Validation of tissue factor pathway inhibitor 2 as a specific biomarker for preoperative prediction of clear cell carcinoma of the ovary.

BACKGROUND: Tissue factor pathway inhibitor 2 (TFPI2) is a novel serum biomarker that discriminates ovarian clear cell carcinoma (CCC) from borderline ovarian tumors (BOTs) and non-clear cell epithelial ovarian cancers (EOCs). Here, we examined the performance of TFPI2 for preoperative diagnosis of CCC. METHODS: Serum samples were obtained preoperatively from patients with ovarian masses, who needed surgical treatment at five hospitals in Japan. The diagnostic powers of TFPI2 and cancer antigen 125 (CA125) serum levels to discriminate CCC from BOTs, other EOCs, and benign lesions were compared. RESULTS: A total of 351 patients including 69 CCCs were analyzed. Serum TFPI2 levels were significantly higher in CCC patients (mean ± SD, 508.2 ± 812.0 pg/mL) than in patients with benign lesions (154.7 ± 46.5), BOTs (181 ± 95.5) and other EOCs (265.4 ± 289.1). TFPI2 had a high diagnostic specificity for CCC (79.5%). In patients with benign ovarian endometriosis, no patient was positive for TFPI2, but 71.4% (15/21) were CA125 positive. TFPI2 showed good performance in discriminating stage II-IV CCC from BOTs and other EOCs (AUC 0.815 for TFPI2 versus 0.505 for CA125) or endometriosis (AUC 0.957 for TFPI2 versus 0.748 for CA125). The diagnostic sensitivity of TFPI2 to discriminate CCC from BOTs and other EOCs was improved from 43.5 to 71.0% when combined with CA125. CONCLUSIONS: High specificity of TFPI2 for preoperative detection of CCC was verified with the defined cutoff level of TFPI2 in clinical practice. TFPI2 and CA125 may contribute substantially to precise prediction of intractable CCC.

Normalization of abnormal plasma amino acid profile-based indexes in patients with gynecological malignant tumors after curative treatment.

BACKGROUND: We developed a novel plasma amino acid profile-based index (API) to detect ovarian, uterine, cervical, and endometrial cancers. In this study, we aimed to evaluate whether abnormal API values could be normalized after curative treatment in patients with gynecological malignant tumors. METHODS: Patients with gynecological cancer with abnormal API values were included in this study. Pre-operative absolute API values were compared with those after curative treatment. The normalization rates of API values in patients negative for the expression of three well-known tumor markers (SCC, CA125, and CA19-9) were also evaluated. In addition, related amino acid profiles in healthy controls and patients under pre- and post-treatment conditions were analyzed. RESULTS: Among 94 patients with abnormal pre-operative API values, the median API value was decreased from 9.52 to 2.17 after treatment (normalization rate: 88.3%). The decreased ranges were similar in patients with adenocarcinoma (6.28; 95% confidence interval [CI]: 5.43-6.95) and squamous carcinoma (7.44; 95% CI: 3.04-8.46). In 93.5% (43/46) of patients negative for tumor markers prior to operation, API values were normalized after the successful treatment. In addition, some pre-operative abnormal amino acid profiles, including Ile, Trp, and His, were reversibly normalized after treatment. CONCLUSION: The API is a promising tumor marker in gynecological malignancies for the diagnosis of remission, particularly in patients negative for general tumor markers. Further studies are needed to explore the mechanisms related to the normalization of abnormal amino acid profiles.

An abdominal ectopic pregnancy following a frozen-thawed ART cycle: a case report and review of the literature.

BACKGROUND: Ectopic pregnancy (EP) occurs in 1% of pregnancies and is reported to be more common in in vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI) pregnancies. An abdominal ectopic pregnancy (AEP) is a rare form of EP, and there are few reports of an AEP after IVF/ICSI. In this case report, a rare case of AEP after frozen-thawed cycle of ICSI is presented. CASE PRESENTATION: After a frozen-thawed cycle of ICSI, the beta-human chorionic gonadotropin (HCG) level at 4 weeks 0 days of gestation was 3.4 IU/L. Subsequent dysfunctional uterine bleeding was mistaken for menstruation; however, an AEP of 9 weeks with a fetal heart beat was observed by ultrasound. After the AEP was observed by ultrasound, it was extracted laparoscopically. CONCLUSION: A rare case of an AEP, which developed after frozen-thawed cycle of ICSI, presented with a very low serum HCG level. Even if the HCG titer is low, follow-up HCG levels and frequent medical examinations are necessary.

Evaluation of endocervical curettage with conization in diagnosis of endocervical lesions.

AIM: Endocervical curettage (ECC) at the time of conization has been reported to be effective for diagnosing cervical intraepithelial neoplasia and/or early stage cervical cancer. We aimed to verify the accuracy of ECC with conization. METHODS: We retrospectively analyzed the records of 540 patients with suspected neoplastic cervical lesions who underwent conization at the Yokohama City University Hospital from January 2008 to December 2015. To validate the effectiveness of ECC for evaluating endocervical lesions, histopathologic findings from ECC samples were compared with those from endocervical specimens obtained by conization. In patients who subsequently underwent hysterectomy, specimens of residual endocervical stump lesions were compared with the specimens obtained by ECC. RESULTS: ECC was performed in 58.9% of patients who underwent conization. Positive findings were only observed in 7.9%, while negative findings were found in 67.3% of ECC samples; however, 24.8% of the samples were inadequate for diagnosis. None of the patients had an upgraded diagnosis according to ECC results. The sensitivity of ECC in predicting endocervical stump lesions that were identified by conization specimens was 25.0%, the specificity was 94.2% and the positive predictive value was 55.0% (κ = 0.238; P < 0.001). ECC samples yielded a sensitivity of 42.9%, a specificity of 83.9%, and positive predictive value of 54.5% (κ = 0.284; P = 0.053) in predicting residual endocervical lesions in the uterus. CONCLUSIONS: As it offers low sensitivity and positive predictive value, ECC at the time of conization is of limited benefit for evaluating endocervical lesions.

Comparison of plasma amino acid profile-based index and CA125 in the diagnosis of epithelial ovarian cancers and borderline malignant tumors.

BACKGROUND: We previously developed a new plasma amino acid profile-based index (API) to detect ovarian, cervical, and endometrial cancers. Here, we compared API to serum cancer antigen 125 (CA125) for distinguishing epithelial ovarian malignant tumors from benign growths. METHODS: API and CA125 were measured preoperatively in patients with ovarian tumors, which were later classified into 59 epithelial ovarian cancers, 21 epithelial borderline malignant tumors, and 97 benign tumors including 40 endometriotic cysts. The diagnostic accuracy and cutoff points of API were evaluated using receiver operating characteristic (ROC) curves. RESULTS: The area under the ROC curves showed the equivalent performance of API and CA125 to discriminate between malignant/borderline malignant and benign tumors (both 0.77), and API was superior to CA125 for discrimination between malignant/borderline malignant lesions and endometriotic cysts (API, 0.75 vs. CA125, 0.59; p < 0.05). At the API cutoff level of 6.0, API and CA125 had equal positive rates of detecting cancers and borderline malignancies (API, 0.71 vs. CA125, 0.74; p = 0.84) or cancers alone (API, 0.73 vs. CA125, 0.85; p = 0.12). However, API had a significantly lower detection rate of benign endometriotic cysts (0.35; 95 % CI, 0.21-0.52) compared with that of CA125 (0.65; 95 % CI, 0.48-0.79) (p < 0.05). CONCLUSIONS: API is an effective new tumor marker to detect ovarian cancers and borderline malignancies with a low false-positive rate for endometriosis. A large-scale prospective clinical study using the cutoff value of API determined in this study is warranted to validate API for practical clinical use.

Annexin A4 is involved in proliferation, chemo-resistance and migration and invasion in ovarian clear cell adenocarcinoma cells.

Ovarian clear cell adenocarcinoma (CCC) is the second most common subtype of ovarian cancer after high-grade serous adenocarcinomas. CCC tends to develop resistance to the standard platinum-based chemotherapy, and has a poor prognosis when diagnosed in advanced stages. The ANXA4 gene, along with its product, a Ca(++)-binding annexin A4 (ANXA4) protein, has been identified as the CCC signature gene. We reported two subtypes of ANXA4 with different isoelectric points (IEPs) that are upregulated in CCC cell lines. Although several in vitro investigations have shown ANXA4 to be involved in cancer cell proliferation, chemoresistance, and migration, these studies were generally based on its overexpression in cells other than CCC. To elucidate the function of the ANXA4 in CCC cells, we established CCC cell lines whose ANXA4 expressions are stably knocked down. Two parental cells were used: OVTOKO contains almost exclusively an acidic subtype of ANXA4, and OVISE contains predominantly a basic subtype but also a detectable acidic subtype. ANXA4 knockdown (KO) resulted in significant growth retardation and greater sensitivity to carboplatin in OVTOKO cells. ANXA4-KO caused significant loss of migration and invasion capability in OVISE cells, but this effect was not seen in OVTOKO cells. We failed to find the cause of the different IEPs of ANXA4, but confirmed that the two subtypes are found in clinical CCC samples in ratios that vary by patient. Further investigation to clarify the mechanism that produces the subtypes is needed to clarify the function of ANXA4 in CCC, and might allow stratification and improved treatment strategies for patients with CCC.