent DPV current response to AA and employs split-type scheme, the constructed electrochemical immunoassay has the merits of high preciseness and anti-interference, and its clinical diagnostic results are comparable to those of commercial kits., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Austria, part of Springer Nature.)

Background: As a biomarker of alveolar-capillary basement membrane injury, Krebs von den Lungen-6 (KL-6) is involved in the occurrence and development of pulmonary diseases. However, the role of the KL-6 in patients with acute exacerbation of chronic obstructive pulmonary disease (AECOPD) has yet to be elucidated. This prospective study was designed to clarify the associations of the serum KL-6 with the severity and prognosis in patients with AECOPD., Methods: This study enrolled 199 eligible AECOPD patients. Demographic data and clinical characteristics were recorded. Follow-up was tracked to evaluate acute exacerbation and death. The serum KL-6 concentration was measured via an enzyme-linked immunosorbent assay., Results: Serum KL-6 level at admission was higher in AECOPD patients than in control subjects. The serum KL-6 concentration gradually elevated with increasing severity of AECOPD. Pearson and Spearman analyses revealed that the serum KL-6 concentration was positively correlated with the severity score, monocyte count and concentrations of C-reactive protein, interleukin-6, uric acid, and lactate dehydrogenase in AECOPD patients during hospitalization. A statistical analysis of long-term follow-up data showed that elevated KL-6 level at admission was associated with longer hospital stays, an increased risk of future frequent acute exacerbations, and increased severity of exacerbation in COPD patients., Conclusion: Serum KL-6 level at admission is positively correlated with increased disease severity, prolonged hospital stay and increased risk of future acute exacerbations in COPD patients. There are positive dose-response associations of elevated serum KL-6 with severity and poor prognosis in COPD patients. The serum KL-6 concentration could be a novel diagnostic and prognostic biomarker in AECOPD patients., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Introduction: Krebs von den Lungen 6 (KL-6) is a mucin-1 glycoprotein produced by type II pneumocytes. High levels of KL-6 in blood may be found in patients with lung fibrosis. In Asia this biomarker is used for diagnosis and prognosis in interstitial lung diseases (ILD). There is a lack of information regarding KL-6 cut-off point for diagnosis and prognosis in European population. The aim of this study was to establish the cut-off point for serum KL-6 associated with the presence of ILD in the Spanish population., Methods: Prospective study including subjects who underwent chest HRCT, PFTs and autoimmune blood analysis. Two groups were created: non-ILD subjects and ILD patients. Serum KL-6 concentrations were measured using a Lumipulse KL-6 reagent assay and the optimal cut-off value was evaluated by a ROC analysis. Data on demographics and smoking history was also collected., Results: One hundred seventy-nine patients were included, 102 with ILD. Median serum KL-6 values overall were 762U/mL, 1080 (±787)U/mL for the ILD group vs 340 (±152)U/mL for the non-ILD group (p<0.0001). The main radiological pattern was NSIP (43%). ROC analysis showed greater specificity (86%) and sensitivity (82%) for KL-6 465U/mL for detecting ILD patients. The multivariate logistic regression model pointed to the male sex, higher KL-6 values, lower FVC and low DLCO values as independent factors associated with ILD., Conclusion: Serum KL-6 values greater than 465U/mL have excellent sensitivity and specificity for detecting ILD in our Spanish cohort. Multicentre studies are needed to validate our results., (Copyright © 2024 SEPAR. Published by Elsevier España, S.L.U. All rights reserved.)

Objectives: To study the prevalence of tumor marker (TM) carcinoembryonic antigen (CEA), cancer antigen 125 (CA 125), and cancer antigen 15-3 (CA 15-3) levels in the Saudi population, based on gender, age, and demographic region, and whether the patients were referred by a hospital or self-referred., Methods: Retrospective analysis was carried out on 7,019 samples gathered from the Western, Northern, Central, Southern, and Eastern regions of Saudi Arabia between 2021-2022. The TMs were categorized into normal and abnormal levels, according to the reference ranges. Statistical analysis was carried out to assess the relations between variants (age groups, gender, and demographic regions) using the Chi-square test, and their correlations were assessed using Spearman's test., Results: Among all patients, CEA, CA 125, and CA 15-3 levels were found to be significantly correlated with age ( p =0.0001). The CEA and CA 15-3 levels increased in both males and females with age. The CA 125 was shown to have an abnormally increased level in males with age., Conclusion: Increased levels of CEA, CA 125, and CA 15-3 TMs in the study population were significantly correlated with age. The CEA and CA 15-3 levels were within the normal range, while CA 125 levels were above the normal range in the older male population. These results suggest that the utilization of such TMs is age dependent and would have validity if applied with other parameters., (Copyright: © Saudi Medical Journal.)

Breast cancer poses the significance of early diagnosis and treatment. Here, we developed an innovative photoelectrochemical (PEC) immunosensor characterized by high-level dual photocurrent signals and exceptional sensitivity. The PEC sensor, denoted as MIL&Ag 2 S, was constructed by incorporating Ag 2 S into a metal-organic framework of MIL-101(Cr). This composite not only enhanced electron-hole separation and conductivity but also yielded robust and stable dual photocurrent signals. Through the implementation of signal switching, we achieved the combined detection of cancer antigen 15-3 (CA15-3) and carcinoembryonic antigen (CEA) with outstanding stability, reproducibility, and specificity. The results revealed a linear range for CEA detection spanning 0.01-32 ng/mL, with a remarkably low detection limit of 0.0023 ng/mL. Similarly, for CA15-3 detection, the linear range extended from 0.1 to 320 U/mL, with a low detection limit of 0.014 U/mL. The proposed strategy introduces new avenues for the development of highly efficient, cost-effective, and user-friendly PEC sensors. Furthermore, it holds promising prospects for early clinical diagnosis, contributing to potential breakthroughs in medical detection and ultimately improving patient outcomes.

We report an ultrasensitive sandwich-type electrochemical immunosensor to detect the breast cancer biomarker CA 15-3. Amine-functionalized composite of reduced graphene oxide and Fe 3 O 4 nanoparticles (MRGO-NH 2 ) was used as an electrochemical sensing platform material to modify the electrodes. The nanocomposite comprising Pt and Fe 3 O 4 nanoparticles (NPs) anchored on multiwalled carbon nanotubes (Pt-Fe 3 O 4 -MWCNTs-NH 2 ) was utilized as a pseudoenzymatic signal-amplifying label. Compared to reduced graphene oxide, the composite MRGO-NH 2 platform material demonstrated a higher electrochemical signal. In the Pt-Fe 3 O 4 -MWCNTs-NH 2 label, multiwalled carbon nanotubes provided the substratum to anchor abundant catalytic Pt and Fe 3 O 4 NPs. The nanocomposites were thoroughly characterized using transmission electron microscopy, Fourier transform infrared spectroscopy, X-ray diffraction, scanning electron microscopy, and X-ray photoelectron spectroscopy. An electroanalytical study and prevalidation of the immunosensor was carried out. The immunosensor exhibited exceptional capabilities in detecting CA 15-3, offering a wider linear range of 0.0005-100 U mL -1 and a lower detection limit of 0.00008 U mL -1 . Moreover, the designed immunosensor showed good specificity, reproducibility, and acceptable stability. The sensor was successfully applied to analyze samples from breast cancer patients, yielding reliable results.

Objective: Obesity is a chronic multisystem disease associated with increased morbidity and mortality. Obesity, which is a complex, multifactorial, and heterogeneous condition, is thought to result from the interaction of environmental, physiological, and genetic factors. In this study, the relationship between serum levels of hemoglobin A1c, mucin-1, and nuclear factor κB in obese and healthy cohorts was evaluated along with biochemical and gene expressions and with demographic and clinical covariates, and their effects on obesity were evaluated., Methods: This case-control study included a total of 80 individuals, 40 healthy controls and 40 obesity patients, consisting of female and male aged between 18 and 63 years. Hemoglobin A1c, mucin-1, and nuclear factor κB levels were determined by ELISA in serum samples obtained from patients. In addition, aspartate aminotransferase, alanine transaminase, low density lipoprotein, and glucose values were measured. The gene expressions of the same markers were analyzed by quantitative real-time polymerase chain reaction, and their regulation status was defined., Results: Serum levels of hemoglobin A1c, mucin-1, and nuclear factor κB were found to be high in obese individuals (p<0.05). The gene expression of these serum markers was found to be upregulated. Of the anthropometric measurements, waist circumference and body mass index were correlated with both serum markers and gene expressions (p<0.05)., Conclusion: In addition to the known association of hemoglobin A1c and nuclear factor κB with obesity, serum levels of mucin-1 as well as upregulation of genes point to its modifier effect on obesity. These parameters can be the powerful markers in the diagnosis of obesity.

Objective: The aim of this study was to investigate the diagnostic potential of Krebs von den Lungen-6 (KL-6) in differentiating between malignant pleural effusion (MPE) induced by non-small cell lung cancer (NSCLC) and benign pleural effusion (BPE)., Methods: We collected 143 pleural effusion samples from August 2018 to March 2021. The samples included 91 cases of MPE and 52 cases of BPE. The KL-6 and other indicators in pleural effusion were detected., Results: The level of pleural effusion KL-6 (pKL-6) in the MPE group was significantly higher than in the BPE group (Mann-Whitney U = 442.500, P = .000). The area under the curve (AUC) of pKL-6/pleural effusion adenosine deaminase (pADA) + pleural effusion carcinoembryonic antigen (pCEA)/pADA (AUC = 0.992) in diagnosing MPE was higher than that of pKL-6 alone (AUC = 0.903), with a sensitivity of 93.26% and specificity of 100%., Conclusion: The measurement of pKL-6 can differentiate NSCLC-induced MPE from BPE. Furthermore, the combined detection of pKL-6/pADA and pCEA/pADA can significantly improve the diagnostic efficiency for distinguishing NSCLC-induced MPE., (© The Author(s) 2023. Published by Oxford University Press on behalf of American Society for Clinical Pathology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Introduction: Mucins released from epithelial tumors have been proposed to play a role in cancer-associated thrombosis. Mucin1 (MUC1) is a transmembrane mucin that is overexpressed in a variety of human malignancies, including breast and pancreatic cancer. We analyzed the association of MUC1 and venous thrombosis in a mouse tumor model and in patients with cancer., Materials and Methods: We used a human pancreatic cancer cell line HPAF-II that expresses a high level of MUC1. We grew HPAF-II tumors in the pancreas of Crl:NU-Foxn1 nu male mice. MUC1 in plasma and extracellular vesicles (EVs) isolated from plasma was measured using an enzyme-linked immunosorbent assay. MUC1 in EVs and venous thrombi from tumor-bearing mice was assessed by western blotting. We measured MUC1 in plasma from healthy controls and patients with stomach, colorectal or pancreatic cancer with or without venous thromboembolism., Results and Discussion: MUC1 was detected in the plasma of mice bearing HPAF-II tumors and was associated with EVs. MUC1 was present in venous thrombi from mice bearing HFAP-II tumors. Recombinant MUC1 did not induce platelet aggregation. Levels of MUC1 were higher in patients with pancreatic cancer compared with healthy controls. In contrast to the mouse model, MUC1 was present in EV-free plasma in samples from healthy controls and patients with cancer. There was no significant difference in the levels of MUC1 in cancer patients with or without VTE. Our data did not find any evidence that MUC1 contributed to VTE in patients with cancer., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: Dermatomyositis (DM) is a rare inflammatory disease. Our research focuses on predicting poor prognosis in DM patients and evaluating the prognostic significance of ferritin and Salivary Sugar Chain Antigen-6 (KL-6) through multivariate logistic regression analysis., Methods: Between February 2018 and April 2020, 80 DM patients at our hospital were categorized into MDA5 positive (n = 20) and negative (n = 60) groups. We conducted multivariate logistic regression to determine DM's poor prognosis risk factors and evaluate ferritin/KL-6's predictive value for prognosis., Results: Analysis showed no gender, age, body mass index (BMI), or lifestyle (smoking, drinking) differences, nor in dyspnea, muscle weakness, skin ulcers, and acetylcysteine treatment effects (p > 0.05). Significant differences emerged in arrhythmias, interstitial pneumonia, C-reactive protein, albumin, and lactate dehydrogenase levels (p < 0.05). Before treatment, differences were negligible (p > 0.05), but post-treatment, serum KL-6 and ferritin levels dropped. MDA5 positive patients had elevated serum KL-6 and ferritin levels than survivors (p < 0.05), with a strong correlation to DM. Combined diagnosis using serum KL-6 and ferritin for DM prognosis showed area under curves of 0.716 and 0.634, significantly outperforming single-index diagnoses with an area under curve (AUC) of 0.926 (p < 0.05)., Conclusion: Serum KL-6 and ferritin show marked abnormalities in DM, useful as indicators for evaluating polymyositis and DM conditions. However, the study's small sample size is a drawback. Expanding the sample size is essential to monitor serum KL-6 and ferritin changes in DM patients under treatment more closely, aiming to improve clinical assessment and facilitate detailed research., (© 2024 The Authors. Skin Research and Technology published by John Wiley & Sons Ltd.)

Background: Currently, no ideal biomarker can accurately stratify the risk of patients with severe community-acquired pneumonia (SCAP). This study aimed to evaluate the role of serum Krebs von den Lungen-6 (sKL-6) in predicting in-hospital mortality in adults with SCAP., Methods: In this retrospective cohort study, 249 severe pneumonia adult patients were recruited between 6 May 2021 to 30 April 2023 in Xiangya Hospital of Central South University. The sKL-6 level within 48 h of admission was measured, and the primary outcome assessed was in-hospital mortality. Multivariable logistic regression analysis was performed to calculate adjusted odds ratios (OR) with 95% confidence intervals (CI). Survival curves were plotted and subgroup analyses were conducted, stratified by relevant covariates., Results: A total of 249 patients were included in the study,with 124 patients having normal sKL-6 levels, and 125 patients having abnormal sKL-6 levels. The overall in-hospital mortality rate was 28.9% (72 out of 249 patients). Univariate and multivariate logistic regression analysis revealed that the patients with abnormal sKL-6 levels had a higher risk of in-hospital mortality compared to those with normal sKL-6 levels, both in the total SCAP patient population (OR: 5.38, 95%CI: 2.41-12.01, P < 0.001) and the non-COVID-19 SCAP patients subgroup (OR: 8.12, 95%CI: 3.16-20.84, P < 0.001). Subgroup and interaction analyses confirmed the stability of the relationship between sKL-6 levels and in-hospital mortality(P for interaction > 0.05). Kaplan-Meier survival curves showed that patients with abnormal sKL-6 levels had a higher in-hospital mortality rate than those with normal sKL-6 levels (P < 0.05). However, the results of restricted cubic spline plots(RCS) analysis demonstrated a nonlinear association between sKL-6 levels (as a continuous variable) and in-hospital mortality in patients with SCAP. Similar results were observed in non-COVID-19 SCAP patients. Furthermore, the receiver operating characteristic curve (ROC) analysis revealed that sKL-6 had superior predictive performance compared to existing biomarkers (e.g., APACHE-II, SOFA, BUN/Cr, PCT, and D-dimer) for in-hospital mortality in non-COVID-19 SCAP patients., Conclusion: sKL-6 is a practical and useful biomarker for predicting in-hospital mortality in patients with SCAP., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: Quantitative evaluation of radiographic images has been developed and suggested for the diagnosis of coronavirus disease 2019 (COVID-19). However, there are limited opportunities to use these image-based diagnostic indices in clinical practice. Our aim in this study was to evaluate the utility of a novel visually-based classification of pulmonary findings from computed tomography (CT) images of COVID-19 patients with the following three patterns defined: peripheral, multifocal, and diffuse findings of pneumonia. We also evaluated the prognostic value of this classification to predict the severity of COVID-19., Methods: This was a single-center retrospective cohort study of patients hospitalized with COVID-19 between January 1st and September 30 th , 2020, who presented with suspicious findings on CT lung images at admission (n = 69). We compared the association between the three predefined patterns (peripheral, multifocal, and diffuse), admission to the intensive care unit, tracheal intubation, and death. We tested quantitative CT analysis as an outcome predictor for COVID-19. Quantitative CT analysis was performed using a semi-automated method (Thoracic Volume Computer-Assisted Reading software, GE Health care, United States). Lungs were divided by Hounsfield unit intervals. Compromised lung (%CL) volume was the sum of poorly and non-aerated volumes (- 500, 100 HU). We collected patient clinical data, including demographic and clinical variables at the time of admission., Results: Patients with a diffuse pattern were intubated more frequently and for a longer duration than patients with a peripheral or multifocal pattern. The following clinical variables were significantly different between the diffuse pattern and peripheral and multifocal groups: body temperature (p = 0.04), lymphocyte count (p = 0.01), neutrophil count (p = 0.02), c-reactive protein (p < 0.01), lactate dehydrogenase (p < 0.01), Krebs von den Lungen-6 antigen (p < 0.01), D-dimer (p < 0.01), and steroid (p = 0.01) and favipiravir (p = 0.03) administration., Conclusions: Our simple visual assessment of CT images can predict the severity of illness, a resulting decrease in respiratory function, and the need for supplemental respiratory ventilation among patients with COVID-19., (© 2021. The Author(s).)

Background: Krebs von den Lungen-6 (KL-6) is a molecule that is predominantly expressed by damaged alveolar type II cells, and has been proposed as a marker of COVID-19 and the severity of the disease. Here, we performed a meta-analysis to determine whether KL-6 could be used as a prognostic factor for severe COVID-19., Methods: PubMed, Cochrane and Google Scholar were searched until April 20, 2021, and 7 studies were included. KL-6 was considered as the outcome and pooled in meta-analyses., Results: All included studies compared KL-6 in severe and non-severe patients. Serum KL-6 was higher in severe COVID-19 patients compared to non-severe (n = 6; SMD = 1.25; 95% CI: 0.99-1.5; P < 0.001) and healthy controls (n = 4; SMD = 3.07; 95% CI: 1.36-4.8; P < 0.001)., Conclusion: This data collection revealed the potential clinical significance of KL-6 as a non-expensive predictive biomarker in severe COVID-19 and for the categorization of COVID-19 clinical severity., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: The clinical course of patients with systemic sclerosis-associated interstitial lung disease (SSc-ILD) is highly variable. The Krebs von den Lungen-6 (KL-6) glycoprotein is a promising biomarker for reflecting epithelial injury. However, serum KL-6 and its association with the progression of SSc-ILD have been understudied., Methods: We reviewed 77 consecutive patients with SSc-ILD seen from 2004 to 2016. A longitudinal study of forced vital capacity (FVC), serum KL-6 levels, and changes in KL-6 levels from baseline (ΔKL-6) was conducted. The progression of ILD was defined as ≥10% relative decline in FVC predicted or 5%-10% decline in FVC predicted along with radiological progression on chest computed tomography. The risk factors for ILD progression were assessed by univariate and multivariate regression., Results: During a 5-year follow-up period, 10 (13%) patients showed rapid progression of ILD within 2 years, 39 (51%) showed overall progression during the 5 years, and 28 (36%) had stable disease. Most patients with progressive ILD showed elevations in serum KL-6 levels over the initial 1-year follow-up period. The best cut-off value for ΔKL-6 that predicted progression of ILD was 193 U/mL (sensitivity 81.6%, specificity 92.9%). Multivariate analysis adjusted by age, sex, smoking status, and immunosuppressant use found that diffuse cutaneous SSc (hazard ratio [HR] 4.51; 95% confidence interval [CI] 1.56-13.04) and ΔKL-6 > 193 U/mL from baseline (HR 7.19; 95% CI 3.30-15.69) were independent predictors for progression of SSc-ILD., Conclusion: Changes in the KL-6 level can be useful for predicting disease progression in patients with SSc-ILD., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

A sensitive detection of carbohydrate antigen 15-3 (CA15-3) levels may allow for early diagnosis and monitoring the treatment of breast cancer, but this can only be made in routine clinical practice if low-cost immunosensors are available. In this work, we developed a sandwich-type electrochemical immunosensor capable of rapid detection of CA15-3 with an ultra-low limit of detection (LOD) of 0.08 fg mL -1 within a wide linear concentration range from 0.1 fg mL -1 to 1 µg mL -1 . The immunosensor had a matrix of a layer-by-layer film of Au nanoparticles and reduced graphene oxide (Au-rGO) co-electrodeposited on screen-printed carbon electrodes (SPCE). The high sensitivity was achieved by using secondary antibodies (Ab 2 ) labeled with horseradish peroxidase (HRP) in the presence of hydrogen peroxide (H 2 O 2 ) as signal amplifiers, and hydroquinone (HQ) was used as an electron mediator. The immunosensor was selective for CA15-3 in human serum and artificial saliva samples, robust, and stable to permit storage at 4 °C for more than 30 days. With its high performance, the immunosensor may be incorporated into future point-of-care (POC) devices to determine CA15-3 in distinct biological fluids, including in blood and saliva samples., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Austria, part of Springer Nature.)

Mucin 1 (MUC1) has been regarded as an ideal target for cancer treatment, since it is overexpressed in a variety of different cancers including the majority of breast cancer. However, there are still no approved monoclonal antibody drugs targeting MUC1. In this study, we generated a humanized MUC1 (HzMUC1) antibody from our previously developed MUC1 mouse monoclonal antibody that only recognizes MUC1 on the surface of tumor cells. Furthermore, an antibody-drug conjugate (ADC) was generated by conjugating HzMUC1 with monomethyl auristatin (MMAE), and the efficacy of HzMUC1-MMAE on the MUC1-positive HER2+ breast cancer in vitro and in 'Xenograft' model was tested. Results from western blot analysis and immunoprecipitation revealed that the HzMUC1 antibody did not recognize cell-free MUC1-N in sera from breast cancer patients. Confocal microscopy analysis showed that HzMUC1 antibody bound to MUC1 on the surface of breast cancer cells. Results from mapping experiments suggested that HzMUC1 may recognize an epitope present in the interaction region between MUC1-N and MUC1-C. Results from colony formation assay and flow cytometry demonstrated that HzMUC1-MMAE significantly inhibited cell growth by inducing G2/M cell cycle arrest and apoptosis in trastuzumab-resistant HER2-positive breast cancer cells. Meanwhile, HzMUC1-MMAE significantly reduced the growth of HCC1954 xenograft tumors by inhibiting cell proliferation and enhancing cell death. In conclusion, our results indicate that HzMUC1-ADC is a novel therapeutic drug that can overcome trastuzumab resistance of breast cancer. HzMUC1-ADC should also be an effective therapeutic drug for the treatment of different MUC1-positive cancers in clinic., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

The clinical relevance of Krebs von den Lungen-6 (KL-6) levels in patients with coronavirus disease 2019 (COVID-19) is unclear. This study aimed to evaluate the correlation between KL-6 levels, laboratory parameters, and clinical outcomes. We enrolled 364 patients with confirmed COVID-19 who were hospitalized within 1 week of symptom onset. Their serum KL-6 level was measured on admission. Demographic data, symptoms, comorbidities, and laboratory parameters were recorded at the time of admission. Days to nucleic acid conversion and days of hospitalization were defined as clinical outcomes for evaluating the clinical relevance of serum KL-6 levels in COVID-19. Patients with elevated KL-6 levels were significantly older; had more reported instances of fever, cough, fatigue, and wheezing; and a longer hospital stays than those with normal KL-6 levels; the difference was statistically significant (p < 0.001). Furthermore, KL-6 levels was associated with the days of hospitalization and various laboratory parameters that influence the severity and prognosis of COVID-19. Elevated KL-6 levels have also been shown to be an independent risk factor for prolonged hospitalization. Our data suggest that serum KL-6 levels on admission can serve as an indicator for assessing the clinical outcomes of COVID-19., (Copyright © 2021. Published by Elsevier Ltd.)

This study was aimed to evaluate serum KL-6 levels to determine if this marker can be used for diagnosing and assessing severity of interstitial lung disease (ILD) in children with connective tissue disorders. In total, 40 patients [18 patients with juvenile systemic lupus erythematosus (JSLE), 10 patients with juvenile idiopathic arthritis (JIA), 8 patients with juvenile mixed connective tissue disease (JMCTD), 3 patients with juvenile systemic sclerosis (JSSc), and 1 patient with juvenile dermatomyositis (JDM)] and 20 healthy controls were included in this study. Age, sex, and duration of CTD and ILD (if any) were recorded. Blood samples from all the patients and controls were examined by ELISA. 20 of the 40 patients with CTD (50%) had ILD, 12 were mild and 8 were severe as assessed by spirometry. The median serum KL-6 level was 102.7 U/mL (76.1-180.8) in the CTD with severe ILD group, 72.2 U/mL (58.4- 100.5) in the CTD with mild ILD group, 56.7 U/mL (35.8-68.5) in the CTD without ILD group, and 52.3 U/mL (32.8-62.4) in the control group. KL-6 levels were significantly higher in the CTD with ILD (p<0.05), at a cutoff of 63.4 U/ml identified by ROC curve, serum KL-6 showed a sensitivity of 95.2% and specificity of 89.7%. KL-6 is a valuable biomarker for diagnostic purposes and to detect severity in ILD in childhood CTD.

Mucin 1/Krebs von den Lungen-6 (KL-6) is proposed as a serum biomarker of several interstitial lung diseases (ILDs), including connective tissue disorders associated with ILD. However, it has not been studied in a large cohort of Caucasian antisynthetase syndrome (ASSD) patients. Consequently, we assessed the role of MUC1 rs4072037 and serum KL-6 levels as a potential biomarker of ASSD susceptibility and for the differential diagnosis between patients with ILD associated with ASSD (ASSD-ILD +) and idiopathic pulmonary fibrosis (IPF). 168 ASSD patients (149 ASSD-ILD +), 174 IPF patients and 523 healthy controls were genotyped for MUC1 rs4072037 T > C. Serum KL-6 levels were determined in a subgroup of individuals. A significant increase of MUC1 rs4072037 CC genotype and C allele frequencies was observed in ASSD patients compared to healthy controls. Likewise, MUC1 rs4072037 TC and CC genotypes and C allele frequencies were significantly different between ASSD-ILD+ and IPF patients. Additionally, serum KL-6 levels were significantly higher in ASSD patients compared to healthy controls. Nevertheless, no differences in serum KL-6 levels were found between ASSD-ILD+ and IPF patients. Our results suggest that the presence of MUC1 rs4072037 C allele increases the risk of ASSD and it could be a useful genetic biomarker for the differential diagnosis between ASSD-ILD+ and IPF patients., (© 2021. The Author(s).)

Background: Lung injury is common in coronavirus disease 2019 (COVID-19) patients. The severity of lung injury appears to be reflected in serum Krebs von den Lungen-6 (KL-6), a glycoprotein expressed on type II alveolar epithelium. This study aims to assess the role of serum KL-6 in reflecting the severity of lung injury in COVID-19 patients., Methods: A systematic search was conducted in Scopus, PubMed, Wiley Online Library, and ProQuest. Articles were screened based on several eligibility criteria and assessed for study quality using Newcastle-Ottawa Scale., Results: This systematic review included four studies involving a total of 151 adult COVID-19 patients. Pooled analysis revealed that serum KL-6 was significantly higher in severe patients (SMD = 1.16; 95% CI = 0.69–1.63) with moderately high pooled sensitivity (79%; 95% CI = 61–91%) and specificity (86%; 95% CI = 72–95%)., Conclusion: High serum KL-6 may depict more severe lung injury in COVID-19 patients with moderately high sensitivity and specificity.

Abstract: The prognosis of patients with postmenopausal breast cancer (PBC) could be improved by the early detection of intraocular metastases (IOMs). However, serum biomarkers for IOMs in PBC remain elusive. In the current study, we investigated patients with PBC, and compared serum parameters in an IOM and a non-IOM group, and then differentiated the risk factors related to IOMs. A comparison between an IOM and a non-IOM (NIOM) group was performed using Student t-test and a Chi-Squared test. After constructing a Poisson regression model to identify risk factors, we plotted receiver operating characteristic curves to evaluate the predictive value of significant risk factors in detecting IOMs. The incidence of IOMs in PBC was 1.16%. The histopathology results were not significantly different between the 2 groups. The levels of serum carbohydrate antigen 125 (CA-125), carbohydrate antigen 15-3 (CA15-3) and alkaline phosphatase were significantly elevated in IOMs compared with NIOMs (P = .082, P < .001, and P < .001, respectively). Compared with NIOMs, age, carbohydrate antigen 19 to 9, hemoglobin, calcium, total cholesterol, low-density lipoprotein (LDL) and apolipoprotein A1 were remarkably lower in IOMs (P = .038, P < .001, P < .001, P = .032, P = .041, P < .001, and P = .001, respectively). Poisson regression suggested that CA-125, CA15-3 and LDL were contributing to IOMs in PBC as risk factors (OR = 1.003, 95% CI: 1.001-1.005; OR = 1.025, 95% CI: 1.019-1.033; OR = 0.238, 95% CI: 0.112-0.505, respectively). A receiver operating characteristic curve revealed that the cut-off values for CA-125, CA15-3 and LDL were 16.78 0 U/mL, 63.175 U/mL, and 2.415 mmol/L, respectively. The combination of CA-125 and CA15-3 showed significant diagnostic value (area under the curve [AUC] = 0.982, P < .001). Our investigation suggests that CA-125, CA15-3 and LDL remarkably predict IOMs in PBC as risk factors, and the combination of CA-125 and CA15-3 shows considerable diagnostic value., Competing Interests: The authors have no conflicts of interests to disclose., (Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.)

COVID-19 pandemic led to a worldwide increase of hospitalizations for interstitial pneumonia with thrombosis complications, endothelial injury and multiorgan disease. Common CT findings include lung bilateral infiltrates, bilateral ground-glass opacities and/or consolidation whilst no current laboratory parameter consents rapidly evaluation of COVID-19 risk and disease severity. In the present work we investigated the association of sFLT-1 and CA 15.3 with endothelial damage and pulmonary fibrosis. Serum sFlt-1 has been associated with endothelial injury and sepsis severity, CA 15.3 seems an alternative marker for KL-6 for fibrotic lung diseases and pulmonary interstitial damage. We analysed 262 SARS-CoV-2 patients with differing levels of clinical severity; we found an association of serum sFlt-1 (ROC AUC 0.902, decision threshold > 90.3 pg/mL, p < 0.001 Sens. 83.9% and Spec. 86.7%) with presence, extent and severity of the disease. Moreover, CA 15.3 appeared significantly increased in COVID-19 severe lung fibrosis (ICU vs NON-ICU patients 42.6 ± 3.3 vs 25.7 ± 1.5 U/mL, p < 0.0001) and was associated with lung damage severity grade (ROC AUC 0.958, decision threshold > 24.8 U/mL, p < 0.0001, Sens. 88.4% and Spec. 91.8%). In conclusion, serum levels of sFlt-1 and CA 15.3 appeared useful tools for categorizing COVID-19 clinical stage and may represent a valid aid for clinicians to better personalise treatment., (© 2021. The Author(s).)

Objectives: Molecular subtypes are employed as a guide for targeted treatment and important prognostic factors. This study focused on investigating the association of serum levels of CEA, CA15-3, and CA125 with clinicopathological characteristics of breast cancer to find prognostic markers for breast cancer and provide precise targeted therapy., Materials and Methods: In this study, 961 breast cancer patients with preoperative serum levels of CEA, CA15-3, and CA125 and molecular subtypes were analyzed. Cut-off values of 5 ng/ml, 25 U/ml, and 35 U/ml were used for CEA, CA15-3, and CA125, respectively. The χ 2 test and Fisher exact test along with logistic multivariate regression analysis were performed for investigating the correlation of CEA, CA15-3, and CA125 serum levels with molecular subtypes and associated factors., Results: An increase in the serum concentrations of CEA, CA15-3, and CA125 was discovered in 48 (4.99%), 54 (5.62%), and 55 (5.72%) breast cancer patients, respectively. Univariate analysis demonstrated that the levels of CEA ( p < 0.01) and CA15-3 ( p < 0.05) were significantly linked with molecular types of breast cancer. Moreover, patients having larger tumor size ( p < 0.01, p < 0.0001, and p < 0.05, respectively) along with nodal metastasis ( p < 0.05, p = 0.0001, and p < 0.05, respectively) exhibited higher rates of elevated CEA, CA15-3, and CA125 levels. Status of Her-2 positive ( p < 0.01) had a significant connection with elevated CEA levels. Multivariate analysis further indicated that molecular subtypes were independent factors associated with CEA and CA15-3 levels. Also, Her-2 status was significantly and independently related to CEA levels., Conclusion: Preoperative serum levels of CEA and CA15-3 were independently associated with molecular subtypes of breast cancer. CEA and CA15-3 might improve the prognostic prediction for patients with breast cancer and inform the selection of specific therapies. A further biological analysis is needed for investigating the relationship between Her-2 expression and CEA levels., Competing Interests: The authors of this study declare no conflict of interests., (Copyright © 2021 Wenjing Zhao et al.)

The new type of coronavirus could cause severe acute respiratory syndrome and injuries in other systems as well. Multiple organ damage can occur rapidly in patients infected with coronavirus disease 2019 (COVID-19). Previous studies have shown that many laboratory biomarkers were not within the normal ranges in COVID-19 patients. We aimed to summarize laboratory parameters and the tumor markers in COVID-19 patients. This is a retrospective cohort study conducted on 53 women between the ages of 19-85 years infected with COVID-19 at a training and research hospital between May 2020 and August 2020. Of the 53 women, 16 (30.2%) had leukopenia. The mean C-reactive protein level was 18.42 ± 59.33 mg/L. The mean procalcitonin level was 0.1 ± 0.21 µg/L. The liver function tests were within normal limits. The mean creatinine level was 0.58 ± 0.37 mg/dl. Elevated levels of α-fetoprotein (AFP) in 1 patient, elevated levels of carcinoembryonic antigen (CEA) in 2 patients, elevated levels of cancer antigen 125 (CA125) in 4 patients, elevated levels of CA19-9 in 2 patients, and elevated levels of CA15-3 in 2 patients were detected. One of 4 patients who were taken to the intensive care unit had elevated levels of AFP. In addition, 2 of 4 patients who were taken to the intensive care unit had elevated levels of CA125 and CA15-3. Except for AFP, levels of all tumor markers of the patient who died were high. We found that COVID-19 had no effect on tumor markers (CA125, CA19-9, CA15-3, AFP, and CEA)., (© 2021 Wiley Periodicals LLC.)

SARS-CoV2-induced direct cytopathic effects against type II pneumocytes are suspected to play a role in mediating and perpetuating lung damage. The aim of this study was to evaluate serum KL-6 behavior in COVID-19 patients to investigate its potential role in predicting clinical course. Sixty patients (median age IQR, 65 (52-69), 43 males), hospitalized for COVID-19 at Siena COVID Unit University Hospital, were prospectively enrolled. Twenty-six patients were selected (median age IQR, 63 (55-71), 16 males); all of them underwent follow-up evaluations, including clinical, radiological, functional, and serum KL-6 assessments, after 6 (t1) and 9 (t2) months from hospital discharge. At t0, KL-6 concentrations were significantly higher than those at t1 (760 (311-1218) vs. 309 (210-408) p = 0.0208) and t2 (760 (311-1218) vs 324 (279-458), p = 0.0365). At t0, KL-6 concentrations were increased in patients with fibrotic lung alterations than in non-fibrotic group (755 (370-1023) vs. 305 (225-608), p = 0.0225). Area under the receiver operating curve (AUROC) analysis showed that basal KL-6 levels showed good accuracy in discriminating patients with fibrotic sequelae radiologically documented (AUC 85%, p = 0.0404). KL-6 concentrations in patients with fibrotic involvement were significantly reduced at t1 (755 (370-1023) vs. 290 (197-521), p = 0.0366) and t2 (755 (370-1023) vs. 318 (173-435), p = 0.0490). Serum concentrations of KL-6 in hospitalized COVID-19 patients may contribute to identify severe patients requiring mechanical ventilation and to predict those who will develop pulmonary fibrotic sequelae in the follow-up., (© 2021. The Author(s).)

Takotsubo syndrome (TTS) is an acute heart failure syndrome with significant rates of in and out-of-hospital mayor cardiac adverse events (MACE). To evaluate the possible role of neoplastic biomarkers [CA-15.3, CA-19.9 and Carcinoembryonic Antigen (CEA)] as prognostic marker at short- and long-term follow-up in subjects with TTS. Ninety consecutive subjects with TTS were enrolled and followed for a median of 3 years. Circulating levels of CA-15.3, CA-19.9 and CEA were evaluated at admission, after 72 h and at discharge. Incidence of MACE during hospitalization and follow-up were recorded. Forty-three (46%) patients experienced MACE during hospitalization. These patients had increased admission levels of CEA (4.3 ± 6.2 vs. 2.2 ± 1.5 ng/mL, p = 0.03). CEA levels were higher in subjects with in-hospital MACE. At long term follow-up, CEA and CA-19.9 levels were associated with increased risk of death (log rank p < 0.01, HR = 5.3, 95% CI 1.9-14.8, HR = 7.8 95% CI 2.4-25.1, respectively, p < 0.01). At multivariable analysis levels higher than median of CEA, CA-19.9 or both were independent predictors of death at long term (Log-Rank p < 0.01). Having both CEA and CA-19.9 levels above median (> 2 ng/mL, > 8 UI/mL respectively) was associated with an increased risk of mortality of 11.8 (95% CI 2.6-52.5, p = 0.001) at follow up. Increased CEA and CA-19.9 serum levels are associated with higher risk of death at long-term follow up in patients with TTS. CEA serum levels are correlated with in-hospital MACE., (© 2021. The Author(s).)

Background: Krebs von den Lungen-6 (KL-6) is a high-molecular-weight (200kDa) glycoprotein proposed as a diagnostic biomarker for differentiating interstitial lung disease (ILD). Systemic sclerosis (SSc) is a rare immune-mediated disorder, and ILD is the leading cause of morbidity and mortality. Pleuroparenchymal fibroelastosis (PPFE) has been described to have a poor prognosis in SSc-ILD patients. This study undertook to compare serial changes in KL-6 in SSc-ILD patients with and without PPFE, to verify its prognostic value as a disease biomarker., Materials and Methods: Twenty-five SSc-ILD patients (median IQR, 62 (56-58); 20% males) were retrospectively enrolled. 12 SSc-ILD patients (48%) had also a radiological diagnosis of PPFE. Serum KL-6 concentrations were measured by KL-6 reagent assay (Fujirebio Europe, Ghent, Belgium)., Results: Serum KL-6 measurements were increased in SSc-ILD patients with and without PPFE compared with healthy controls (P < .0001). Comparative analysis of the rate of variation of KL-6 over the 6 years of follow-up was performed by serial two-yearly KL-6 measurements: Δ1(t1-t0), Δ2(t2-t1) and Δ3(t3-t2). In SSc-ILD patients with PPFE pattern, Δ3 was significantly different than those without PPFE pattern (P = .0020). Serum KL-6 levels were significantly different (P = .0455) either at Δ2 and Δ3 in the PPFE group. In SSc-ILD patients with PPFE, at t3 serum KL-6 concentrations were inversely correlated with FEV1 (r = -.76; P = .037) and FVC percentages (r = -.79; P = .028)., Conclusion: These results suggest that serial measurements of KL-6 in the follow-up of these patients may help to monitor disease progression. In real life, in SSc-ILD patients PPFE should be always evaluated at CT and when present should suggest a tight follow-up to monitor its evolution., (© 2021 Stichting European Society for Clinical Investigation Journal Foundation. Published by John Wiley & Sons Ltd.)

Background: Circulating levels of cancer antigen (CA) 15-3, a tumor marker and regulator of cellular metabolism, were reduced by metformin in a nonrandomized neoadjuvant study. We examined the effects of metformin (vs placebo) on CA 15-3 in participants of MA.32, a phase III randomized trial in early-stage breast cancer., Methods: A total of 3649 patients with T1-3, N0-3, M0 breast cancer were randomly assigned; pretreatment and 6-month on-treatment fasting plasma were centrally assayed for CA 15-3. Genomic DNA was analyzed for the rs11212617 single nucleotide polymorphism. Absolute and relative change of CA 15-3 (metformin vs placebo) were compared using Wilcoxon rank and t tests. Regression models adjusted for baseline differences and assessed key interactions. All statistical tests were 2-sided., Results: Mean (SD) age was 52.4 (10.0) years. The majority of patients had T2/3, node-positive, hormone receptor-positive, HER2-negative breast cancer treated with (neo)adjuvant chemotherapy and hormone therapy. Mean (SD) baseline CA 15-3 was 17.7 (7.6) and 18.0 (8.1 U/mL). At 6 months, CA 15-3 was statistically significantly reduced in metformin vs placebo arms (absolute geometric mean reduction in CA 15-3 = 7.7% vs 2.0%, P  <   .001; relative metformin: placebo level of CA 15-3 [adjusted for age, baseline body mass index, and baseline CA 15-3] = 0.94, 95% confidence interval = 0.92 to 0.96). This reduction was independent of tumor characteristics, perioperative systemic therapy, baseline body mass index, insulin, and the single nucleotide polymorphism status (all Ps  >   .11)., Conclusions: Our observation that metformin reduces CA 15-3 by approximately 6% was corroborated in a large placebo-controlled randomized trial. The clinical implications of this reduction in CA 15-3 will be explored in upcoming efficacy analyses of breast cancer outcomes in MA.32., (© The Author(s) 2021. Published by Oxford University Press.)

Endometriosis is one of the most common benign gynaecologic diseases and its clinical presentation is generally ovarian endometrioma. We aimed to assess the association of tumour markers with histopathological structure of ovarian endometriomas to assess their roles in clinical management. Data from 86 women who underwent laparoscopic surgery for ovarian endometrioma were evaluated. The possible risk factors for inadvertently removed normal ovarian parenchyma (IRNOP) during laparoscopic cystectomy and the relationship between tumour markers and histopathologic parameters of ovarian endometrioma were assessed. Age and the depth of penetration of endometrial tissue into the cyst wall showed a significant positive correlation with thickness of IRNOP. There was a significant negative correlation between IRNOP and the thickness of fibrosis on cyst wall. Thickness of fibrosis and the depth of penetration represented significant positive correlations with tumour markers (CA 125, CA 15-3, and CA 19-9), respectively. This is the first study that reveals the association between tumour markers and the histopathologic features of ovarian endometrioma. The outcome of the present study indicated that lower levels of tumour markers may permit a conservative management, rising levels may help in timing of a possible surgical intervention and high levels may help in counselling postoperative outcomes.Impact statement What is already known on this subject? Endometriosis is defined as a benign gynaecologic disease, and the vast majority of women who suffer from endometriosis are of reproductive age. Ovarian endometriotic cysts are found in one-fifth to one-half of patients with endometriosis. Laparoscopic cystectomy is accepted as the gold standard for the surgical management of ovarian endometriotic cysts because of the procedure's several clinical advantages, such as lower recurrence and higher pregnancy rates. However, studies have indicated that laparoscopic excision of an ovarian endometrioma capsule could be associated with a reduction in both the ovarian volume and the follicle count. What do the results of this study add? Our retrospective data indicate that tumour markers may have role in planning the management of ovarian endometriomas. What are the implications of these findings for clinical practice and/or further research? Low tumour markers levels may permit a conservative management, elevating levels may help in timing of a possible surgical intervention and finally high levels may help in counselling the patient about her possible postoperative outcomes.

Background: Due to insufficient scientific evidence, panels of tumour markers (TMs) are currently not recommended for use in suspected cancer. However, recent well-designed studies have revealed a potential clinical value in lung cancer. We analysed the diagnostic accuracy of a panel of 11 circulating TMs with clinically controlled thresholds in the differentiation of cancer from nonmalignant diseases., Methods: We prospectively recruited 4776 consecutive patients presenting with focal or nonspecific symptoms suggestive of cancer who underwent testing for 11 serum TMs before diagnosis was known. The study abided by 2015 STARD guidelines. Tumour markers included, among others, carbohydrate antigen 19-9, carcinoembryonic antigen, alpha-fetoprotein, squamous cell carcinoma-associated antigen, prostate-specific antigen (males), neuron-specific enolase, progastrin-releasing peptide and carbohydrate antigen 125. Thresholds were adjusted for the presence of kidney failure, liver disease, effusions and dermatological disorders. Results showing ≥1 TMs with concentrations above threshold were considered positive., Results: Benign diseases were diagnosed in 3281 (68.7%) patients and cancer in 1495 (31.3%), with epithelial cancers in 1214 (77% at stage IV). When applying criteria for controlled thresholds, overall specificity was 98%. Overall sensitivity of the panel in epithelial cancers was 72.2%, positive predictive value 93% and negative predictive value 90.5%. The area under the receiver operating characteristic curve was 0.920 (95% confidence interval, 0.902-0.924)., Conclusions: By using clinically controlled cut-offs, the combined panel demonstrated an excellent ability to discriminate epithelial cancers from nonmalignant diseases. However, its use in clinical practice would need formal validation through a multicentre controlled trial assessing a panel-guided strategy vs. standard diagnosis., (© 2021 Stichting European Society for Clinical Investigation Journal Foundation. Published by John Wiley & Sons Ltd.)