Diagnostic algorithm based on ratio of ascites-serum tumor markers is superior to tumor markers in the differentiation of benign ascites from malignant ascites.

BACKGROUND: Differential diagnosis between benign ascites and malignant ascites remains challenging in clinical practice, the aim of our study is to determine the differential value of the ratio of ascitic-serum tumor markers between benign ascites and malignant ascites. METHODS: 418 patients with new-onset ascites were retrospectively enrolled in this study. The pertinent data of patients enrolled were collected; diagnostic value of tumor markers, ascites-serum tumor marker ratio, and diagnostic algorithm based on ascitic tumor markers and ascites-serum tumor marker ratio in patients with ascites were investigated. RESULTS: 81.25.% of the patients with benign ascites had low (<1) ratio of ascites-serum tumor markers (Max [A/S CEA, A/S CA15-3, A/S CA19-9]); and 91.88% of patients with benign ascites had the ratio of ascites-serum tumor marker less than 1.5. On the other hand, 94.96% of the patients with malignant ascites had high (≥1) ratio of ascites-serum tumor markers; and 97.29% of patients with malignant ascites had the ratio of ascites-serum tumor markers more than 0.67. Finally, diagnostic algorithm based on ascitic tumor markers and ascites-serum tumor marker ratio showed 96.37% of the sensitivity, and 94.37% of the accuracy in the diagnosis of malignant ascites, while ascitic tumor markers with a sensitivity of 78.29%, and an accuracy of 84.93%. CONCLUSIONS: Diagnostic algorithm based on ascitic tumor markers and ascites-serum tumor marker ratio exhibited an excellent performance in distinguishing benign and malignant ascites, which should be recommended in patients with new-onset ascites in clinical practice.

Down-regulated lncRNA ROR in tumor-educated platelets as a liquid-biopsy biomarker for nasopharyngeal carcinoma.

PURPOSES: To evaluate the diagnostic value of tumor-educated platelets (TEP) lncRNA ROR for nasopharyngeal carcinoma (NPC). METHODS: Quantitative real-time PCR was used to determine the expression level of TEP lncRNA ROR in NPC patients (n = 50) as compared to normal subjects (n = 33). The ROC curve analysis was performed to assess the diagnostic value of TEP lncRNA ROR for NPC. Correlations between TEP lncRNA ROR and clinical parameters were further analyzed. RESULTS: The median of TEP lncRNA ROR was significantly lower in NPC patients than that in normal subjects (0.0209 vs 0.0610, p = 0.0019), while no significant difference was found in plasma lncRNA ROR. ROC analysis showed that TEP lncRNA ROR had a sensitivity of 60%, specificity of 70%, and accuracy of 63.9% in diagnosing NPC, and the area under ROC curve (AUC) was 0.70. The expression level of TEP lncRNA ROR in NPC showed no significant difference among different TNM stages. However, low level of TEP lncRNA ROR correlated well with positive Epstein-Barr virus (EBV) DNA (kappa value = 0.314, p = 0.06), TEP lncRNA ROR and EBV DNA had similar diagnostic positive rate (58.3%) for NPC, and the combination of TEP lncRNA ROR and EBV DNA increased the positive rate to 74%. CONCLUSION: The expression level of TEP lncRNA ROR was down-regulated in NPC and the diagnostic value of TEP lncRNA ROR was similar to EBV DNA. Our study indicated that TEP lncRNA ROR might serve as a novel type of liquid biopsy biomarker in diagnosis of NPC patients.

Utility of ascitic tumor markers and adenosine deaminase for differential diagnosis of tuberculous peritonitis and peritoneal carcinomatosis.

BACKGROUND: Differential diagnosis between tuberculous peritonitis and peritoneal carcinomatosis remains challenging in clinical practice; thus, in-patients diagnosed with tuberculous peritonitis or peritoneal carcinomatosis were retrospectively enrolled, and diagnostic values of ascitic tumor markers and adenosine deaminase were determined. METHODS: Consecutive patients diagnosed with tuberculous peritonitis or peritoneal carcinomatosis were retrospectively enrolled. The pertinent data of 169 patients enrolled were collected. RESULTS: A panel of ascitic tumor makers (CEA, CA15-3, CA19-9) had high specificity (96.83%) and accuracy (94.67%) in the differentiation of peritoneal carcinomatosis from tuberculous peritonitis; and ascitic ADA was a good discriminator between these patients, with an accuracy of 91.72%. Combined use of ascitic tumor makers and ADA (ascitic ADA < 22.5 IU/L or ascitic CEA > 3.65 ng/mL or CA15-3 > 42.70 U/mL or CA19-9 > 25.10 U/mL) performed high sensitivity (99.06%) and accuracy (94.08%) for the diagnosis of peritoneal carcinomatosis. In addition, combined ascitic ADA and tumor marker (positive ascitic tumor makers and ADA < 22.50 IU/L) had 100% of the specificity in diagnosing peritoneal carcinomatosis. CONCLUSIONS: Combined use of ascitic tumor markers and adenosine deaminase showed excellent efficiency in the differential diagnosis between tuberculous peritonitis and peritoneal carcinomatosis, thus these two simple and cost-effective parameters should be determined when tuberculous peritonitis or peritoneal carcinomatosis was suspected in clinic practice.

Duration of antibody responses following severe acute respiratory syndrome coronavirus 2 infection.

BACKGROUND: Little is known on the duration of anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) immunoglobulin G (IgG) antibodies in patients following SARS-CoV-2 infection. AIMS: We aimed to determine the duration of the immunoglobulin G (IgG) and M (IgM) antibody responses following SARS-CoV-2 infection and to evaluate the risk factors for a short duration of anti-SARS-CoV-2 IgG. METHODS: We measured antibody responses in 94 patients who had recovered from SARS-CoV-2 infection. The chi-square test and multivariable logistic regression analysis were used to identify risk factors for a short duration (< 6 months) of anti-SARS-CoV-2 IgG. RESULTS: IgG antibodies were detectable in all patients until 4 months; 19 (21.8%) convalescent patients reverted to IgG negative 4-6 months after symptom onset. IgM antibodies decreased significantly to 5.7% at 4-6 months after symptom onset. Patient characteristics were not associated with a short duration of detectable IgG. CONCLUSIONS: A substantial fraction of convalescents may exhibit a transient IgG response following SARS-CoV-2 infection. Our findings suggest that patients who have recovered from SARS-CoV-2 infection should also be vaccinated if their anti-SARS-CoV-2 IgG antibodies are undetectable.

MS275 as Class I HDAC inhibitor displayed therapeutic potential on malignant ascites by iTRAQ-based quantitative proteomic analysis.

BACKGROUND: Malignant ascites is a manifestation of end stage events in a variety of cancers and is associated with significant morbidity. Epigenetic modulators play a key role in cancer initiation and progression, among which histone deacetylases (HDACs) are considered as one of the most important regulators for various cancer development, such as liver cancer, ovarian cancer, and pancreatic cancer et al. Thus, in this paper, we sought to explore the therapeutic effect of HDAC inhibitor on malignant ascites. METHODS: In this report, we tested the therapeutic effect of different isoform selective HDAC inhibitors (Class I HDACI MS275, Class IIa HDACI MC1568, pan-HDAC inhibitors SAHA) on malignant ascites in vitro and in vivo. We further used proteome analysis to find the potential mechanisms for malignant ascites therapy. RESULTS: Among the different isoform-selective HDAC inhibitors, the class I selective HDACI, MS275, exhibited preferential inhibition on various ascites cells. MS275 could induce cell cycle arrest in G0/G1 phase and promote apoptosis on ascites cells. Through proteome analysis, we found MS275 could downregulate proteins related to cell cycle progression, such as CDK4, CDC20, CCND1; MS275 could upregulate pro-apoptosis proteins such as PAPR1, LMNB2 and AIFM1; in addition, MS275 could change the expression of tumorigenic proteins related to the specific malignant ascites bearing tumors, such as TSP1 and CDK4 for bladder cancer. We then confirmed that abemaciclib (CDK4/6 selective inhibitor) could inhibit the proliferation of ascites cells, and the combination of abemaciclib and MS275 had synergistic anti-tumor effect. Finally, we found that MS275 could in vivo inhibit malignant ascites progression (ascites volume: 2.9 ± 1.0 mL vs 7.5 ± 1.2 mL, p < 0.01), tumor growth, and prolong 66% of the life-span when compared with the untreated group. CONCLUSION: This present research revealed that the class I selective HDAC inhibitor, MS275, could effectively inhibit malignant ascites development and tumor growth via multiple pathways. These results indicated that HDACI could have great potential for clinical therapy of malignant ascites.

Tumor-Educated Platelet miR-18a-3p as a Novel Liquid-Biopsy Biomarker for Early Diagnosis and Chemotherapy Efficacy Monitoring in Nasopharyngeal Carcinoma.

AIMS: To evaluate the value of tumor-educated platelet (TEP) miR-18a-3p in the early diagnosis and chemotherapy efficacy monitoring of nasopharyngeal carcinoma (NPC). METHODS: Expression levels of miR-18a-3p in platelets and plasma were detected by relative quantitative real-time PCR in NPC patients (n=54) and normal subjects (n=36). Diagnostic values of TEP miR-18a-3p for NPC was assessed by receiver operating characteristic (ROC) curve analysis. Follow up study was carried out to observe the dynamic changes of TEP miR-18a-3p with chemotherapy on 3 NPC patients. RESULTS: The expression levels of TEP miR-18a-3p in NPC patients were significantly higher than that in healthy controls (p < 0.0001). ROC curve analysis showed that the area under the curve (AUC) value was 0.841, the sensitivity and specificity for the diagnosis of NPC were 87% and 72.7%. No correlation was found between expression levels of TEP miR-18a-3p and patients' clinical parameters and their NPC tumor-node-metastasis (TNM) stage. The positive rate of TEP miR-18a-3p and EBV DNA for NPC diagnosis were 85.4% and 66.7%. TEP miR-18a-3p expression were down-regulated after 77.8% (7 of 9) of chemotherapy, and in 66.7% (2 of 3) patients, TEP miR-18a-3p levels decreased after 3 cycles of chemotherapy. CONCLUSION: The expression levels of TEP miR-18a-3p are upregulated in NPC and have a high probability to downregulated after chemotherapy, indicating a significant clinical value. TEP miR-18a-3p might serve as a novel type of liquid-biopsy biomarker for early diagnosis and chemotherapy efficacy monitoring in NPC.

Follow-up study on serum cholesterol profiles and potential sequelae in recovered COVID-19 patients.

BACKGROUND: COVID-19 patients develop hypolipidemia. However, it is unknown whether lipid levels have improved and there are potential sequlae in recovered patients. OBJECTIVE: In this follow-up study, we evaluated serum lipidemia and various physiopathological laboratory values in recovered patients. METHODS: A 3-6 month follow-up study was performed between June 15 and September 3, 2020, to examine serum levels of laboratory values in 107 discharged COVID-19 patients (mild = 59; severe/critical = 48; diagnoses on admission). Sixty-one patients had a revisit chest CT scan. A Wilcoxon signed-rank test was used to analyze changes in laboratory values at admission and follow-up. RESULTS: LDL-c and HDL-c levels were significantly higher at follow-up than at admission in severe/critical cases (p <  0.05). LDL-c levels were significantly higher at follow-up than at admission in mild cases (p <  0.05). Coagulation and liver functional values were significantly improved at follow-up than at admission for patients (p <  0.05). Increases in HDL-c significantly correlated with increases in numbers of white blood cells (p <  0.001) during patients' recovery. With exclusion of the subjects taking traditional Chinese medicines or cholesterol-lowering drugs, LDL-c and HDL-c levels were significantly increased at follow-up than at admission in severe/critical cases (p <  0.05). Residue lesions were observed in CT images in 72% (44 of 61) of follow-up patients. CONCLUSIONS: Improvements of LDL-c, HDL-c, liver functions, and incomplete resolution of lung lesions were observed at 3-6 month follow-up for recovered patients, indicating that a long-term recovery process could be required and the development of sequelae such as pulmonary fibrosis could be expected in some patients.

Fecal occult blood and urinary cytology tests for rapid screening of inflammatory infection in the gastrointestinal and urological systems in patients with Coronavirus disease 2019.

BACKGROUND: Gastrointestinal infections (GI) and urological infections (UI) have not been fully addressed in COVID-19 patients. We aimed to evaluate the values of routine fecal occult blood (FOB) test and urinary cytology test (UCT) for screening of GI and UI in COVID-19 patients. METHODS: In this retrospective study, COVID-19 patients without associated comorbidities were divided into FOB- or UCT-positive or FOB- or UCT-negative groups. Their clinical characteristics and laboratory findings were then compared. RESULTS: A total of 13.6% of patients (47 of 345) tested positive for FOB, and 57.4% (27 of 47) of these patients lacked gastrointestinal symptoms. A total of 30.1% of patients (104 of 345) exhibited gastrointestinal symptoms, and 38.0% (131 of 345) were positive for either FOB or gastrointestinal symptoms. FOB-positive patients possessed significantly higher levels of C-reactive protein and fewer lymphocytes than FOB-negative patients. A total of 36.9% of patients (80 of 217) exhibited positive UCT, and 97.5% (78 of 80) of these patients possessed normal levels of serum markers for renal injuries. Significant differences in age and sex ratios were observed between the UCT-positive and UCT-negative groups, and 72.4% (42 of 58) of female patients over 60 years old were UCT-positive. CONCLUSIONS: Fecal occult blood test in combination with gastrointestinal symptoms could serve as a simple and useful screening approach for GI diagnoses for COVID-19. Age and sex are risk factors for UI in COVID-19 patients. UCT could be a sensitive tool for assessing early UI at a stage in which serum markers for renal injuries appear normal.

Hypolipidemia is associated with the severity of COVID-19.

BACKGROUND: Many patients with coronavirus disease 2019 (COVID-19) suffer multiple organ dysfunctions. However, whether patients develop dyslipidemia is unknown. OBJECTIVE: In this study, we aimed to investigate the pathological alterations of low-density lipoprotein cholesterol (LDL-c), high-density lipoprotein cholesterol (HDL-c), and total cholesterol (TC) in COVID-19 patients and their relationships with the disease severity. METHODS: A retrospective study was performed to examine serum levels of LDL-c, HDL-c, and TC on 597 COVID-19 patients (mild: 394; severe, 171; critical: 32) who were hospitalized in our center between February 1 and March 3, 2020. Age- and gender-matched normal subjects (n = 50) who had routine laboratory lipid tests between October 1 and November 1, 2019 in our center were included as the control group. RESULTS: LDL-c and TC levels were significantly lower in COVID-19 patients as compared with normal subjects (P < .001). There were significant and gradual decreases in levels of LDL-c (median (IQR) in mg/dL, mild: 91 (76, 104); severe: 86 (69, 102); critical: 69 (48, 81); P < .02) and TC (mild: 173 (148, 203); severe: 167 (138, 197); critical: 125 (95, 162); P < .05) across all three groups. HDL-c levels only decreased significantly in critical cases as compared with levels in mild and severe cases. LDL-c and TC levels inversely correlated with C-reactive protein and interleukin-6, and positively correlated with the number of lymphocytes in patients. CONCLUSIONS: Development of hypolipidemia begins in patients with mild symptoms. It progressively becomes worse in an association with the disease severity.

Elevations of serum cancer biomarkers correlate with severity of COVID-19.

In this retrospective study, we evaluated the levels of a series of serum biomarkers in coronavirus disease 2019 (COVID-19) patients (mild: 131; severe: 98; critical: 23). We found that there were significant increases in levels of human epididymis protein 4 (HE4) (73.6 ± 38.3 vs 46.5 ± 14.7 pmol/L; P < .001), cytokeratin-19 fragment (CYFRA21-1) (2.2 ± 0.9 vs 1.9 ± 0.8 µg/L; P < .001), carcinoembryonic antigen (CEA) (3.4 ± 2.2 vs 2.1 ± 1.2 µg/L; P < .001), carbohydrate antigens (CA) 125 (18.1 ± 13.5 vs 10.5 ± 4.6 µg/L; P < .001), and 153 (14.4 ± 8.9 vs 10.1 ± 4.4 µg/L; P < .001) in COVID-19 mild cases as compared to normal control subjects; their levels showed continuous and significant increases in severe and critical cases (HE4, CYFRA21-1, and CA125: P < .001; CEA and CA153: P < .01). Squamous cell carcinoma antigen (SCC) and CA199 increased significantly only in critical cases of COVID-19 as compared with mild and severe cases and normal controls (P < .01). There were positive associations between levels of C-reactive protein and levels of HE4 (R = .631; P < .001), CYFRA21-1 (R = .431; P < .001), CEA (R = .316; P < .001), SCC (R = .351; P < .001), CA153 (R = .359; P < .001) and CA125 (R = .223; P = .031). We concluded that elevations of serum cancer biomarkers positively correlated with the pathological progressions of COVID-19, demonstrating diffuse and acute pathophysiological injuries in COVID-19.

Tumor-educated platelet miR-34c-3p and miR-18a-5p as potential liquid biopsy biomarkers for nasopharyngeal carcinoma diagnosis.

Background: Nasopharyngeal carcinoma (NPC) is the common malignant tumor of nasopharynx in southern China and other southeastern Asian countries. MicroRNAs (miRNAs) have been shown to play important roles in carcinogenesis. Recently, miR-34c-3p and miR-18a-5p have been found to be involved in carcinogenesis of NPC. Furthermore, platelets in NPC patients may acquire RNAs from NPC cells and turn into "tumor-educated platelet (TEP)", which may serve as potential biomarkers for a diagnosis of NPC. However, the expression profiles of TEP miR-34c-3p and miR-18a-5p in NPC patients and their diagnostic values are yet to be determined. Aims: To investigate expression levels of TEP miR-34c-3p and miR-18a-5p and determine their diagnostic values for NPC. Materials and methods: Relative quantitative real-time PCR was used to determine the expression levels of TEP miR-34c-3p and miR-18a-5p in NPC patients (n=54) as compared to normal subjects (n=36). The receiver operating characteristic (ROC) curve analysis was performed to assess the diagnostic values of TEP miR-34c-3p and miR-18a-5p for NPC. Results: The expression levels of TEP miR-34c-3p and miR-18a-5p were significantly higher in NPC patients as compared to healthy subjects. The ROC analysis showed that the area under the ROC curve (AUC), sensitivity, specificity and accuracy for TEP miR-34c-3p, miR-18a-5p, or a combination of both miRNAs for NPC diagnostic tests were 0.952, 94.44%, 86.11%, 91.11%, or 0.884, 85.19%, 86.11%, 85.55%, or 0.954, 92.59%, 86.11%, 90.00%, respectively. No correlation was found between expression levels of TEP miR-34c-3p or miR-18a-5p and patients' demographic variables and their NPC tumor/node/metastasis stages. The positive rates of TEP miR-34c-3p and miR-18a-5p for NPC diagnosis were 93.8% and 87.5%, respectively, which were significantly higher than Epstein-Barr virus DNA with a positive rate of 66.7%. Conclusion: The expression levels of TEP miR-34c-3p and miR-18a-5p are upregulated in NPC, rendering a significant clinical value for NPC diagnosis. The TEP miRNAs might serve as a novel type of liquid biopsies for NPC diagnosis.

A Logistic Regression Model for Noninvasive Prediction of AFP-Negative Hepatocellular Carcinoma.

α-Fetoprotein is commonly used in the diagnosis of hepatocellular carcinoma. However, the diagnostic significance of α-fetoprotein has been questioned because a number of patients with hepatocellular carcinoma are α-fetoprotein negative. It is therefore necessary to develop novel noninvasive techniques for the early diagnosis of hepatocellular carcinoma, particularly when α-fetoprotein level is low or negative. The current study aimed to evaluate the diagnostic efficiency of hematological parameters to determine which can act as surrogate markers in α-fetoprotein-negative hepatocellular carcinoma. Therefore, a retrospective study was conducted on a training set recruited from Zhongnan Hospital of Wuhan University-including 171 α-fetoprotein-negative patients with hepatocellular carcinoma and 102 healthy individuals. The results show that mean values of mean platelet volume, red blood cell distribution width, mean platelet volume-PC ratio, neutrophils-lymphocytes ratio, and platelet count-lymphocytes ratio were significantly higher in patients with hepatocellular carcinoma in comparison to the healthy individuals. Most of these parameters showed moderate area under the curve in α-fetoprotein-negative patients with hepatocellular carcinoma, but their sensitivities or specificities were not satisfactory enough. So, we built a logistic regression model combining multiple hematological parameters. This model presented better diagnostic efficiency with area under the curve of 0.922, sensitivity of 83.0%, and specificity of 93.1%. In addition, the 4 validation sets from different hospitals were used to validate the model. They all showed good area under the curve with satisfactory sensitivities or specificities. These data indicate that the logistic regression model combining multiple hematological parameters has better diagnostic efficiency, and they might be helpful for the early diagnosis for α-fetoprotein-negative hepatocellular carcinoma.

Ascitic cholesterol is superior to serum-ascites albumin gradient in the detection of non-portal hypertensive ascites and the diagnosis of mixed ascites.

BACKGROUND: The diagnostic value of ascitic cholesterol in the differential diagnosis of ascites is controversial. AIM: To investigate the diagnostic performance of ascitic cholesterol in the differential diagnosis of ascites. METHODS: Consecutive patients with new-onset ascites were enrolled prospectively. The pertinent data were collected from 629 patients with all forms of ascites. RESULTS: In the training cohort, determination of the ascitic cholesterol level was a highly effective method of distinguishing non-portal hypertension (NPH) from portal hypertension (PH). At the pre-determined cut-off value of 45 mg/dL, the sensitivity of ascitic cholesterol was superior to the serum-ascites albumin gradient (SAAG) in identifying NPH-related ascites; the area under the receiver operating characteristic curve was 0.945. In the patients misdiagnosed based on SAAG classification, the diagnostic accuracy of ascitic cholesterol was 69%. The ascitic cholesterol level showed excellent performance in identifying peritoneal lesions in patients with mixed ascites. CONCLUSION: Ascitic cholesterol is an excellent measure for detecting NPH ascites and for identifying peritoneal lesions in mixed ascites. Thus, this simple and cost-effective measure should be determined in patients with new-onset ascites (www.chictr.org.cn; ChiCTR-DCD-15006907).