A Novel Online Calculator Based on Serum Biomarkers to Detect Hepatocellular Carcinoma among Patients with Hepatitis B.

BACKGROUND: Early detection of hepatocellular carcinoma (HCC) among hepatitis B virus (HBV)-infected patients remains a challenge, especially in China. We sought to create an online calculator of serum biomarkers to detect HCC among patients with chronic hepatitis B (CHB). METHODS: Participants with HBV-HCC, CHB, HBV-related liver cirrhosis (HBV-LC), benign hepatic tumors, and healthy controls (HCs) were recruited at 11 Chinese hospitals. Potential serum HCC biomarkers, protein induced by vitamin K absence or antagonist-II (PIVKA-II), α-fetoprotein (AFP), lens culinaris agglutinin A-reactive fraction of AFP (AFP-L3) and α-l-fucosidase (AFU) were evaluated in the pilot cohort. The calculator was built in the training cohort via logistic regression model and validated in the validation cohort. RESULTS: In the pilot study, PIVKA-II and AFP showed better diagnostic sensitivity and specificity compared with AFP-L3 and AFU and were chosen for further study. A combination of PIVKA-II and AFP demonstrated better diagnostic accuracy in differentiating patients with HBV-HCC from patients with CHB or HBV-LC than AFP or PIVKA-II alone [area under the curve (AUC), 0.922 (95% CI, 0.908-0.935), sensitivity 88.3% and specificity 85.1% for the training cohort; 0.902 (95% CI, 0.875-0.929), 87.8%, and 81.0%, respectively, for the validation cohort]. The nomogram including AFP, PIVKA-II, age, and sex performed well in predicting HBV-HCC with good calibration and discrimination [AUC, 0.941 (95% CI, 0.929-0.952)] and was validated in the validation cohort [AUC, 0.931 (95% CI, 0.909-0.953)]. CONCLUSIONS: Our results demonstrated that a web-based calculator including age, sex, AFP, and PIVKA-II accurately predicted the presence of HCC in patients with CHB. CLINICALTRIALSGOV IDENTIFIER: NCT03047603.

Review on Vitamin K Deficiency and its Biomarkers: Focus on the Novel Application of PIVKA-II in Clinical Practice.

BACKGROUND: Vitamin K (VK) is a co-factor of the γ-glutamyl carboxylase that catalyzes the conversion of glutamate residues to γ-carboxyglutamate in VK-dependent proteins. The carboxylation reaction imparts the essential calcium-binding residues for the biological function of several proteins involved in the process of coagulation and bone metabolism. VK deficiency is frequently encountered in newborns and can lead to fatal hemorrhagic complications. This review describes and discusses the clinical application of VK deficiency testing. METHODS: References and data were researched in PubMed and reviewed. RESULTS: In adults, VK deficiency is associated with uncontrolled bleeding, liver dysfunction, osteoporosis, and coronary diseases. An improved understanding of the role of VK deficiency in health and illness can be achieved by setting a gold-standard in the inter-laboratory estimations of VK. However, conventional methods used to measure the VK deficiency based upon the coagulation time lack sensitivity and specificity. Recently, the alterations in proteins induced by VK absence or antagonism (PIVKA) have proven to be suitable biomarkers for detecting VK deficiency. The measurement of PIVKA-II exhibits an enhanced sensitivity and specificity in comparison to other methods conventionally used for the assessment of VK deficiency in newborns and adults. CONCLUSIONS: PIVKA-II could potentially be employed as an effective biomarker in the diagnosis of VK deficiency.

Serum ARCHITECT PIVKA-II reference interval in healthy Chinese adults: Sub-analysis from a prospective multicenter study.

BACKGROUND: Protein induced by vitamin K absence or antagonist-II (PIVKA-II) has been widely used as a biomarker for liver cancer diagnosis in Japan for decades. However, the reference intervals for serum ARCHITECT PIVKA-II have not been established in the Chinese population. Thus, this study aimed to measure serum PIVKA-II levels in healthy Chinese subjects. METHODS: This is a sub-analysis from the prospective, cross-sectional and multicenter study (ClinicalTrials.gov Identifier: NCT03047603). A total of 892 healthy participants (777 Han and 115 Uygur) with complete health checkup results were recruited from 7 regional centers in China. Serum PIVKA-II level was measured by ARCHITECT immunoassay. All 95% reference ranges were estimated by nonparametric method. RESULTS: The distribution of PIVKA-II values showed significant difference with ethnicity and sex, but not age. The 95% reference range of PIVKA-II was 13.62-40.38 mAU/ml in Han Chinese subjects and 15.16-53.74 mAU/ml in Uygur subjects. PIVKA-II level was significantly higher in males than in females (P < 0.001). The 95% reference range of PIVKA-II was 15.39-42.01 mAU/ml in Han males while 11.96-39.13 mAU/ml in Han females. CONCLUSIONS: The reference interval of serum PIVKA-II on the Architect platform was established in healthy Chinese adults. This will be valuable for future clinical and laboratory studies performed using the Architect analyzer. Different ethnic backgrounds and analytical methods underline the need for redefining the reference interval of analytes such as PIVKA-II, in central laboratories in different countries.

Development and validation of a novel diagnostic nomogram model based on tumor markers for assessing cancer risk of pulmonary lesions: A multicenter study in Chinese population.

PURPOSE: This study aimed to build a valid diagnostic nomogram for assessing the cancer risk of the pulmonary lesions identified by chest CT. PATIENTS AND METHODS: A total of 691 patients with pulmonary lesions were recruited from three centers in China. The cut-off value for each tumor marker was confirmed by minimum P value method with 1000 bootstrap replications. The nomogram was based on the predictive factors identified by univariate and multivariate analysis. The predictive performance of the nomogram was measured by concordance index and calibrated with 1000 bootstrap samples to decrease the overfit bias. We also evaluated the net benefit of the nomogram via decision curve analysis. Finally, the nomogram was validated externally using a separate cohort of 305 patients enrolled from two additional institutions. RESULTS: The cut-off for CEA, SCC, CYFRA21-1, pro-GRP, and HE4 was 4.8 ng/mL, 1.66 ng/mL, 1.83 ng/mL, 56.55 pg/mL, and 63.24Lpmol/L, respectively. Multivariate logistic regression model (LRM) identified tumor size, CEA, SCC, CYFRA21-1, pro-GRP, and HE4 as independent risk factors for lung cancer. The nomogram based on LRM coefficients showed concordance index of 0.901 (95% CI: 0.842-0.960; P < 0.001) for lung cancer in the training set and 0.713 (95% CI: 0.599-0.827; P < 0.001) in the validation set. Decision curve analysis reported a net benefit of 87.6% at 80% threshold probability superior to the baseline model. CONCLUSION: Our diagnostic nomogram provides a useful tool for assessing the cancer risk of pulmonary lesions identified in CT screening test.

Serum reference interval of ARCHITECT alpha-fetoprotein in healthy Chinese Han adults: Sub-analysis of a prospective multi-center study.

OBJECTIVES: Alpha-fetoprotein (AFP) has been widely used in clinical practice for decades. However, large-scale survey of serum reference interval for ARCHITECT AFP is still absent in Chinese population. This study aimed to measure serum AFP levels in healthy Chinese Han subjects, which is a sub-analysis of an ongoing prospective, cross-sectional, multi-center study (ClinicalTrials.gov Identifier: NCT03047603). METHODS: This analysis included a total of 530 participants (41.43±12.14years of age on average, 48.49% males), enrolled from 5 regional centers. Serum AFP level was measured by ARCHITECT immunoassay. Statistical analysis was performed using SAS 9.4 and R software. RESULTS: AFP distribution did not show significant correlation with age or sex. The overall median and interquartile range of AFP was 2.87 (2.09, 3.83) ng/mL. AFP level did not show a trend of increasing with age. The new reference interval was 2.0-7.07ng/mL (LOQ- 97.5th percentiles). CONCLUSIONS: The reference interval for ARCHITECT AFP is updated with the data of adequate number of healthy Han adults. This new reference interval is more practical and applicable in Chinese adults.

Galectin-3 as a novel biomarker for disease diagnosis and a target for therapy (Review).

Galectin-3 is a member of the galectin family, which are ß­galactoside­binding lectins with ≥1 evolutionary conserved carbohydrate­recognition domain. It binds proteins in a carbohydrate­dependent and ­independent manner. Galectin­3 is predominantly located in the cytoplasm; however, it shuttles into the nucleus and is secreted onto the cell surface and into biological fluids including serum and urine. It serves important functions in numerous biological activities including cell growth, apoptosis, pre­mRNA splicing, differentiation, transformation, angiogenesis, inflammation, fibrosis and host defense. Numerous previous studies have indicated that galectin­3 may be used as a diagnostic or prognostic biomarker for certain types of heart disease, kidney disease and cancer. With emerging evidence to support the function and application of galectin­3, the current review aims to summarize the latest literature regarding the biomarker characteristics and potential therapeutic application of galectin­3 in associated diseases.

Induction therapy of loco-regional non-small-cell lung cancer with reliable response and low toxicity (low dose radiotherapy sensitizes tumor to subsequent chemotherapy?).

INTRODUCTION: For the induction therapy of non-small-cell lung cancer, we need to look for a regimen which produces a reliable high response rate with a low treatment related morbidity and mortality. METHODS: Patients in clinical stages IB, IIA and B, IIIA and B received a course of therapy with 20Gy of radiation in 2 weeks. This was followed by two courses of chemotherapy consisting of paclitaxel 180mg/m(2), cisplatin 45mg/m(2), and ifosfamide 1000mg/m(2). Two to 3 weeks after chemotherapy, the patients were re-evaluated and, if suitable, underwent surgical therapy. RESULTS: A total of 35 patients were entered into the study. The overall response rate was 82.86% (95% confidence interval, 66.35-94.5%). Complete response (CR) was 20% (95% confidence interval, 8.44-36.94%). Twenty-five patients had surgical resection. Subsequently 18 patients received completion radiotherapy of additional 45Gy. The median follow up is 30 months. In 12 patients with stages IB, IIA and B, the median survival was 61 months, and 5-year survival was 55%. In 23 patients with stages IIIA and B, the median survival was 26 months, and 5-year survival was 9.5%. There was 1 patient with Grade 4 and 13 patients with Grade 3 leukopenia, and half of them received granulocyte colony stimulating factor. By the completion radiotherapy, 6 out of 18 patients had less than Grade 2 esophagitis. Five patients had Grade 2 radiation pneumonitis and one Grade 5 (one mortality). There was no postoperative death. The survival results were comparable to those reported recently by others, however the regimen produced a high response rate with low treatment related morbidity/mortality. CONCLUSION: It is a suitable regimen for induction therapy to include earlier stage resectable non-small-cell lung cancers.