Serum CA125 level as predictors of the efficacy of olaparib maintenance therapy for platinum-sensitive relapsed ovarian cancer.

AIM: Ovarian cancer is a gynecological malignancy with a poor prognosis. For platinum-sensitive relapsed ovarian cancer, maintenance therapy with poly-ADP ribose polymerase (PARP) inhibitors after chemotherapy is considered; however, olaparib treatment does not always lead to sufficient progression-free survival (PFS). This study aimed to identify factors that predict the efficacy of maintenance therapy using olaparib in platinum-sensitive relapsed ovarian cancer. METHODS: Twenty-seven patients with platinum-sensitive relapsed ovarian cancer, who received initial treatment and showed complete or partial response to prior chemotherapy at our hospital, were included. The primary outcome was the time from the end of previous platinum-based chemotherapy to disease progression (PFS). The Kaplan-Meier method was used to generate time-to-event curves for PFS; multivariate analysis was performed using the Cox proportional hazards regression model. RESULTS: The median PFS was 12 months (95% confidence interval [CI]: 8.3-15.8). Before olaparib administration, the median PFS was 12 months in the <4.1 neutrophil-to-lymphocyte ratio group and 4 months in the ≥4.1 group, with PFS being significantly better in the <4.1 group (log-rank: p = 0.023). When comparing serum cancer antigen 125 (CA125) levels, the median PFS was 13 months in the <18 U/mL group and 6 months in the >18 U/mL group (log-rank: p = 0.022). Multivariate Cox regression analysis revealed that CA125 was the factor affecting PFS (hazard ratio: 4.85; 95% CI: 1.53-15.38). CONCLUSIONS: Serum CA125 levels at olaparib initiation in patients with platinum-sensitive relapsed ovarian cancer may predict PFS as an effect of maintenance therapy using olaparib to treat recurrent disease.

A case of low-grade intestinal-type mucinous neoplasm of the fallopian tube with KRAS exon 2 mutation.

Several types of mucinous lesions of the fallopian tube have been reported, including metaplastic and neoplastic lesions, most of which exhibit gastric phenotypes. Here, we report a unique case of a mucinous tumor arising in the right fallopian tube of a 36-year-old female who presented with refractory abdominal pain for approximately one year. Abdominal CT and MRI found a cystic lesion leading to the diagnosis of hematosalpinx, thus right salpingo-oophorectomy and appendectomy were performed. Macroscopic findings included cystic dilatation of the distal portion of the right fallopian tube, filled with gelatinous mucin. Histologically, mucinous columnar cells proliferated in papillary configurations in the cystic region without invasion, resembling low-grade appendiceal mucinous neoplasms. Immunohistochemical analysis revealed that the neoplastic cells expressed CDX-2 and SATB2, but not WT-1, PAX8, ER, PgR, or claudin 18. Sanger sequencing of the mucinous lesion identified a KRAS exon 2 mutation (p.G12A), confirming similar pathologic and genetic characteristics to ovarian mucinous borderline tumors. This rare low grade intestinal-type mucinous tumor indicates the fallopian tube epithelium can give rise to tumors resembling low-grade appendiceal mucinous neoplasms and cause pseudomyxoma peritonei without appendiceal lesions.

Significance of histology and nodal status on the survival of women with early-stage cervical cancer: validation of the 2018 FIGO cervical cancer staging system.

OBJECTIVE: To assess the efficacy of the FIGO 2018 classification system for nodal-specific classifications for early-stage cervical cancer; specifically, to examine the impact of nodal metastasis on survival and the effect of postoperative treatments, according to histological subtypes. METHODS: This society-based retrospective observational study in Japan examined 16,539 women with the 2009 FIGO stage IB1 cervical cancer who underwent primary surgical treatment from 2004 to 2015. Associations of cause-specific survival (CSS) with nodal metastasis and postoperative adjuvant therapy were examined according to histology type (squamous cell carcinoma [SCC], n=10,315; and non-SCC, n=6,224). RESULTS: The nodal metastasis rate for SCC was higher than that for non-SCC (10.7% vs. 8.3%, p<0.001). In multivariable analysis, the impact of nodal metastasis on CSS was greater for non-SCC tumors (adjusted-hazard ratio [HR], 3.11; 95% confidence interval [CI], 2.40-4.02) than for SCC tumors (adjusted-HR, 2.20; 95% CI, 1.70-2.84; p<0.001). Propensity score matching analysis showed significantly lower CSS rates for women with pelvic nodal metastasis from non-SCC tumors than from SCC tumors (5-year CSS rate, 75.4% vs. 90.3%, p<0.001). The CSS rates for women with nodal metastasis in SCC histology were similar between the postoperative concurrent chemoradiotherapy/radiotherapy and chemotherapy groups (89.2% vs. 86.1%, p=0.42), whereas those in non-SCC histology who received postoperative chemotherapy improved the CSS (74.1% vs. 67.7%, p=0.043). CONCLUSION: The node-specific staging system in the 2018 FIGO cervical cancer classification is applicable to both non-SCC tumors and SCC tumors; however, the prognostic significance of nodal metastases and efficacy of postoperative therapies vary according to histology.

A Case of Metastatic Uterine Tumor Originating from Small-Cell Lung Cancer (SCLC) Mimicking Uterine Sarcoma.

Metastatic uterine tumors originating from extragenital cancers are a rare clinical occurrence. We report a case of metastatic uterine cancer derived from small-cell lung cancer (SCLC) that necessitated surgical treatment. The patient was a 59 y/o female who had undergone chemotherapy for stage IIIB SCLC. A 15 cm uterine tumor lesion was initially detected on CT scans. The patient had previously been diagnosed with uterine fibroids, but compared to the most recent CT scans taken one and a half months earlier, imaging diagnosis revealed a sudden increase in the size of the tumor when compared to the 8 cm myoma fibroid noted previously. Additional work-up with MRI scans revealed T2-enhanced images of a tumor that had almost completely invaded the myometrium; the tumor presented with marked diffusion-weighted enhancement, and a flow void was noted within the tumor. A differential diagnosis of uterine sarcoma was considered, but due to the lack of focal hemorrhage or necrosis findings on MRI imaging, the possibility of differential diagnosis of metastatic SCLC was also noted. As the patient was experiencing abdominal symptoms including abdominal distension and tenderness due the tumor, a simple hysterectomy and bilateral salpingo-oophorectomy were performed to palliate the symptoms. During the surgical procedures, intra-abdominal findings noted peritoneal dissemination while intraoperative cell cytology diagnosis of ascites revealed small-cell cancer. The final histopathological diagnosis likewise revealed metastatic small-cell cancer from the primary lung cancer. The clinical status of the lung cancer was evaluated as progressive disease (PD), and a change in chemotherapy regimen was necessitated. Further disease progression was noted on CT scans at 2 and a half months after surgery, and with gradual systemic disease progression, the patient died of disease at 3 months postsurgery. Initial evaluation of rapidly enlarging uterine tumors should include a differential diagnosis of uterine sarcoma; additionally, it is necessary to also consider the rare possibility of metastatic disease as in the present case with a clinical history of extragenital malignancy.

Utility of the maximum standardized uptake value on positron emission tomography for predicting therapeutic effect in recurrent gynecological malignancies: A preliminary study.

AIM: The maximum standardized uptake value (SUVmax) of primary tumors in positron emission tomography can be used to predict prognosis in various cancers, but its significance in recurrent tumors remains unclear. In the present study, we evaluated the utility of the SUVmax for predicting therapeutic effects in recurrent gynecological malignancies. METHODS: From February 2012 to July 2014, patients with recurrent gynecological cancer who were treated with chemotherapy or radiotherapy were enrolled in this study. The SUVmax of recurrent lesions before treatment were compared to the therapeutic effects. RESULTS: Fifty patients with recurrent gynecological cancer were enrolled. The mean SUVmax was significantly higher in patients with stable disease/progressive disease than in patients who achieved complete remission/partial remission (13.24 ± 9.78 vs 8.61 ± 5.34, P = 0.039). In patients who were administered chemotherapy, the SUVmax was significantly higher in those with stable disease/progressive disease than in those who achieved complete remission/partial remission (13.24 ± 9.78 vs 8.61 ± 5.34, P = 0.0392) as well as those administered radiotherapy or concurrent chemoradiation therapy (18.15 ± 3.25 vs 11.33 ± 3.98, P = 0.0073). In ovarian cancer patients administered chemotherapy, when the cut-off value of the SUVmax was set as 6.94, the sensitivity and specificity of predicting therapeutic effects were 0.75 and 0.846, respectively. CONCLUSION: Although the number of enrolled cases was small, our study revealed that the SUVmax in recurrent gynecological tumors might predict therapeutic effects. If the SUVmax is relatively high, multimodal therapy, including surgical removal, should be considered.

Histologic grade and peritoneal cytology as prognostic factors in type 1 endometrial cancer.

BACKGROUND: Prognostic clinicopathological factors for type 1 endometrial cancer are unknown and the purpose of the current study was to determine the independent prognostic variables for type 1 endometrial cancer. METHODS: We performed a retrospective study of 168 patients with type 1 endometrial cancer primarily treated with comprehensive staging surgery. The median follow-up time was 68 (12-100) months. Independent risk factors for disease-free survival (DFS) and overall survival (OS) were determined using multivariate Cox regression models. Sub-group analysis of stage I was also performed. We also assessed the patterns of failure among patients with recurrences and investigated the associations with the prognostic variables determined by multivariate analysis. RESULTS: Twenty patients (11.9%) had recurrence and 13 patients (7.7%) died of the disease overall. Multivariate analysis revealed that grade 2 (G2) histology (p = 0.008) and positive peritoneal cytology (p = 0.001) predicted the recurrent event in type 1 endometrial cancer. G2 histology (p = 0.007) and positive peritoneal cytology (p = 0.003) were also found to be independent risk factors for tumor-related deaths. Among stage I patients, G2 histology and positive peritoneal cytology were also independent prognostic variables for DFS and OS. Patients with G2 histology and/or positive peritoneal cytology were more likely to have recurrence at distant sites. CONCLUSIONS: G2 histology and positive peritoneal cytology were independent prognostic factors for DFS and OS in type 1 endometrial cancer.

Endometriotic cyst fluid induces reactive oxygen species (ROS) in human immortalized epithelial cells derived from ovarian endometrioma.

OBJECTIVES: Endometriotic cyst fluid (ECF) contains a large amount of reactive oxygen species (ROS), and endometriotic cysts are exposed to strong oxidative stress, which may cause malignant transformation. In this study, ROS production by ECF was clinically analysed. METHODS: Human immortalized epithelial cells derived from ovarian endometrioma (EMosis-CC/TERT 1) were treated with ECF. In addition, ROS production in EMosis-CC/TERT 1 was measured, and its clinical significance was analysed. RESULTS: A total of 38 ECF samples were obtained from patients diagnosed with endometriotic cysts. In EMosis-CC/TERT1, significantly higher levels of ROS were induced by ECF than by the vehicle control and ferric nitrilotriacetate. There were no significant differences in ROS production by laterality and preoperative serum CA125 values. There were several patients whose cyst sizes were approximately 5 cm and had relatively high ROS production. Production of ROS by ECF was relatively higher in patients older than 40 years of age than in those younger than 40. DISCUSSION: Our study revealed that ROS are highly produced by ECF in EMosis-CC/TERT1 cells; therefore, exposure to ECF induced strong oxidative stress. Development of a therapeutic strategy to reduce ROS production might be useful for preventing malignant transformation of endometriotic cysts.

Elevation of plasma D-dimer levels associated with rupture of ovarian endometriotic cysts.

OBJECTIVE: The marker for the early diagnosis of endometriotic cyst rupture is unknown. We report a preliminary study designed to evaluate the relationship between plasma D-dimer levels and endometriotic cyst rupture in clinical case series. MATERIALS AND METHODS: We reviewed the patients' records of endometriotic cyst rupture cases, and the background (i.e., age, body mass index, and parity) and preoperative laboratory assessments (i.e., white blood cell count, levels of serum C-reactive protein, serum CA125, and plasma D-dimer) of the patients were compared with those of unruptured cases. RESULTS: Emergency surgery cases of endometriotic cyst rupture (n = 6) and planned surgery cases of unruptured endometriotic cysts as controls (n = 16) were reviewed. Backgrounds of the patients were not significantly different between the two groups. The plasma D-dimer level was significantly higher in the rupture cases (8.5 µg/mL vs. 0.20 µg/mL, p < 0.001). Differences in white blood cell count and serum C-reactive protein level, but not serum CA125 level, were found to be statistically significant between groups. CONCLUSION: An elevation of plasma D-dimer level is associated with endometriotic cyst rupture.

Uterine cervical cancer with brain metastasis as the initial site of presentation.

Brain metastasis from uterine cervical cancer is rare, with an incidence of 0.5%, and usually occurs late in the course of the disease. We report a case of uterine cervical cancer with brain metastasis as the initial site of presentation. A 50-year-old woman with headache, vertigo, amnesia and loss of appetite was admitted for persistent vomiting. Contrast enhanced computed tomography showed a solitary right frontal cerebral lesion with ring enhancement and uterine cervical tumor. She was diagnosed with uterine cervical squamous cell carcinoma with parametrium invasion and no other distant affected organs were detected. The cerebral lesion was surgically removed and pathologically proved to be metastasis of uterine cervical squamous cell carcinoma. The patient underwent concurrent chemoradiotherapy, followed by cerebral radiation therapy, but multiple metastases to the liver and lung developed and the patient died 7 months after diagnosis of brain metastasis.

Preoperative evaluation of deep venous thrombosis in patients with pelvic organ prolapse.

AIM: The incidence of preoperative deep venous thrombosis (DVT) was examined in patients with pelvic organ prolapse (POP). MATERIAL AND METHODS: Preoperative screening for DVT was performed on the basis of D-dimer levels; if D-dimer levels were beyond the cut-off limit (0.5 µg/mL), ultrasound examination of the lower extremities was performed. A total of 75 consecutive patients who were scheduled for POP operation in our department were examined retrospectively. RESULTS: D-dimer levels were elevated in 24 patients (31.6%). Further, DVT was detected in 10 of the 75 patients, resulting in an incidence rate of 13.3% in the present study. D-dimer levels were significantly higher in the patients with DVT (1.25 ± 0.52 µg/mL vs 0.41 ± 0.26 µg/mL). There was no significant difference in age, and although body mass index and the number of diabetes mellitus cases were relatively higher in the patients with DVT than in those without DVT, there were no statistically significant differences. According to a receiver-operator curve, the suggested cut-off D-dimer value was 0.71 µg/mL (sensitivity and specificity was 0.9 and 0.877, respectively). CONCLUSIONS: Although this was a preliminary study, to the best of our knowledge, this is the first report describing the incidence of preoperative DVT in patients with POP. Our study indicates that the incidence of DVT in patients with POP might have been underestimated thus far. Therefore, every surgeon should evaluate patients for DVT prior to any surgical procedure for POP, particularly in those patients with obesity or diabetes mellitus.

Primary retroperitoneal Müllerian adenocarcinoma arising from endometriosis.

Primary retroperitoneal Müllerian adenocarcinoma (PRMA) is an extremely rare tumor and the cause remains unknown. We report a case of PRMA arising from endometriosis. A 52-year-old woman with a history of malignant lymphoma underwent a follow-up computed tomography scan, which revealed a retroperitoneal tumor. Immunohistochemical analysis of tumor resected during laparoscopic surgery showed adenocarcinoma positive for cytokeratin 7 and negative for cytokeratin 20. The patient had undergone hysterectomy and bilateral salpingo-oophorectomy 14 years ago for myoma uteri and endometrial cysts and was treated with estrogen-replacement therapy. The size of the tumor increased and laparotomy was performed. Histopathological examination showed adenocarcinoma resembling endometrial adenocarcinoma, which stained positive for cancer antigen 125, cancer antigen 19-9, estrogen receptor, and progesterone receptor immunohistochemically. The focus of the endometriosis was found at the edge of the tumor, and the stromal cells around the tumor cells were CD10 positive. The patient was diagnosed as having PRMA arising from endometriosis, and treated with adjuvant chemotherapy.

Hypoxia alters phosphorylation status of insulin-like growth factor (IGF)-binding protein-1 and attenuates biological activities of IGF-I in HepG2 cell cultures.

AIM: Insulin-like growth factor (IGF)-I is known to stimulate fetal growth. One of the IGF-binding proteins, IGFBP-1, suppresses IGF-I activity, and thereby inhibits fetal growth. Because hypoxic stress in the uterus is known to cause fetal growth restriction, we examined the effects of hypoxia on IGFBP-1 production and phosphorylation status. METHODS: Because liver is a main IGFBP-1 production site in the fetus, we used a hepatoma cell line, HepG2 cells, that secrete a large amount of IGFBP-1, express IGF-I receptors and model fetal liver metabolism in vitro. IGFBP-1 was analyzed by sodium dodecylsulfate polyacrylamide gel electrophoresis (PAGE) following immunoblotting, and IGFBP-1 phosphorylation status was analyzed by native PAGE following immunoblotting. RESULTS: Total concentrations of IGFBP-1 in media were higher and the highly phosphorylated isoforms were dominant in low oxygen conditions. Phosphorylation of IGF-I receptor by IGF-I was attenuated in low oxygen conditions. IGF-I-induced phosphorylation of insulin receptor substrate-1 (IRS-1) was attenuated in low oxygen conditions as well. However, attenuated phosphorylation of IGF-I receptor and IRS-1 were not observed in low oxygen conditions if the cells were stimulated with LR³IGF-I that has a similar binding affinity to IGF-I receptor but much less binding affinity to IGFBP-1 compared to those of native IGF-I. While IGF-I-induced cell proliferation was also inhibited in low oxygen conditions, LR³IGF-I-stimulated cell proliferation was not inhibited. These findings indicate that low oxygen conditions inhibit IGF-I action by increasing IGFBP-1, especially phosphorylated IGFBP-1, which inhibits IGF-I action. CONCLUSION: This study has indicated that hypoxia-induced IGFBP-1 production in the fetus may be a conserved physiological mechanism for restricting IGF-I-stimulated fetal growth.

Burkitt lymphoma of the ovary: a case report and literature review.

We report an extremely rare case of primary ovarian Burkitt lymphoma. A 15-year-old girl was referred to our department because of persistent constipation and abdominal distension. Abdominal computed tomography and magnetic resonance imaging revealed a 10-cm-diameter solid tumor located on the right side of the uterus. Serum lactate dehydrogenase and carbohydrate antigen-125 levels were elevated at 3250 IU/L and 235.7 U/mL, respectively. Initially, ovarian dysgerminoma was suspected, but poor performance and progressive disease were suggestive of malignant lymphoma. However, bone marrow aspiration and ascitic fluid cytology findings were not indicative of lymphoma. Laparotomy was performed to confirm pathology. On laparotomy, the right ovary was firm and enlarged, but the uterus and left ovary were normal. Diffuse thickness of retroperitoneal space was observed. Right salpingo-oophorectomy was performed, and the tumor was diagnosed as Burkitt lymphoma. Although intensive chemotherapy was administered, the patient died 171 days after the initial operation.