Cellular angiofibroma in the retroperitoneal space during pregnancy: A case report.

BACKGROUND: Cellular angiofibroma (CA) is a rare, benign mesenchymal tumor first described by Nucci et al. (Am J Surg Pathol 21:636-644, 1997. 10.1097/00000478-199706000-00002). It affects both men and women, although it is more common in middle-aged women. CA is well circumscribed and usually observed on the body surface, primarily in distal genital regions. Aggressive angiomyxoma and angiomyofibroblastoma are clinically and histologically similar; therefore, it may be necessary to distinguish between CA and these similar tumors. We present a rare case of CA, with atypical features, in the retroperitoneal space during pregnancy. CASE PRESENTATION: The presence of a 130 mm tumor was detected in a 19-year-old woman. The tumor, located in the retroperitoneal space, was found during first pregnancy examination. At 16 weeks of gestation, the woman developed nausea and fever, and it was diagnosed with acute pyelonephritis. After a few days, the amniotic membranes prematurely ruptured, leading to a miscarriage. The woman underwent a tumor resection, after miscarriage. This case presented with atypical features of CA. This included the young age of the patient, and presence of a tumor in the retroperitoneal space. CONCLUSION: In this case, the diagnosis of CA was difficult due to the rarity of the disease and its atypical clinical features. From this experience, we recommend that the discussion on the efficacy of surgical treatment and pregnancy outcomes should be done based on individual case, and not generalized.

Differential roles of the Wip1-p38-p53 DNA damage response pathway in early/advanced-stage ovarian clear cell carcinomas.

BACKGROUND: Ovarian clear cell carcinoma (OCCC) is one of the most lethal types of ovarian cancer. Early-stage OCCC can be cured by surgery; however, advanced-stage disease shows poor prognosis due to chemoresistance unlike the more common high-grade serous carcinoma. METHODS: We explored the differential roles of the Wip1-p38-p53 DNA damage response pathway in respective early- or advanced-stage OCCC by immunohistochemistry of Wip1, phospho-p38, p53, and phospho-p53 from consecutive 143 patients. RESULTS: High Wip1 expression correlated with positive p53 (p=0.011), which in turn correlated with low nuclear phospho-p38 expression (p=0.0094). In the early stages, positive p53 showed trends toward worse overall survival (OS) (p=0.062), whereas in the advanced stages, high Wip1 correlated with worse OS (p=0.0012). The univariate and multivariate analyses of prognostic factors indicated that high Wip1 was significant and independent for worse OS (p=0.011) in the advanced stages, but not in the early stages. Additionally, high Wip1 showed trends toward shorter treatment-free interval (TFI) in the advanced stages, but not in the early stages (p=0.083 vs. 0.93). Furthermore, high Wip1 was significantly associated with positive p53 only in the patients with shorter TFI (<6 months), but not in those with longer TFI (≥6 months) (p=0.036 vs. 0.34). CONCLUSIONS: Wip1 appears to play a crucial role for the prognosis of OCCC through chemoresistance specifically in the advanced stages, implicating that Wip1 possibly serves as a reasonable therapeutic target for improving chemoresistance and poor prognosis of advanced-stage OCCC.

Ovarian metastases from ileum cancer in a patient with germline EPCAM gene deletion successfully treated with surgical resection and CAPOX chemotherapy: a case report.

BACKGROUND: Despite recent findings that epithelial cell adhesion molecule (EPCAM) deletions can cause Lynch syndrome (LS), its clinical characteristics are still unknown. We present the first case of ileum cancer in a patient with germline EPCAM gene deletion, which was discovered during ovarian tumor surgery. CASE PRESENTATION: A 59-year-old woman presented with a history of colon cancer occurring at 38 and 55 years old. Five of her siblings had a history of colon cancer, and an elder sister had confirmed LS. As imaging examination revealed an ovarian tumor, and we performed hysterectomy and bilateral salpingo-oophorectomy. Careful observation during surgery revealed a cherry-sized tumor in the ileum, prompting partial ileal resection. Pathological examination showed the ovarian tumor to be a metastasis of ileum cancer. Genetic testing with blood-relative information using multiplex ligation-dependent probe amplification showed EPCAM exons 8 and 9 deletions, confirming LS. The patient received adjuvant chemotherapy with CAPOX (capecitabine and oxaliplatin) and has remained disease-free for 24 months. CONCLUSIONS: We were fortunate to identify ileum cancer that would have been difficult to find preoperatively through careful observation during ovarian tumor surgery and successfully treated the patient by using surgical resection and CAPOX chemotherapy. When treating patients with hereditary cancer syndromes including LS, we should keep all associated cancers in mind.

PD-L1 and CD4 are independent prognostic factors for overall survival in endometrial carcinomas.

BACKGROUND: Tumor microenvironment (TME) including the immune checkpoint system impacts prognosis in some types of malignancy. The aim of our study was to investigate the precise prognostic significance of the TME profile in endometrial carcinoma. METHODS: We performed immunohistochemistry of the TME proteins, PD-L1, PD-1, CD4, CD8, CD68, and VEGF in endometrial carcinomas from 221 patients. RESULTS: High PD-L1 in tumor cells (TCs) was associated with better OS (p = 0.004), whereas high PD-L1 in tumor-infiltrating immune cells (TICs) was associated with worse OS (p = 0.02). High PD-L1 in TICs correlated with high densities of CD8+ TICs and CD68+ TICs, as well as microsatellite instability (p = 0.00000064, 0.00078, and 0.0056), while high PD-L1 in TCs correlated with longer treatment-free interval (TFI) after primary chemotherapy in recurrent cases (p = 0.000043). High density of CD4+ TICs correlated with better OS and longer TFI (p = 0.0008 and 0.014). Univariate and multivariate analyses of prognostic factors revealed that high PD-L1 in TCs and high density of CD4+ TICs were significant and independent for favorable OS (p = 0.014 and 0.0025). CONCLUSION: The current findings indicate that PD-L1 and CD4+ helper T cells may be reasonable targets for improving survival through manipulating chemosensitivity, providing significant implications for combining immunotherapies into the therapeutic strategy for endometrial carcinoma.

Prevalence of venous thromboembolism at pretreatment screening and associated risk factors in 2086 patients with gynecological cancer.

AIM: Postoperative pulmonary embolism can be a fatal surgical complication and is thought to occur secondary to asymptomatic venous thromboembolism (VTE) that exists preoperatively in some patients. The purpose of this study was to clarify the frequency and risk factors of pretreatment VTE in gynecological cancer patients. METHODS: This study investigated 2086 patients with gynecological cancer (cervix, n = 754; endometrium, n = 862; ovary, n = 470) who underwent initial treatment between 2004 and 2017. Pretreatment VTE screening was performed with D-dimer (DD) levels in these patients. Based on this, the associated risk factors were retrospectively analyzed. RESULTS: Pretreatment VTE was discovered in 7.3% of patients with cervical cancer, 11.5% of those with endometrial cancer and 27.0% of those with ovarian cancer. Significant independent risk factors were: age greater than or equal to 60 years and tumor long diameter greater than or equal to 40 mm for cervical cancer; age greater than or equal to 60 years, stage III/IV advanced disease, clear cell carcinoma and tumor long diameter greater than or equal to 60 mm for endometrial cancer; and age greater than or equal to 60 years, clear cell carcinoma and massive ascites for ovarian cancer. CONCLUSION: Pretreatment asymptomatic VTE is very frequent in gynecological cancer patients. It may be beneficial to consider measuring DD or performing venous ultrasonography in patients with the above risk factors.

Predictors of favorable survival after secondary cytoreductive surgery for recurrent endometrial cancer.

OBJECTIVE: The selection criteria for secondary cytoreductive surgery (SCS) for recurrent endometrial cancer (EC) remain to be defined. The present study aimed to identify predictors for favorable survival after SCS for the disease. METHODS: We retrospectively reviewed the medical records of 112 patients who relapsed by 2016 among 1052 who were diagnosed with primary EC between 1985 and 2014. Characteristics associated with overall survival (OS) after SCS were identified using univariate and multivariate analyses. RESULTS: Twenty-nine of the 112 patients who relapsed underwent SCS. Complete resection was achieved in 18 (62%) patients, whose OS after SCS was significantly better than that of patients receiving incomplete resection (68 vs. 20 months; p = 0.001). Endometrioid histology and performance status (PS) 0 were significant and independent factors for a favorable OS (p = 0.005, and 0.049). The OS of patients with both factors was better than patients with one or no factors (median 75, 19 and 4 months; p = 0.001 and 0.00001). The number of predictors was associated with the rate of complete resection (p = 0.001). CONCLUSIONS: Patients with endometrioid histology and PS 0 should be offered SCS for recurrent EC. Prospective trials are warranted to verify this proposal.

Japan Society of Gynecologic Oncology guidelines 2015 for the treatment of vulvar cancer and vaginal cancer.

BACKGROUND: Vulvar cancer and vaginal cancer are relatively rare tumors, and there had been no established treatment principles or guidelines to treat these rare tumors in Japan. The first version of the Japan Society of Gynecologic Oncology (JSGO) guidelines for the treatment of vulvar cancer and vaginal cancer was published in 2015 in Japanese. OBJECTIVE: The JSGO committee decided to publish the English version of the JSGO guidelines worldwide, and hope it will be a useful guide to physicians in a similar situation as in Japan. METHODS: The guideline was created according to the basic principles in creating the guidelines of JSGO. RESULTS: The guidelines consist of five chapters and five algorithms. Prior to the first chapter, basic items are described including staging classification and history, classification of histology, and definition of the methods of surgery, radiation, and chemotherapy to give the reader a better understanding of the contents of the guidelines for these rare tumors. The first chapter gives an overview of the guidelines, including the basic policy of the guidelines. The second chapter discusses vulvar cancer, the third chapter discusses vaginal cancer, and the fourth chapter discusses vulvar Paget's disease and malignant melanoma. Each chapter includes clinical questions, recommendations, backgrounds, objectives, explanations, and references. The fifth chapter provides supplemental data for the drugs that are mentioned in the explanation of clinical questions. CONCLUSION: Overall, the objective of these guidelines is to clearly delineate the standard of care for vulvar and vaginal cancer with the goal of ensuring a high standard of care for all women diagnosed with these rare diseases.

Expression of Tissue Factor in Epithelial Ovarian Carcinoma Is Involved in the Development of Venous Thromboembolism.

OBJECTIVES: Our 2007 study of 32 patients with ovarian cancer reported the possible involvement of tissue factor (TF) in the development of venous thromboembolism (VTE) before treatment, especially in clear cell carcinoma (CCC). This follow-up study further investigated this possibility in a larger cohort. METHODS: We investigated the intensity of TF expression (ITFE) and other variables for associations with VTE using univariate and multivariate analyses in 128 patients with epithelial ovarian cancer initially treated between November 2004 and December 2010, none of whom had received neoadjuvant chemotherapy. Before starting treatment, all patients were ultrasonographically screened for VTE. The ITFE was graded based on immunostaining of surgical specimens. RESULTS: Histological types were serous carcinoma (n = 42), CCC (n = 12), endometrioid carcinoma (n = 15), mucinous carcinoma (n = 53), and undifferentiated carcinoma (n = 6). The prevalence of VTE was significantly higher in CCC (34%) than in non-CCC (17%, P = 0.03). As ITFE increased, the frequencies of CCC and VTE increased significantly (P < 0.001 and P = 0.014, respectively). Multivariate analysis identified TF expression and pretreatment dimerized plasmin fragment D level as significant independent risk factors for VTE development. These factors showed particularly strong impacts on advanced-stage disease (P = 0.021). CONCLUSIONS: The 2007 cohort was small, preventing multivariate analysis. This study of a larger cohort yielded stronger evidence that the development of VTE in epithelial ovarian cancer may involve TF expression in cancer tissues.

Current status of tertiary debulking surgery and prognosis after secondary debulking surgery for recurrent Müllerian epithelial cancer in Japan: a retrospective analysis of 164 patients (KCOG-G1402).

BACKGROUND: This study aimed to evaluate the current status of secondary debulking surgery (SDS) and tertiary debulking surgery (TDS; performed for recurrence after SDS) and to assess the overall survival after recurrence of Müllerian epithelial cancer in Japan. We also evaluated the data of patients who underwent a fourth debulking surgery (i.e., quaternary debulking surgery (QDS)). METHODS: We conducted a retrospective study of 164 patients with recurrent Müllerian epithelial cancers (i.e., ovarian, tubal, and peritoneal cancers). The SDS was performed between January 2000 and September 2014 in 20 Japanese hospitals. Clinicopathological data were collected and analyzed. RESULTS: Of the 164 patients, 66 patients did not have a recurrence or died after SDS. Ninety-eight patients had a recurrence after SDS. Forty-three of the 98 patients underwent TDS; 55 of the 98 patients did not undergo TDS and were classified into the non-TDS group. The overall survival (OS) after SDS was significantly better in the TDS group than in the non-TDS group. The median OS after SDS was 123 and 42 months in the TDS group and non-TDS group, respectively. Of the 43 patients who received TDS, 11 patients were further treated with QDS. The median OS after SDS was 123 months for patients who underwent QDS. CONCLUSIONS: This multicenter study on the prognosis of post-SDS is apparently the first report on QDS in Japan. Patients undergoing TDS have a good prognosis, compared to patients in the non-TDS group. Novel drugs are being evaluated; however, debulking surgery remains a necessary treatment for recurrence.

Clinicopathologic implications of DNA mismatch repair status in endometrial carcinomas.

OBJECTIVE: Endometrial carcinoma is the most common malignancy in women with Lynch syndrome caused by mismatch repair (MMR) deficiency. We investigated the clinicopathologic significance of deficient MMR and Lynch syndrome presumed by MMR analyses in unselected endometrial carcinomas. METHODS: We analyzed immunohistochemistry of MMR proteins (MLH1/MSH2/MSH6/PMS2) and MLH1 promoter methylation in primary endometrial carcinomas from 221 consecutive patients. Based on these results, tumors were categorized as sporadic or probable Lynch syndrome (PLS). Clinicopathologic variables and prognosis were compared according to MMR status and sporadic/PLS classification. RESULTS: Deficient MMR showed only trends towards favorable overall survival (OS) compared with intact MMR (p=0.13), whereas PLS showed significantly better OS than sporadic (p=0.038). Sporadic was significantly associated with older age, obesity, deep myometrial invasion, and advanced stage (p=0.008, 0.01, 0.02 and 0.03), while PLS was significantly associated with early stage and Lynch syndrome-associated multiple cancer (p=0.04 and 0.001). The trend towards favorable OS of PLS was stronger in advanced stage than in early stage (hazard ratio, 0.044 [95% CI 0-25.6] vs. 0.49 [0.063-3.8]). In the subset receiving adjuvant therapies, PLS showed trends towards favorable disease-free survival compared to sporadic by contrast with patients receiving no adjuvant therapies showing no such trend (hazard ratio, 0.045 [95% CI 0-20.3] vs. 0.81 [0.095-7.0]). CONCLUSIONS: The current findings suggest that analyzing MMR status and searching for Lynch syndrome may identify a subset of patients with favorable survival and high sensitivity to adjuvant therapies, providing novel and useful implications for formulating the precision medicine in endometrial carcinoma.

Proposal for selection criteria of secondary cytoreductive surgery in recurrent epithelial ovarian, tubal, and peritoneal cancers.

BACKGROUND: The selection criteria for secondary cytoreductive surgery (SCS) in recurrent ovarian cancer are yet to be defined. The aim of this study was to propose the selection criteria through identifying predictive factors for successful SCS. METHODS: All patients who underwent SCS for recurrent epithelial ovarian, tubal, and peritoneal cancers between 1982 and 2012 at our institution were identified through our database. Potential prognostic factors were evaluated in univariate and multivariate analyses. Survival after SCS was examined by the grouping model based on the number of prognostic factors. RESULTS: We performed SCS in 80 consecutive patients, 48 (60 %) of whom achieved complete resection. Complete/incomplete resection significantly influenced survival (median 65 vs. 26 months; p = 0.0005). Among favorable prognostic factors determined before SCS, treatment-free interval >12 months, absent distant metastasis, solitary disease, and performance status 0 were independently associated with better survival (p = 0.0009, 0.00003, 0.0004, and 0.015, respectively). Patients with 3-4 of those factors had better survival than those with 2 or 0-1 factors (median 79, 26, and 19 months; p < 0.00001 and <0.0000000001, respectively). Complete resection of visible tumors was achieved in 79 % of patients with 3-4 factors, in 40 % of those with 2 factors, and in 33 % of those with 0-1 factor. Importantly, even when tumor removal was incomplete at SCS, median survival of patients with 3-4 factors was still quite favorable (83 vs. 67.5 months for complete/incomplete resection, respectively), while those of patients with 2 factors (41 vs. 25 months) and 0-1 factor (19 vs. 19 months) were not. CONCLUSION: We strongly recommend SCS for patients with 3-4 of the above favorable factors at recurrence. As for patients with 2 factors, SCS may be considered if complete resection is expected to be achieved. Prospective studies are warranted to validate our proposal.

High Pretreatment Plasma D-dimer Levels Are Associated With Poor Prognosis in Patients With Ovarian Cancer Independently of Venous Thromboembolism and Tumor Extension.

OBJECTIVE: Elevated plasma D-dimer (DD) is associated with decreased survival among patients with breast, lung, and colon cancers. The present study clarifies the prognostic significance of pretreatment plasma DD levels in patients with epithelial ovarian cancer (EOC). METHODS: We investigated pretreatment DD levels and other variables for overall survival using univariate and multivariate analyses in 134 consecutive patients with EOC stages II to IV who were initially treated between November 2004 and December 2010. RESULTS: The median follow-up period was 53 (7-106) months. Univariate analysis significantly associated elevated pretreatment DD (≥2.0 µg/mL) levels to poor 5-year overall survival rates irrespective of previously treated venous thromboembolism (72.2% vs 52.6%, P = 0.039). Cancer antigen 125 levels of 200 U/mL or higher (P = 0.011), distant metastases (P = 0.0004), residual tumors (P < 0.0001), and International Federation of Gynecology and Obstetrics stage III/IV (P = 0.0033) were also poor prognostic factors. Multivariate analysis independently associated DD levels of 2.0 µg/mL or higher (P = 0.041), distant metastases (P = 0.013), and residual tumors (P < 0.0001) with poor overall survival. CONCLUSIONS: High pretreatment DD levels are associated with poor overall survival in patients with EOC independently of venous thromboembolism and tumor extension and might comprise a promising prognostic biomarker for patients with EOC.

Optimizing biopsy procedures during colposcopy for women with abnormal cervical cancer screening results: a multicenter prospective study.

BACKGROUND: In cervical cancer screening programs, women with abnormal cytology results are referred to colposcopy for histological diagnosis. This study was designed to evaluate the sensitivity of colposcopic procedures for detecting cervical cancer and its precursor, cervical intraepithelial neoplasia (CIN). METHODS: Women referred to colposcopy for abnormal cytology were enrolled from four hospitals. Gynecologists were required to take a colposcopy-guided biopsy from the worst of the abnormal-looking areas as a first biopsy. They were also asked to take ≥ 3 cervical specimens including by endocervical curettage (ECC). Random biopsies were performed at the gynecologist's discretion. We analyzed 827 biopsy results from 255 women who were diagnosed by central pathologists as having histology of CIN or cancer. RESULTS: In this study, 78.1% of diagnoses of CIN grade 2 or worse (CIN2+) (the threshold that would trigger intensive management) were obtained from a first colposcopy-guided biopsy. The additional diagnostic utility of second and third colposcopy-guided biopsies was 16.4 and 1.8%, respectively. The combined sensitivity of two colposcopy-directed biopsies for CIN2+ detection was >90%, regardless of the colposcopist. Random biopsies and ECC increased the diagnostic yield of CIN2+ lesions otherwise missed by colposcopy-guided biopsies alone, but only by 1.2 and 2.4%, respectively. Random biopsies were more useful for women referred after low-grade abnormal cytology (P = 0.01). The utility of ECC was greatest among women with unsatisfactory colposcopy (P = 0.03) or aged ≥ 40 years (P = 0.02). CONCLUSIONS: Our data suggest that at least two colposcopy-directed biopsies should be taken for histological diagnosis. Random biopsies and ECC are recommended for special populations.

The influence of infertility treatment on the prognosis of endometrial cancer and atypical complex endometrial hyperplasia.

INTRODUCTION: Many patients with endometrial cancer have no children when diagnosed, and thus are reluctant to undergo hysterectomy, hoping to preserve their fertility. Their requirement is met, at least partially, with high-dose medroxyprogesterone acetate that brings good response rate in the treatment of endometrial cancer in the early stage and atypical complex endometrial hyperplasia (EC/ACEH). Actually, a number of successful pregnancies after the conservative treatment have been reported. To conceive, many of them need infertility treatment because of ovulation disorders which might have induced the cancer with unopposed estrogens. However, on the other side, hyperestrogenic status caused by ovulation induction or controlled ovarian stimulation might promote the progression and the recurrence of the disease. OBJECTIVE: This study aimed to assess the effectiveness and safety of infertility treatment after conservative therapy for EC/ACEH, to confirm the significance of fertility-sparing therapy. METHODS: The patients with EC/ACEH who achieved complete response after high-dose medroxyprogesterone acetate were eligible for this retrospective study. Characteristics of the patients, whether they underwent infertility treatment, conceived, or relapsed, and the interval from complete response to conception or recurrence were retrospectively analyzed. RESULTS: The clinical outcomes of 36 patients were investigated. Twenty-six of them desired to conceive soon after complete response. All of them underwent infertility treatment, and 16 women delivered healthy babies. Kaplan-Meyer curve and log-rank test analysis revealed that women who achieved live birth had a significantly lower risk of recurrence than those without live birth. There was not a significant difference between the patients with and without infertility treatment. CONCLUSIONS: Use of ovulation induction drugs after conservative treatment of endometrial cancer did not increase the recurrence of the disease. Moreover, resulting pregnancy seems to have an advantageous effect on the oncologic outcome.

Safety and efficacy of substituting nedaplatin after carboplatin hypersensitivity reactions in gynecologic malignancies.

AIM: Repeated treatment with carboplatin increases the incidence of hypersensitivity reactions. Current managements for carboplatin hypersensitivity reactions involve premedication, desensitization, and replacing agents. However, preventive effects for recurrent reactions by the former two methods are still limited, and substituting non-platinum agent can attenuate efficacy against platinum-sensitive diseases. The aim of this study was to evaluate the safety and efficacy of substituting nedaplatin, another platinum compound, as a strategy to deal with carboplatin hypersensitivity reactions in gynecologic cancers. MATERIAL AND METHODS: Patients who experienced carboplatin hypersensitivity reactions and subsequently switched to nedaplatin between 2001 and 2009 were identified through our database. The incidence and severity of nedaplatin hypersensitivity were examined. Response to nedaplatin therapy was evaluated according to Response Evaluation Criteria in Solid Tumors (RECIST) and serum CA-125 levels. RESULTS: Forty-six of 570 patients (8.1%) experienced carboplatin hypersensitivity reactions, and the increased cycle numbers of carboplatin-based regimens correlated with the high incidence of hypersensitivity (≤6, 0.9% vs ≥7, 19.2%). Of these 46 patients, 38 subsequently switched to nedaplatin-based regimens (ovarian, tubal or peritoneal carcinoma, 30; endometrial carcinoma, 6; cervical carcinoma, 2). Three of the 38 patients (7.9%) eventually developed hypersensitivity against nedaplatin, and all their reactions were grade 2. The response rate to nedaplatin therapy among 32 evaluable patients was 31.3%. CONCLUSION: Replacing carboplatin with nedaplatin provided a safe and efficacious approach to manage carboplatin hypersensitivity. To the authors' knowledge, this study is the first to indicate the usefulness of nedaplatin after carboplatin hypersensitivity reactions. Further evaluations are warranted to confirm our finding.

Molecular biomarkers for facilitating genome­directed precision medicine in gynecological cancer (Review).

Prominent recent advancements in cancer treatment include the development and clinical application of next-generation sequencing (NGS) technologies, alongside a diverse array of novel molecular targeting therapeutics. NGS has enabled the high-speed and low-cost sequencing of whole genomes in individual patients, which has opened the era of genome-based precision medicine. The development of numerous molecular targeting agents, including anti-VEGF antibodies, poly (ADP-ribose) polymerase inhibitors and immune checkpoint inhibitors, have all improved the efficacy of systemic cancer therapy. Accumulating bench and translational research evidence has led to identification of various cancer-related biomarker profiles. In particular, companion diagnostics have been developed for some of these biomarkers, which can be clinically applied and are now widely used for guiding cancer therapies. Selecting biomarkers accurately will improve therapeutic efficacy, avoid overtreatment, enable earlier diagnosis and reduce the cost of preventing and treating gynecological cancer. Therefore, biomarkers are fast becoming indispensable tools in the practice of genome-directed precision medicine. In the present review, the current evidence of cancer-related biomarkers in the field of gynecological oncology, their molecular interpretations and future perspectives are outlined. The aim of the present review is to provide potentially useful information for the formulation of clinical trials.

Preoperative Venous Thromboembolism Screening and Postoperative Selective Anticoagulant Therapy Effectively Prevents Postoperative Symptomatic Venous Thromboembolism in Gynecological Malignancies: A 15-Year, Single-Center Study.

The aim of this study was to determine which type of prophylaxis was effective for postoperative symptomatic venous thromboembolism (VTE) in patients with gynecological malignancies. A total of 1756 consecutive patients undergoing laparotomy as first-line treatment were included. In Period 1 (2004-2009), low-molecular weight heparin (LMWH) was not available for postoperative VTE prophylaxis, but available in after Period 2 (2009-2013). In Period 3 (2013-2020), patients with pretreatment VTE could switch from LMWH to direct oral anticoagulant (DOAC) as of 2015. Preoperative VTE was screened by measuring D-dimer, followed by venous ultrasound imaging, and computed tomography and/or perfusion lung scintigraphy. Postoperative symptomatic VTE occurred with an incidence of 2.8% by the measures without prophylactic LMWH administration in Period 1. The incidence of postoperative symptomatic VTE was 0.6% in Period 2 and 0.3% in Period 3, being significantly reduced compared with Period 1 (P < .01 and < .0001). The incidences were not significantly different between Periods 2 and 3, but no patient switching to DOAC in Period 3 (n = 79) developed symptomatic VTE. Our preoperative VTE screening and postoperative selective LMWH administration were significantly preventive against postoperative symptomatic VTE.

Comparing Characteristics of Pelvic High-grade Serous Carcinomas with and without Breast Cancer Gene Variants on MR Imaging.

PURPOSE: To compare MRI findings of high-grade serous carcinoma (HGSC) with and without breast cancer (BRCA) gene variants to explore the feasibility of MRI as a genetic predictor. METHODS: We retrospectively reviewed MRI data from 16 patients with BRCA variant-positive (11 patients of BRCA1 and 5 patients of BRCA2 variant-positive) and 32 patients with BRCA variant-negative HGSCs and evaluated tumor size, appearance, nature of solid components, apparent diffusion coefficient (ADC) value, time-intensity curve, several dynamic contrast-enhanced curve descriptors, and nature of peritoneal metastasis. Age, primary site, tumor stage, bilaterality, presence of lymph node metastasis, presence of peritoneal metastasis, and tumor markers were also compared between the groups with the Mann-Whitney U and chi-square tests. RESULTS: The mean tumor size of BRCA variant-positive HGSCs was 9.6 cm, and that of variant-negative HGSCs was 6.8 cm, with no significant difference (P = 0.241). No significant difference was found between BRCA variant-positive and negative HGSCs in other evaluated factors, except for age (mean age, 53 years old; range, 32-78 years old for BRCA variant-positive and mean age, 61 years old; range, 44-80 years old for BRCA variant-negative, P = 0.033). Comparing BRCA1 variant-positive and BRCA2 variant-positive HGSCs, BRCA1 variant-positive HGSCs were larger (P = 0.040), had greater Max enhancement (P = 0.013), Area under the curve (P = 0.013), and CA125 (P = 0.038), and had a higher frequency of lymph node metastasis (P = 0.049), with significance. CONCLUSION: There was no significant difference in the MRI findings between patients with HGSCs with and without BRCA variants. Although studied in small numbers, BRCA1 variant-positive HGSCs were larger and more enhanced than BRCA2 variant-positive HGSCs with higher CA125 and more frequent lymph node metastases, and may represent more aggressive features.

Interleukin-10 -1082 gene polymorphism and susceptibility to cervical cancer among Japanese women.

Polymorphisms in cytokine genes can influence immune responses to human papillomavirus infection, possibly modifying risks of cervical cancer. Using an amplification refractory mutation system-polymerase chain reaction method, we analyzed a single nucleotide polymorphism (A/G) at position -1082 in interleukin-10 promoter region in 440 Japanese women: 173 women with normal cytology, 163 women with cervical intraepithelial neoplasia and 104 women with invasive cervical cancer. The carrier frequency of interleukin-10 -1082 G alleles associated with higher interleukin-10 production increased with disease severity: 9.8% for normal cytology; 19.6% for cervical intraepithelial neoplasia; 29.8% for invasive cervical cancer (P for trend < 0.001). Among cytologically normal women, human papillomavirus infections were more common in those who were positive for an interleukin-10 -1082 G allele (P = 0.04). In conclusion, our data suggest that interleukin-10 -1082 gene polymorphism may serve as a marker of genetic susceptibility to cervical cancer among Japanese women.

[Molecular mechanism of cervical carcinogenesis].

Cervical cancer is the second leading cause of cancer death in women worldwide; approximately 500,000 women develop cervical cancer every year, and more than half of them die from the disease. While the incidence of cervical cancer in developed countries is decreasing due to the widespread use of cervical cytology screening, the incidence among those in their 20's and 30's in Japan is rapidly increasing because of gradually younger sexual debut. High-risk human papilloma viruses (HPVs) such as HPV16 and 18 are thought to be responsible for more than 90% of cervical cancers. HPVs reach and infect the basal layer of the stratified epithelia via small epithelial injuries produced by sexual intercourse, and the viral DNAs are maintained as episomes in the basal cells. When the host cells initiate terminal differentiation, the viral DNAs start to replicate by reactivating the DNA synthesis machinery through degrading p53 by E6 and inactivating Rb by E7. Viral propagation results in the host cells' death, whereas on rare occasions HPV genomes are integrated into the host chromosomes. The cells constantly over expressing E6 and E7 from the integrated viral genomes develop multiple steps towards carcinogenesis through numerous E6 and E7 oncoprotein functions. However, the over-expressions of E6 and E7 are known to be insufficient for carcinogenesis; additional accumulation of genetic and epigenetic abnormalities in oncogenes and tumor suppressors are required. In this review, we outline the current understanding of the molecular mechanisms of high-risk HPV-induced cervical carcinogenesis.