Hiroshi Kobayashi

Assessment of tissue factor pathway inhibitor 2 (TFPI2) as a novel serum marker for malignant tumors of the ovary before and after treatment: A case‐control study

AbstractAimTissue factor pathway inhibitor 2 (TFPI2) is a preoperative biomarker that was developed to discriminate ovarian benign tumors from cancer and is covered by health insurance in Japan. The purpose of this study was to evaluate how the TFPI2 changes after treatment.MethodsSerum levels of TFPI2 (cut off 191 pg/mL) and CA125 (cut off 35 U/mL) before and after primary debulking surgery in patients with ovarian malignant tumors were evaluated among recurrent and nonrecurrent cases, respectively.ResultsA total of 46 cases were analyzed, including 11 borderline tumors, 13 clear cell carcinomas, 15 serous carcinomas, 4 endometrioid carcinomas, and 3 mucinous carcinomas. Among 37 patients without recurrence, the preoperative mean levels of TFPI2 (235.3 pg/mL, range: 78.3–607.7) and CA125 (1125.5 U/mL, range: 6.2–6272.0) were higher than the cutoff values. The mean minimum level of TFPI2 decreased to below the cutoff (150.2 pg/mL, range 56.4–471.1) at 3 months or more after primary debulking surgeries. The postoperative TFPI2 level exceeded the cutoff in 11 out of 37 patients without recurrence (29.7%); however, the postoperative TFPI2 level decreased in 8 patients. The mean maximum levels of TFPI2 and CA125 in 9 patients after recurrence were 492.6 pg/mL and 727.4 U/mL, respectively. Moreover, the mean TFPI2 level was higher than the preoperative one (421.5 pg/mL), different from CA125 (2903.8 U/mL).ConclusionsOur results suggest the clinical validity of TFPI2 as a serum tumor marker for postoperative recurrence screening among malignant ovarian tumors.

Toward an understanding of tissue factor pathway inhibitor‐2 as a novel serodiagnostic marker for clear cell carcinoma of the ovary

AbstractAimsTissue factor pathway inhibitor (TFPI)‐2 has recently emerged as a serodiagnostic marker for patients with epithelial ovarian cancer (EOC), especially clear cell carcinoma (CCC). This review discusses the biological properties of TFPI‐2 and why serum levels are elevated in CCC patients.MethodsA comprehensive literature search was conducted in PubMed up until March, 2021.ResultsTFPI‐2 is a Kunitz‐type protease inhibitor and negatively regulates the enzymatic activities, such as plasmin. TFPI‐2 has been characterized as a tumor suppressor gene and was frequently downregulated through promoter hypermethylation in various human cancers. In contrast, TFPI‐2 was overexpressed only in CCC. TFPI‐2 may be involved in the pathophysiology of CCC, possibly through regulation of coagulation system, stabilization of extracellular matrix (ECM), and induction of intracellular signal transduction. TFPI‐2 suppresses tissue factor‐induced hypercoagulation in a hypoxic environment. TFPI‐2, secreted by CCC cells, platelets, and adjacent vascular endothelial cells, may suppress tumor growth and invasion through ECM remodeling. Nuclear TFPI‐2 may suppress matrix metalloproteinase production via transcription factors and modulate caspase‐mediated cell apoptosis. CCC cells may upregulate the TFPI‐2 expression to adapt to survival in the demanding environment. TFPI‐2 is secreted by CCC cells and enters the systemic circulation, resulting in elevated blood levels.DiscussionSerum TFPI‐2 reflects the overexpression of TFPI‐2 in CCC tissues and is a potential serodiagnostic marker. Further research is needed to explore the expression, clinical significance, biological function, and potential mechanism of TFPI‐2 in CCC.

Tissue factor pathway inhibitor 2: A potential diagnostic marker for discriminating benign from malignant ovarian tumors

AbstractObjectivesCarbohydrate antigen 125 (CA125), CA19‐9, carcinoembryonic antigen (CEA), human epididymis protein 4 (HE4), and the Risk of Ovarian Malignancy Algorithm (ROMA) are widely used as tumor markers and algorithms for the diagnosis of ovarian cancer (OC). Tissue factor pathway inhibitor 2 (TFPI2) has been developed as a potential serodiagnostic marker for OC in Japan. The aim of this study is to evaluate the diagnostic accuracy of the six markers alone and in combination to find the best marker for discriminating between benign and malignant ovarian tumors.MethodsFrozen serum samples collected from 484 patients were divided into three groups based on histopathological results: OC (n = 119), borderline ovarian tumors (BR) (n = 48), and benign ovarian tumors (BN) (n = 317). Diagnostic accuracy was calculated with an area under a receiver operating characteristic (AUC) curve.ResultsTFPI2 achieved the highest discrimination between the OC + BR group versus the BN group (AUC 0.8076). ROMA values best discriminated patients with OC from those with BN (AUC, 0.8966), which was equivalent to TFPI2 (AUC, 0.8937). For discriminating the OC group from the BR + BN group, the highest AUC value was achieved by ROMA values (AUC, 0.8884), and TFPI2 also showed comparable diagnostic accuracy (AUC, 0.8845). Combining TFPI2 with ROMA had the highest AUC (0.8420–0.9357).ConclusionTFPI2 may be a clinically useful single marker comparable to conventional ROMA values for discriminating between benign and malignant ovarian tumors.

Tissue Factor Pathway Inhibitor 2: A Novel Biomarker for Predicting Asymptomatic Venous Thromboembolism in Patients with Epithelial Ovarian Cancer

<b><i>Objectives:</i></b> Patients with asymptomatic venous thromboembolism (VTE) are associated with an increased risk of pulmonary thromboembolism events. However, due to low specificity and high false-positive rates, D-dimer testing cannot be used alone to diagnose VTE. Tissue factor pathway inhibitor 2 (TFPI2), a new serodiagnostic marker for ovarian cancer, plays a role in blood coagulation system regulation. We hypothesized that combining D-dimer and TFPI2 would improve its utility in diagnosing VTE. This study aimed to look into the clinical utility of serum D-dimer and TFPI2 levels in detecting asymptomatic VTE in patients with epithelial ovarian cancer (EOC). <b><i>Design:</i></b> From January 2008 to December 2015, researchers at Nara Medical University Hospital’s Department of Gynecology conducted a single-center retrospective study. The receiver operating characteristic (ROC) curve analysis was used to determine the diagnostic value of preoperative D-dimer, TFPI2, and D-dimer combined with TFPI2 in distinguishing VTE patients from those who did not have VTE. <b><i>Participants:</i></b> This study included 122 patients with EOC who met the inclusion and exclusion criteria out of 223 admitted to the hospital with EOC. The patients were divided into two groups: VTE (<i>n</i> = 25) and non-VTE (<i>n</i> = 97). <b><i>Results:</i></b> There were significant differences in D-dimer, TFPI2, and CA125 levels and residual tumor between the VTE and non-VTE groups. The D-dimer level was found to be significantly related to age, body mass index, VTE, massive ascites, residual tumor, histology, and Federation of Gynecology and Obstetrics stage, whereas the TFPI2 level was only related to VTE. Multivariate analysis revealed that D-dimer (the optimal cutoff value, 3.5 μg/mL) and TFPI2 (the optimal cutoff value, 400 pg/mL) are independent risk factors for preoperative VTE. ROC analysis revealed that the area under the curve was 0.8266 for D-dimer, 0.7963 for TFPI2, and 0.8495 for the combination of D-dimer and TFPI2. When compared to the D-dimer test alone, the combination of D-dimer and TFPI2 had higher specificity (77.3–96.9%) and positive predictive value (48.8–81.2%) for the diagnosis of VTE. <b><i>Limitations:</i></b> This is a single-center retrospective study. <b><i>Conclusion:</i></b> The combination of D-dimer and TFPI2 may be useful to safely exclude VTE and select patients at high risk of VTE.