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Background: The aim of this study was to evaluate the clinicopathological factors and prognosis of mucinous carcinoma (MC) with infiltrative invasion, MC with expansile invasion, and high-grade serous carcinoma (HGSC). Methods: Cases of MC and HGSC between 1984 and 2019 were identified. The clinicopathological factors and prognosis of MC with infiltrative invasion or expansile invasion and HGSC were retrospectively compared. Although our present study included cases in our previous studies, we extended observational period when analysis was performed. Accordingly, our study added increased cases and survival analysis was newly conducted. Results: After pathological review, 27 cases of MC with infiltrative invasion, 25 cases of MC with expansile invasion, and 219 cases of HGSC were included. MC had a better prognosis in terms of progression-free survival (PFS, p < 0.01) and overall survival (OS, p < 0.01) than HGSC for all International Federation of Gynecology and Obstetrics (FIGO) stages; however, multivariate analysis did not show statistical differences in PFS and OS. There were no statistically significant differences in PFS and OS for all FIGO stages between MC with infiltrative invasion and HGSC. However, in cases with FIGO stages II to IV, MC with infiltrative invasion had worse PFS (p < 0.01) and OS (p < 0.01) than HGSC. In univariate analysis, MC with infiltrative invasion was a worse prognostic factor for PFS (hazard ratio [HR] 2.83, p < 0.01) and OS (HR 3.83, p < 0.01) than HGSC. Compared with HGSC, MC with expansile invasion had better PFS (p < 0.01) and OS (p < 0.01). Multivariate analysis demonstrated that MC with expansile invasion was a better prognostic factor for PFS (HR 0.17, p < 0.01) and OS (HR 0.18, p = 0.03) than HGSC. Conclusions: Compared to the prognosis of HGSC, that of MC was different according to the invasive pattern and FIGO stage. Therefore, future study may be needed to consider this association. [ABSTRACT FROM AUTHOR]

Purpose: The aim of this study was to investigate the association between changes in the levels of vascular endothelial growth factors (VEGFs) after treatment with bevacizumab and gemcitabine (Bev-Gem) and the clinical outcome.Methods: Platinum-resistant ovarian cancer patients treated with Bev-Gem therapy at our hospital between 2014 and 2018 were identified. Serum VEGF levels at the first and second treatment cycle were measured by ELISA. All patients were categorized into two groups-patients with > 50% decrease in serum VEGF-A levels (Group A) and patients with < 50% decrease serum VEGF-A levels (Group B). The association between clinical outcome and serum VEGF levels was investigated between the two groups.Results: Among 18 patients, 10 were in Group A and 8 in Group B. Group A exhibited a lower response rate (0% vs.75% p < 0.01) and clinical benefit rate (60% vs.100% p = 0.02) than Group B. The median serum VEGF-A level of Group A before the first cycle of Bev-Gem therapy was higher than that in Group B (61.2 vs. 3.7 pg/mL, p < 0.01). Group A exhibited worse PFS (7 vs., 10 months, p < 0.01) and OS (17 vs. 26 months, p = 0.04) than Group B. There were more patients with > 10% increase in serum VEGF-B levels in Group A than in Group B (p < 0.01).Conclusion: The rapid decrease in VEGF-A levels and the resultant increase in serum VEGF-B levels might be associated with an unfavorable clinical outcome. Large-scale studies are needed to further examine these results. [ABSTRACT FROM AUTHOR]

Background: This study aimed to examine the clinical significance and risk factors of thromboembolic events (TEEs) in patients with ovarian carcinoma. Methods: Patients with ovarian carcinoma treated at our hospital between 2000 and 2017 were identified. The risk factors of TEEs, including venous TEEs and arterial TEEs, and the association between TEEs and prognosis were investigated. Patients with TEEs were classified into two groups: those with severe TEEs, defined as patients who required urgent treatment for deep vein thrombosis, massive pulmonary embolism, acute myocardial infarction, and symptomatic cerebral infarction, and those with mild TEEs. The risk factors of severe TEEs and the association between severe TEEs and prognosis were investigated. Results: A total of 369 patients were enrolled. Among them, 53 patients (14.4%) were complicated with TEEs. Clear cell carcinoma (CCC) was a greater risk factor of TEEs than serous carcinoma (hazard ratio [HR] = 2.81, p = 0.03). In multivariate analysis for survival, TEEs were a prognostic factor of poor progression-free survival (PFS; HR = 2.90, p < 0.01) and overall survival (OS; HR = 2.89, p < 0.01). Among 53 patients with TEEs, 17 (32.1%) developed severe TEEs. CCC was strongly associated with severe TEEs (HR = 42.6, p = 0.02). Multivariate analysis for survival demonstrated that severe TEEs were a risk factor of worse PFS (HR = 4.34, p < 0.01) and OS (HR = 3.30, p = 0.03). Conclusion: TEEs induced poor prognosis and was associated with CCC. A standard treatment for CCC should be included in the strategy of TEEs. [ABSTRACT FROM AUTHOR]

Objective: The clinical significance of lymphocyte infiltration (LI) at the invasive front in endometrial carcinomas (EC) has not been determined. The aim of the current study was to evaluate the association between zone formation of LI at the invasive front of the tumor margin and prognoses of the patients with EC. Methods: All available pathological slides of the enrolled cases were reviewed, and the degree of LI at the invasive front was categorized into 2 groups: strong LI and weak LI. Clinical significance of LI was evaluated retrospectively. Results: A total of 333 cases with EC were enrolled in the study: 225 cases with weak LI and 108 cases with strong LI. Weak LI was more frequently observed in the patients with grade1/2 endometrioid EC. Multivariate analyses for progression-free survival (PFS) and overall survival (OS) revealed that weak LI was identified as an independent worse prognostic factor for OS (p = 0.004) in addition to PFS (p = 0.022). Conclusion: Weak LI at the invasive front of the tumor margin was associated with worse prognoses in EC. Although further studies are needed, it is suggested that LI could be a biomarker of prognoses in EC. [ABSTRACT FROM AUTHOR]

The activation of JAK2/STAT3 pathway has been reported to have critical roles in several solid tumors. The present study aimed to evaluate the correlation between JAK2/STAT3 activation and clinicopathological parameters in ovarian cancer types. Tissue microarrays made from the patients treated at the National Defense Medical College Hospital between 1984 and 2008 were evaluated using immunohistochemical (IHC) stainings. Medical charts of these patients including IHC results were retrospectively analyzed, and prognostic factors for progression-free survival and overall survival were evaluated. Among 341 enrolled patients, positive expression of p-STAT3 was observed in 95 cases (28%). Positive p-STAT3 was an independent worse prognostic factor for overall survival in all the cases. Additionally, p-STAT3 expression was related with overall survival in patients with clear-cell histology, but not in serous histology. The effect of an inhibitor of STAT3, niclosamide, was evaluated in ovarian clear-cell cancer cells, and niclosamide treatment decreased expression of p-STAT3, leading to increased apoptosis in a dose-dependent manner in vitro. The activation of JAK2/STAT3 pathway had significant impact on survival of ovarian cancers, especially for the cases with clear-cell histology. Although further analyses are needed, suppression of this pathway could be a candidate for the treatment of ovarian cancers. [ABSTRACT FROM AUTHOR]

Objective: Most of the endometrial carcinomas are detected in early stages and have a better prognosis; however, predictive factors for recurrence have not been determined. Methods: Patients with grade 1 endometrioid carcinoma (EG1) according to the 2014 WHO criteria at FIGO 2009 stage IA that were identified through scanning medical charts were included, and we assessed whether the presence of uterine serous carcinoma (SC) component which comprised less than 5% of the total volume using the ovarian two-tiered grading system could be a recurrent risk factor in these patients. Results: Among 126 cases which met inclusion criteria, 12 cases had SC. SC tumors were divided into 2 groups: SC resembling high-grade serous carcinoma (HGSC) and SC resembling low-grade serous carcinoma (LGSC). Five (3.9%) cases had HGSC and 7 (5.6%) cases had LGSC. Recurrence was observed in 3 of all cases (2.3%): 2 cases with HGSC, and 1 case with LGSC. Regarding several clinicopathological factors, only the presence of SC was associated with recurrence. The sensitivity and specificity to predict recurrence using this system were 100 and 93%, respectively. Conclusion: The identification of SC using the ovarian two-tiered grading system could be an accurate predictor of recurrence in stage IA EG1. [ABSTRACT FROM AUTHOR]

Although treatment for recurrent epithelial ovarian, tubal, and peritoneal cancers is usually not curative and intends to be palliative, a certain significance of secondary cytoreductive surgery (SCS) for recurrent tumor has been reported; still, there are limitations in this strategy including difficulty in predicting successful complete resection and selecting good candidates. The purpose of this study was to explore the potential survival benefit of SCS in patients with recurrent epithelial ovarian, tubal, and peritoneal cancers.Among all patients who underwent primary therapy for epithelial ovarian, tubal, and peritoneal cancers between 1994 and 2006 at our institute, medical records of patients who were submitted to SCS for recurrence following complete remission after primary therapy were retrospectively investigated. Kaplan-Meier method and log-rank test were used for survival analysis, and Cox proportional hazard regression model was used for quantifying the relations between survival and covariates.Thirty-four patients met the inclusion criteria. Complete resection of all visible tumors at SCS was achieved in 24 of patients (75%). Median postrecurrence survival was 60 months. On univariate analysis, solitary recurrence, disease-free interval, CA125 value at recurrence, and complete resection were significant prognostic factors on postrecurrence survival; whereas on multivariate analysis, CA125 value at recurrence and complete resection were independent prognostic factors. In addition, a comparison according to the initial method that detected recurrence revealed that patients whose recurrence was detected with CA125 elevations had significantly worse postrecurrence survival than those detected with routine examinations including image scans (P = 0.021).In the present study, the impact of SCS on the significant survival benefit was identified for patients with low CA125 value at recurrence as well as with complete resection. Although further analyses are needed, patients whose recurrence was diagnosed by routine examinations without CA125 elevation might be better candidates for SCS. [ABSTRACT FROM AUTHOR]

Almost a quarter of a century has passed since the term sarcopenia was defined. Sarcopenia is recognized as a poor prognostic factor in a variety of cancer types. In ovarian cancer, it remains controversial whether sarcopenia affects prognosis and how it should be evaluated. The present study aimed to evaluate the association between the volume of the psoas major muscle and survival in patients with epithelial ovarian cancer. Medical charts of patients with epithelial ovarian cancer who received first-line chemotherapy with paclitaxel and carboplatin at the National Defense Medical College Hospital (Tokorozawa, Japan) between April 2010 and January 2015 were retrospectively reviewed. The bilateral psoas major muscle areas at the fifth lumbar vertebra were measured using computed tomography images. The Institutional Review Board at National Defense Medical College Hospital (Tokorozawa, Japan) approved the study protocol. A total of 72 patients with epithelial ovarian cancer who received combination therapy with paclitaxel and carboplatin were identified and enrolled. The median psoas muscle index (PMI; psoas muscle major cross-sectional area divided by height squared) was 5.4 cm2/m2 (range, 3.3-10.0). Patients with higher PMI had significantly improved overall survival (OS) compared with those with lower PMI [log-rank test P=0.014; hazard ratio (HR), 2.61; 95% confidence interval (CI), 1.21-6.06]. Multivariate analysis for OS revealed that lower PMI was an independent unfavorable prognostic factor (HR, 3.87; 95% CI, 1.37-12.1; P=0.0098). The volume of psoas major muscle mass could be a potential biomarker for prognosis in patients with epithelial ovarian cancer. [ABSTRACT FROM AUTHOR]

Low-grade and high-grade endometrial stromal sarcomas (LGESS and HGESS) and undifferentiated uterine sarcomas (UUS) are rare tumors whose pathological classification and staging system have changed recently. These tumors are reported to contain fusion genes. We aimed to clarify the genetic background, clinical features, prognostic factors, and optimal therapy of these tumors using a new classification and staging system. We analyzed the clinical features and prognostic information of 72 patients with LGESS, 25 with HGESS, and 16 with UUS using central pathological review. Estrogen and progesterone receptors (PgRs) were examined by immunohistochemistry. JAZF1–SUZ12 and YWHAE-NUTM2A/B gene fusions were tested using real-time polymerase chain reaction. The 5-year overall survival (OS) rates of LGESS, HGESS, and UUS were 94%, 53%, and 25%, respectively. In LGESS, stage IV, incomplete surgery, and absence of PgR were associated with poor OS. The presence of JAZF1-SUZ12 fusion gene was not associated with OS. In HGESS, the relationship between stage and prognosis was unclear. None of the 3 patients with YWHAE-NUTM2A/B fusion gene died during follow-up. Adjuvant chemotherapy was associated with a favorable OS. Incomplete resection of UUS was associated with poor OS; however, residual tumors frequently occurred. Although most patients underwent adjuvant chemotherapy, their prognosis was extremely poor even in stage I disease. Prognosis of LGESS is generally good; however, stage IV, incomplete surgery, and PgR-negative tumors are associated with poor prognosis. Adjuvant chemotherapy may be useful for HGESS. Prognosis of UUS is extremely poor, even with adjuvant chemotherapy. • LGESS: Good prognosis, but progesterone receptor absence predicts poorer outcome. • HGESS: The relationship between stage and prognosis is unclear. Adjuvant chemotherapy may be useful. • USS: Although complete resection is desired because of its extremely poor prognosis, residual tumors often occur. [ABSTRACT FROM AUTHOR]

To analyze the clinical behavior of neuroendocrine tumors (NETs) of the uterine cervix, we conducted a multicenter, retrospective study of 193 patients. We evaluated the prognosis of NETs according to the new International Federation of Gynecology and Obstetrics (FIGO) staging system, compared the clinical response to different chemotherapy regimens, and compared different histological subtypes of NETS. Diagnoses of the subjects were atypical carcinoid tumor (ACT, n = 37), small cell neuroendocrine carcinoma (SCNEC, n = 126), large cell neuroendocrine carcinoma (LCNEC, n = 22), and NET, not elsewhere classified (n = 8), according to central pathological review. According to FIGO 2018, 69, 17, 74, and 33 patients were at stage I, II, III, or IV, respectively. Five-year survival was 64.5%, 50.1%, 30.2%, and 3.4% for patients at stage I, II, III and IV. About 40% of patients with stage IIIC1 survived >5 years. On multivariate analyses, locally-advanced disease, para-aortic node metastasis, distant metastasis, and <4 cycles of chemotherapy were associated with poor survival. Histological subtype and pelvic node metastasis had no prognostic significance. Response rates to etoposide-platinum (EP) or irinotecan-platinum (CPT-P) regimens were 43.8% (28/64), but only 12.9% to a taxane-platinum (TC) regimen (4/31). The response rate for ACT was 8.7% (2/23), significantly less than the 36.6% for high-grade neuroendocrine carcinomas (HGNEC: both SCNEC and LCNEC, 41/111). Locally-advanced, extra-pelvic disease and insufficient chemotherapy were independent prognostic factors for cervical NET. HGNEC showed good responses to EP or CPT-P but not TC. Chemotherapy was less effective for ACT, which had a prognosis identical to HGNEC. • A multicenter, retrospective study of neuroendocrine tumors of the uterine cervix was undertaken. • Locally-advanced and extra-pelvic disease were independent prognostic factors for NET of the cervix. • HGNEC showed good responses to EP or CPT-P regimens but not to TC. • ACT was less responsive to chemotherapy and had a prognosis identical to HGNEC. [ABSTRACT FROM AUTHOR]

Aim The aim of this study was to investigate prognostic factors, including postoperative chemotherapy regimen, for the treatment of ovarian yolk sac tumour (YST), and resulting fertility outcome. Methods A multi-institutional retrospective investigation was undertaken to identify patients with ovarian pure or mixed YST who were treated between 1980 and 2007. Postoperative chemotherapy regimen and other variables were assessed in univariate and multivariate analyses. Additionally, the reproductive safety of the BEP (bleomycin, etoposide and cisplatin) regimen was evaluated. Results There were 211 patients enrolled from 43 institutions. The BEP regimen and a non-BEP regimen were administered to 112 and 99 patients as postoperative chemotherapy, respectively. In univariate and multivariate analyses, age ⩾ 22, alpha-fetoprotein ⩾ 33,000 ng/ml, residual tumours after surgery and non-BEP regimen were independently and significantly associated with poor overall survival (OS). BEP was significantly superior to non-BEP in 5-year OS (93.6% versus 74.6%, P = 0.0004). Reduced-dose BEP (<75% standard-dose bleomycin and < 50% etoposide dose) was significantly associated with poorer 5-year OS compared with standard-dose BEP (89.4% versus 100%, P = 0.02 and 62.5% versus 96.9%, P = 0.0002). All patients who underwent fertility-sparing surgery recovered their menstrual cycles. Sixteen of 23 patients receiving BEP (70.0%) and 13 of 17 patients receiving non-BEP (76.5%) who were nulliparous at fertility-sparing surgery and married at the time of investigation gave birth to 21 and 19 healthy children, respectively. Conclusions The results of the present study suggest that standard-dose BEP should be administered for ovarian YST. BEP is as safe as non-BEP for preserving reproductive function. [ABSTRACT FROM AUTHOR]

Abstract: Objectives: The purpose of this study was to identify genes that predict progression-free survival (PFS) in advanced epithelial ovarian cancer (aEOC) receiving standard therapy. Methods: We performed microarray analysis on laser microdissected aEOC cells. All cases received staging laparotomy and adjuvant chemotherapy (carboplatin+paclitaxel) as primary therapy. Results: Microarray analysis identified 50 genes differentially expressed between tumors of patients with no evidence of disease (NED) or evidence of disease (ED) (p <0.001). Six genes (13%) were located at 8q24, and 9 genes (19.6%), at 20q11–13. The ratio of selected gene set/analyzed gene set in chromosomes 8 and 20 are significantly higher than that in other chromosome regions (6/606 vs. 32/13656, p =0.01) and (12/383 vs. 32/13656, p =1.3×10− 16). We speculate that the abnormal chromosomal distribution is due to genomic alteration and that these genes may play an important role in aEOC and choose GNAS (GNAS complex locus, NM_000516) on 20q13 based on the p value and fold change. Genomic PCR of aEOC cells also showed that amplification of GNAS was significantly correlated with unfavorable PFS (p =0.011). Real-time quantitative RT-PCR analysis of independent samples revealed that high mRNA expression levels of the GNAS genes, located at chromosome 20q13, was significantly unfavorable indicators of progression-free survival (PFS). Finally, GNAS amplification was an independent prognostic factor for PFS. Conclusions: Our results suggest that GNAS gene amplification may be an independent, qualitative, and reproducible biomarker of PFS in aEOC. [Copyright &y& Elsevier]