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.

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.

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.

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.

Pretreatment thrombocytosis as an independent predictive factor for chemoresistance and poor survival in epithelial ovarian cancer.

BACKGROUND: Thrombocytosis is related to tumor stage and survival in ovarian cancer in addition to the common complications of malignant diseases, such as anemia and inflammation. The aim of our study was to clarify the precise prognostic impact of pretreatment thrombocytosis in epithelial ovarian cancer. METHODS: We retrospectively analyzed 280 consecutive patients who were treated for epithelial ovarian cancer at our institution between 2001 and 2011. RESULTS: Pretreatment thrombocytosis was observed in 18.9% of all patients and was associated with advanced FIGO stage, primary treatment, operation achievement, histologic subtype, microcytic hypochromic anemia (MHA), and nonmalignant inflammatory condition (P = 0.0018, 0.0028, 0.00050, 0.034, 0.00090 and 0.0022). In the patients who relapsed after primary adjuvant chemotherapy (n = 126), thrombocytosis was associated with a shorter treatment-free interval (TFI) (P = 0.0091). The univariate and multivariate analyses revealed that thrombocytosis was independently associated with TFI and MHA (P = 0.021 and 0.0091). Patients with thrombocytosis had worse progression-free survival (PFS) and overall survival (OS) than those without thrombocytosis (P <  0.0001 and <  0.0001). The multivariate analyses for prognostic factors demonstrated that thrombocytosis was significant for poor PFS and OS (P = 0.0050 and 0.022) independent of stage, histology, primary treatment, operation achievement, nonmalignant inflammatory condition and MHA. CONCLUSIONS: The current findings indicate that the detrimental survival impact of pretreatment thrombocytosis in epithelial ovarian cancer may be independent of tumor extent but rather attributed to chemoresistance, further supporting the therapeutic potential of targeting thrombopoietic cytokines in the disease.

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.

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.

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.

Abnormal accumulation of p53 predicts radioresistance leading to poor survival in patients with endometrial carcinoma.

Type II endometrial carcinoma mainly originates from p53 aberration. However, the detailed prognostic significance of p53 aberration in endometrial carcinoma remains to be clarified. In the present study, abnormal p53 accumulation was analyzed using immunohistochemical techniques in endometrial carcinoma samples derived from 221 consecutive patients. The expression levels of p53 were associated with clinicopathological parameters and patient survival. P53 overexpression was observed in 37/221 patients (17%), and was associated with non-endometrioid histology, post-menopause and advanced tumor stage (III/IV; P=0.0006, P=0.03 and P=0.025, respectively). Survival analysis indicated that patients with p53-overexpressing tumors exhibited poor overall survival (OS) compared with patients without p53 overexpression (P<0.000001). Univariate and multivariate analyses demonstrated that the parameters p53 overexpression, age ≥70, non-endometrioid histology and advanced stage were significant and independent prognostic factors for poor OS (P=0.00012, P=0.00048, P=0.0027 and P=0.0015, respectively). Additionally, adjuvant radiotherapy was associated with increased OS in patients without p53 overexpression. This finding was not observed for patients with adjuvant chemotherapy. In contrast to patients without p53 overexpression, patients with p53 overexpression exhibited no association with OS (P=0.02 vs. P=0.40). Notably, adjuvant radiotherapy was identified to be a significant prognostic factor for favorable OS in the subset of patients that did not exhibit p53 overexpression and received post-operative treatment (P=0.026). The findings suggested that abnormal p53 accumulation may influence patient survival via unfavorable biological tumor properties, including rapid progression and radioresistance. The present study offered valuable insights for the genome-directed management of endometrial carcinoma.

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.

Human papillomavirus genotype and prognosis of cervical cancer: Favorable survival of patients with HPV16-positive tumors.

The prognostic impact of human papillomavirus (HPV) type on invasive cervical cancer (ICC) was analyzed for 137 women treated for ICC at a single institution between 1999 and 2007. The study subjects were divided into three groups according to HPV genotype: HPV16-positive (n = 59), HPV18-positive (n = 33), and HPV16/18-negative ICC (non-HPV16/18, n = 45). The median follow-up time was 102.5 months (range, 5-179). The 10-year overall survival (10y-OS) rates in women with FIGO stage I/II disease were similar among HPV genotypes: 94.7% for HPV16 (n = 39), 95.2% for HPV18 (n = 26), and 96.4% for non-HPV16/18 (n = 29). However, the 10y-OS rates in women with FIGO stage III/IV tumors were 73.7% for HPV16 (n = 20), 45.7% for HPV18 (n = 7), and 35.7% for other types (n = 16), with significantly higher survival in HPV16-positive compared with HPV16-negative ICC (10y-OS; 73.7% vs. 39.5%, P = 0.04). This difference in FIGO stage III/IV tumors remained significant after adjusting for age and histology (hazard ratio 0.30, 95% confidence interval 0.09-0.86, P = 0.02). These results suggest that detection of HPV16 DNA may be associated with a favorable prognosis in patients with FIGO stage III/IV ICC. Given that most women with FIGO stage III/IV tumors received concurrent chemoradiotherapy, this finding may imply that HPV16-positive tumors are more chemoradiosensitive.

Prognostic significance of PIK3CA mutation in stage IIB to IVA cervical cancers treated by concurrent chemoradiotherapy with weekly cisplatin.

The standard treatment for locally advanced cervical cancer is cisplatin-based concurrent chemoradiotherapy (CCRT). Although the activated PI3-kinase/Akt pathway is known to be involved in both cisplatin-resistance and radioresistance, to date, only a few studies have reported significant associations between PIK3CA gene mutational status and outcome by CCRT in the disease. The aim of this study was to clarify the prognostic significance of PIK3CA mutational status in cervical cancers treated by CCRT.We analyzed PIK3CA mutation in 59 patients with stage IIB to IVA cervical carcinomas primarily treated by CCRT with weekly cisplatin using formalin-fixed paraffin-embedded biopsy specimens before treatment. Fifty-seven of 59 patients (97%) had locally advanced cancers with stage IIIA to IVA. Clinicopathologic data and patient survival were retrospectively compared according to PIK3CA mutational status.PIK3CA mutation was found in 7 of 59 patients (12%). No significant differences in clinicopathologic characteristics were observed according to PIK3CA mutational status. Patients with wild-type PIK3CA showed significantly improved cancer-specific survival as compared with mutated patients (P = .044). Subsequent survival analyses revealed that PIK3CA mutation was a significant prognostic factor for poor overall survival [multivariate adjusted hazard ratio (HR), 3.9; 95% confidence interval (95% CI), 1.3-11.8; P = .017] and cancer-specific survival (multivariate adjusted HR, 3.6; 95% CI, 1.2-11.0; P = .024).Together with previous published findings, the current study further supports the clinical significance of PIK3CA mutation in cervical cancer. Our observations suggest that molecular inhibitors targeting the PI3-kinase/Akt pathway may improve the outcome by CCRT in cervical cancers harboring PIK3CA mutation, providing significant implications for novel treatment strategy based on precision medicine in the disease.

Separate analysis of human papillomavirus E6 and E7 messenger RNAs to predict cervical neoplasia progression.

A few studies previously suggested that human papillomavirus (HPV) E6 messenger RNA (mRNA) may exist uniformly in all grades of cervical intraepithelial neoplasia (CIN), whereas the detection rate of E7 mRNA may increase with disease progression from low-grade CIN to invasive carcinoma. The aim of this study was to clarify the different roles of E6 and E7 mRNAs in cervical carcinogenesis. The presence of each E6 and E7 mRNA was analyzed in 171 patients with pathologically-diagnosed CIN or cervical carcinoma. We utilized a RT-PCR assay based on consensus primers which could detect E6 mRNA (full-length E6/E7 transcript) and E7 mRNAs (spliced E6*/E7 transcripts) separately for various HPV types. E7 mRNAs were detected in 6% of CIN1, 12% of CIN2, 24% of CIN3, and 54% of cervical carcinoma. The presence of E7 mRNAs was significantly associated with progression from low-grade CIN to invasive carcinoma in contrast with E6 mRNA or high-risk HPV (HR-HPV) DNA (p = 0.00011, 0.80 and 0.54). The presence of both E6 and E7 mRNAs was significantly associated with HPV16/18 DNA but not with HR-HPV DNA (p = 0.0079 and 0.21), while the presence of E6 mRNA was significantly associated with HR-HPV DNA but not with HPV16/18 DNA (p = 0.036 and 0.089). The presence of both E6 and E7 mRNAs showed high specificity and low sensitivity (100% and 19%) for detecting CIN2+ by contrast with the positivity for HR-HPV DNA showing low specificity and high sensitivity (19% and 89%). The positive predictive value for detecting CIN2+ was even higher by the presence of both E6 and E7 mRNAs than by the positivity for HR-HPV DNA (100% vs. 91%). In 31 patients followed up for CIN1-2, the presence of both E6 and E7 mRNAs showed significant association with the occurrence of upgraded abnormal cytology in contrast with E6 mRNA, HR-HPV DNA, or HPV16/18 DNA (p = 0.034, 0.73, 0.53, and 0.72). Our findings support previous studies according to which E7 mRNA is more closely involved in cervical carcinogenesis than E6 mRNA. Moreover, the separate analysis of E6 and E7 mRNAs may be more useful than HR-HPV DNA test for detecting CIN2+ precisely and predicting disease progression. Further accumulation of evidence is warranted to validate our findings.

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.

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.

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.

Posttreatment human papillomavirus testing for residual or recurrent high-grade cervical intraepithelial neoplasia: a pooled analysis.

OBJECTIVE: We conducted a pooled analysis of published studies to compare the performance of human papillomavirus (HPV) testing and cytology in detecting residual or recurrent diseases after treatment for cervical intraepithelial neoplasia grade 2 or 3 (CIN 2/3). METHODS: Source articles presenting data on posttreatment HPV testing were identified from the National Library of Medicine (PubMed) database. We included 5,319 cases from 33 articles published between 1996 and 2013. RESULTS: The pooled sensitivity of high-risk HPV testing (0.92; 95% confidence interval [CI], 0.90 to 0.94) for detecting posttreatment CIN 2 or worse (CIN 2+) was much higher than that of cytology (0.76; 95% CI, 0.71 to 0.80). Co-testing of HPV testing and cytology maximized the sensitivity (0.93; 95% CI, 0.87 to 0.96), while HPV genotyping (detection of the same genotype between pre- and posttreatments) did not improve the sensitivity (0.89; 95% CI, 0.82 to 0.94) compared with high-risk HPV testing alone. The specificity of high-risk HPV testing (0.83; 95% CI, 0.82 to 0.84) was similar to that of cytology (0.85; 95% CI, 0.84 to 0.87) and HPV genotyping (0.83; 95% CI, 0.81 to 0.85), while co-testing had reduced specificity (0.76; 95% CI, 0.75 to 0.78). For women with positive surgical margins, high-risk HPV testing provided remarkable risk discrimination between test-positives and test-negatives (absolute risk of residual CIN 2+ 74.4% [95% CI, 64.0 to 82.6] vs. 0.8% [95% CI, 0.15 to 4.6]; p<0.001). CONCLUSION: Our findings recommend the addition of high-risk HPV testing, either alone or in conjunction with cytology, to posttreatment surveillance strategies. HPV testing can identify populations at greatest risk of posttreatment CIN 2+ lesions, especially among women with positive section margins.

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.

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.