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In endometrial cancer (EC), lymph node (LN) metastasis significantly impacts prognosis. Thus far, no studies have reported the molecular genetics of each metastatic lesion. This study aimed to investigate the molecular characteristics of primary and metastatic LNs and their association with clinical outcomes.The clinicopathological and molecular characteristics of 33 patients with EC with regional LN metastasis (FIGO stage IIIC) were investigated; we evaluated the mutational status of p53 and DNA mismatch repair (MMR) proteins in the primary lesion, all the positive LNs (102 lesions), mutational variation between primary and paired metastatic lesions, inter-lesion heterogeneity, and their association with clinical outcomes.Immunohistochemically, 12 patients (36.4%) displayed aberrant p53 expression in metastatic lesions, and a concordant rate of 93.4% was observed between primary and metastatic lesions. Inter-lesion heterogeneity was observed in 20 cases (60.6%). In Kaplan-Meier analysis, patients with aberrant p53 expression in metastatic LNs exhibited worse progression-free survival (PFS) than those with wild-type p53 expression (p=0.008). Wild-type p53 expression in primary lesion with inter-lesion heterogeneity had a significantly worse PFS (p=0.049) than those without heterogeneity. In the Cox univariate analysis, p53 expression in metastatic LNs was significantly associated with recurrence (p=0.013). Genetic diversity between primary and metastatic lesions and among metastases was validated by evaluating the p53 and MMR proteins using immunohistochemistry analysis.The molecular characteristics of metastatic lesions in addition to those of primary lesions could provide beneficial prognostic information in patients with EC with regional LN metastasis.

In endometrial cancer (EC), lymph node (LN) metastasis significantly impacts prognosis. In this study, the clinicopathological and molecular characteristics of 33 patients with EC with regional LN metastasis (FIGO stage IIIC) were investigated. We evaluated the mutational status of p53 and DNA mismatch repair (MMR) proteins in positive LNs (102 lesions), mutational variation between primary and paired metastatic lesions, inter-lesion heterogeneity in the metastatic lesions, and their association with clinical outcomes. Immunohistochemically, 13 patients (39.4%) displayed aberrant p53 expression in metastatic lesions, and a concordant rate of 93.4% was found between the primary and metastatic lesions. Genetic diversity between primary and metastatic lesions and among metastases was validated by evaluating p53 and MMR proteins. In Kaplan–Meier analysis, patients with aberrant p53 expression in metastatic LNs exhibited worse progression-free survival (PFS) than those with wild-type expression (p=0.024). Aberrant expression of p53 in the primary lesion did not show a significant difference in PFS compared with wild-type expression. In Cox univariate analysis, only p53 expression in metastatic LNs was significantly associated with recurrence (p=0.031). In conclusion, p53 expression in metastatic LNs is an independent and superior predictor of PFS in patients with EC with regional LN metastasis.

Background/aim The objective of this study was to determine the molecular and clinicopathological features, as well as the prognosis of patients with endometrial cancer (EC) having prior malignancy (second primary EC: SPEC) compared with those without a history of prior malignancy (first primary EC: FPEC). Materials and methods We enrolled 294 FPEC patients and 32 SPEC patients who had undergone surgical resection with curative intent. EC was divided into four groups according to Cancer Genome Atlas Research Network (TCGA) classification. Results SPEC patients having greater than a 10-year interval from prior malignancy had risk factors including type II histology, deeper myometrial invasion, cervical invasion, and copy number high (CNH) phenotype compared with patients having less than a 10-year interval (p=0.007, p=0.002, p=0.015 and p=0.001). Conclusion SPEC patients having greater than a 10-year interval from prior malignancy possessed numerous high-risk factors for EC.

The aim of the present study was to determine whether chronic diseases (CD), such as hypertension, diabetes mellitus, dyslipidemia, heart diseases and cerebrovascular diseases, are occurrence risk factors and affect the survival of patients with gynecological cancers (GC). The correlations between CD and the characteristics and survival of 1,590 GC patients [685 with cervical cancer (CC), 613 with endometrial cancer (EM) and 292 with ovarian cancer (OV)] were investigated in the present study. Of the CD patients, 189 had CC (27.6%), 265 had EM (43.2%) and 72 had OV (24.7%). The incidence of CD increased with age in GC patients. The number of CD patients aged ≥70 years, was 8.6-fold higher in the CC group, 3.0-fold higher in the EM group, and 9.6-fold higher in the OV group compared with those aged 24% of the occurrence risk factors in GC patients in Japan.

// Yoshiko Mori 1, 2 , Akihiro Nyuya 3 , Kazuya Yasui 1 , Toshiaki Toshima 1 , Takashi Kawai 1 , Fumitaka Taniguchi 1 , Keisuke Kimura 1 , Ryo Inada 1 , Masahiko Nishizaki 1 , Junko Haraga 4 , Keiichiro Nakamura 4 , Yuzo Umeda 1 , Hiroyuki Kishimoto 1 , Toshiyoshi Fujiwara 1 , Yosuke Katata 3 , Yoshiyuki Yamaguchi 3 and Takeshi Nagasaka 3 1 Departments of Gastroenterological Surgery, Okayama University Graduate School of Medicine Dentistry and Pharmaceutical Sciences, Okayama, Japan 2 Clinical Genomic Medicine, Okayama University Graduate School of Medicine Dentistry and Pharmaceutical Sciences, Okayama, Japan 3 Department of Clinical Oncology, Kawasaki Medical School, Kurashiki City, Japan 4 Obstetrics and Gynecology, Okayama University Graduate School of Medicine Dentistry and Pharmaceutical Sciences, Okayama, Japan Correspondence to: Takeshi Nagasaka, email: takeshin@med.kawasaki-m.ac.jp Keywords: ovarian metastases; colorectal cancer; ovarian metastatectomy; BRAF; RAS Received: August 15, 2017 Accepted: February 21, 2018 Published: March 27, 2018 ABSTRACT We clarified the clinical prevalence of ovarian metastases from colorectal cancers (CRCs) in 296 female patients with CRC and evaluated clinical outcomes with relation to their mutational profiles, such as BRAF/KRAS mutation and microsatellite instability (MSI) status. The female CRCs were categorised into three subsets: CRCs with ovarian metastases [6.4% ( n = 19), 5-year overall survival (OS) = 24.7%], CRCs with extra-ovarian metastases only [32.4% ( n = 96), 5-year OS = 34.5%] and CRCs without any recurrence or metastasis [61.2% ( n = 181), 5-year OS = 91.3%]. All patients with ovarian metastases underwent oophorectomy; of these, 9 who received preoperative chemotherapy had measurable metastases to extra-ovarian sites and the ovaries. Although 5 of 9 (56%) achieved partial response or complete response at extra-ovarian sites, no patient archived objective response at ovarian sites. Regarding the mutation profiles, in CRCs with extra-ovarian metastases only, the median survival time (MST) after initial treatments to progression to stage IV or recurrence was 13 [95% confidence interval (CI): 7–16 months] in BRAF-mutant and 34 months (95% CI: 22–58 months) in BRAF wild-type ( P = 0.0033). Although ovarian metastases demonstrated poor response to systemic chemotherapy in CRCs with ovarian metastases, the MST after initial treatments to progression to stage IV or recurrence was 22 (95% CI: 21–25 months) in BRAF-mutant and 38 months (95% CI: 24–42 months) in BRAF wild-type ( P = 0.0398). The outcomes of patients with ovarian metastases could be improved by oophorectomy regardless of their mutation profiles.

Collision tumors, which are characterized by the coexistence of two or more completely distinct and independent tumors in the uterine corpus, are very rare. A collision tumor is mainly composed of two distinct tumor types, epithelial and mesenchymal. To the best of our knowledge, there has only been a single case in which a choriocarcinoma with an endometrial carcinoma were coexistent but histologically distinct. We herein report the first case of a collision tumor in a 52-year-old woman, with a history of two pregnancies and two deliveries. The collision tumor was composed of three histologically distinct neoplasms in the uterine corpus, namely an endometrioid carcinoma, an undifferentiated carcinoma and a choriocarcinoma. The patient underwent hysterectomy, bilateral adnexectomy and pelvic lymph node dissection, followed by six cycles of adjuvant chemotherapy with paclitaxel/carboplatin due to the high risk of endometrial cancer, and an additional five cycles of chemotherapy with methotrexate, as the β-human chorionic gonadotropin level was beyond the normal range. Following adjuvant chemotherapy, the tumor markers were within normal limits and no relapses of the cancer have been observed during 1 year of follow-up. Diagnosing a collision tumor prior to surgery is difficult if the neoplasms are in close proximity, or if one of the tumors predominates. Careful pathological examination is crucial for accurately diagnosing the neoplasms in a collision tumor and ensuring appropriate management and a favorable prognosis.

ObjectiveThis study aimed to investigate the correlation of sarcopenia findings with prognostic factors in patients with cervical cancer (CC) undergoing concurrent chemoradiotherapy (CCRT).MethodsWe retrospectively collected data on body composition and clinicopathological features from the medical records of 60 patients with CC who underwent CCRT and analyzed correlations between prognosis and changes in body composition as measured by computed tomography (skeletal muscle and iliopsoas muscle [IM]). Statistical analyses were performed using the Mann-Whitney U test. Progression-free survival (PFS) and overall survival (OS) were analyzed using the Kaplan-Meier method. Cox proportional hazard regression was used for univariate and multivariate analyses.ResultsThe median follow-up for all patients who were alive at the last follow-up was 33.5 months (range, 1–104 months). The PFS and OS rates were worse for patients with at least 15.0% than for those with less than 15.0% loss of skeletal muscle and IM from baseline (P < 0.001 for both). Furthermore, multivariate analyses showed that at least 15.0% loss of IM was an independent prognostic factor for PFS and OS (P = 0.002 for both).ConclusionsSarcopenia (≥15.0% loss of IM from baseline) was revealed to be an important prognostic factor in patients with CC undergoing CCRT.

ObjectiveThe objective of this observational study was to investigate correlations between adverse effects (lower-extremity lymphedema [LEL], dysuria, and severe gastrointestinal symptoms) and quality of life (QOL) (physical well-being [PWB], social well-being, emotional well-being [EWB], and functional well-being) before treatment, at least 6 weeks after treatment (posttreatment1), and 3 or 6 months after treatment (posttreatment2) of patients with gynecologic cancer (GC).MethodsFrom August 2012 to October 2016, questionnaire responses and clinical data of 75 patients with GC were collected and assessed by treatment received. The χ2 test was used to determine the significance of correlations.ResultsParticipants with LEL had significantly poorer QOL than did those without it in the domains of PWB at posttreatment1 (P = 0.026) and EWB at posttreatment2 (P = 0.020). Moreover, patients with 2 adverse effects (LEL plus dysuria or severe gastrointestinal symptoms) had significantly poorer QOL than did those with no or single adverse effect in the domains of PWB at posttreatment1 and posttreatment2 (posttreatment1: P = 0.049, P = 0.001; posttreatment2: P = 0.002, P = 0.028) and poorer QOL compared with those with no adverse effect in the domain of EWB at posttreatment1 (P = 0.017).ConclusionsPoorer QOL in emotional and physical domains is associated with adverse effects of treatment in patients with GC. It is important to consider the effects of radical therapy not only on survival but also on the QOL of survivors.

Background Gynecologic cancer is one of the most common malignant diseases in working-age women. This study investigated whether several characteristics influence return to work after treatment of gynecologic cancer. Methods We investigated the correlations between return to work and several other characteristics in 199 gynecologic cancer survivors. Questionnaires were distributed to patients with cancer (≥1 year after treatment and age of

This study investigated whether pretreatment neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR) and prognostic nutritional index (PNI) are prognostic factors in patients with cervical cancer who undergo concurrent chemoradiotherapy (CCRT) and radiotherapy (RT). A total of 131 patients who underwent CCRT and RT for cervical cancer were retrospectively investigated and the correlations of NLR, PLR and PNI with clinical parameters and prognosis were assessed in CCRT and RT. The CCRT and RT groups had a median progression-free survival (PFS) of 41.82 and 24.72 months, respectively, and an overall survival of 49.70 and 29.56 months, respectively. At a cut-off value of NLR≥2.85, the PFS and OS in patients with higher NLR undergoing RT were significantly shorter compared with those in patients with lower NLR (P=0.029 and P=0.017, respectively). At a cut-off value for PNI of ≤48.55 in patients undergoing CCRT and ≤45.80 in patients undergoing RT, the PFS and OS in patients with lower PNI were significantly shorter compared with those in patients with higher PNI (PFS and OS with CCRT, P

Inflammatory markers are important prognostic factors in various cancers. This study investigated whether inflammatory markers of the Glasgow prognostic score (GPS) predicted progression‐free survival (PFS) and overall survival (OS) for patients with all cases of epithelial ovarian cancer (OC). Pretreatment GPS was examined for the correlations with PFS and OS in 216 patients in all stages of epithelial OC. Statistical analyses were performed using the Mann–Whitney U‐test. PFS and OS were analyzed using the Kaplan–Meier method. Cox's proportional hazard regression was used for univariate and multivariate analyses. For all patients, the median PFS was 35.1 months, and median OS was 46.7 months; follow‐up range was 1–162 months. Kaplan–Meier analysis revealed that patients with high GPS (GPS 2) at pretreatment had a shorter PFS and OS than did patients with lower GPS (GPS 0 + 1) in for early, advanced, and all‐stages of OC (PFS: P

ObjectiveThe Glasgow prognostic score (GPS) determined at pretreatment is important in the prediction of prognosis in various cancers. We investigated if the GPS used both at pretreatment and during concurrent chemoradiotherapy (CCRT) could predict the prognosis of patients with cervical cancer.MethodsWe collected GPS and clinicopathological data from the medical records of 91 patients who underwent CCRT for cervical cancer; their GPSs at pretreatment and during CCRT were retrospectively analyzed for correlations with recurrence and survival. Statistical analyses were performed using the Mann-WhitneyUtest. Disease-free survival (DFS) and overall survival (OS) were analyzed using the Kaplan-Meier method. Cox’s proportional hazard regression was used for univariate and multivariate analyses.ResultsThe median follow-up for all patients who were alive at the time of last follow-up was 38.0 months (range, 1–108 months). The DFS and OS rates of patients with a high GPS during CCRT (GPS 1 + 2; 55 patients; 60.4%) were significantly shorter than those for patients with a low GPS (GPS 0; 36 patients; 39.6%) (DFS,P< 0.001; OS,P< 0.001). Furthermore, multivariate analyses showed that high GPS during CCRT was an independent prognostic factor of survival for OS (P= 0.008).ConclusionsDuring CCRT, a high GPS was revealed to be an important predictor of survival for cervical cancer.

The aim of the present study was to identify the correlations between inflammation markers such as neutrophil-lymphocyte ratio (NLR), platelet-lymphocyte ratio (PLR) and C-reactive protein (CRP) and the prognosis in patients with recurrent cervical cancer. The associations among NLR, PLR and CRP and clinical characteristics and prognosis were examined in 32 patients receiving chemotherapy with recurrent cervical cancer following concurrent chemoradiation therapy (CCRT). The patient median survival time was 198 days (range, 42-1,022 days). Pretreatment NLR and PLR were significantly correlated with the recurrence of cervical cancer following CCRT (R=-0.538, P=0.002; and R=-0.542, P=0.001, respectively). Pretreatment PLR >322.0 was significantly associated with a poor prognosis for recurrent cervical cancer following CCRT by univariate and multivariate analyses (P=0.015 and P=0.029). These findings indicate that pretreatment PLR is an important predictor of prognosis in patients with recurrent cervical cancer following CCRT.

Background: Classification of colorectal cancer (CRC) according to gene expression profiling remains controversial with regards to their ability to stratify patients for precision therapy. Several studies have suggested that ‘stem cell like’ or ‘epithelial-mesenchymal transition (EMT)’ signature associates with poor prognosis. Meanwhile CRCs with BRAF V600E mutation have shown poor outcomes in several clinical trials, but the biological roles of BRAF mutation have not been fully elucidated. Materials and Methods: To evaluate biological roles of BRAF mutations in CRC, we performed mRNA microarray analysis in the following three subsets; eight BRAF-mutant CRC tissues without MSI, six BRAF-mutant CRCs with MSI and five BRAF-wild type CRCs with MSI. Pathway analyses were performed by Gene Set Enrichment Analysis (GSEA). Following identification of candidate biomarkers that influence poor outcomes and associate with BRAF V600E mutation, we examined these candidate biomarkers in a cohort of 1068 CRC patients who underwent surgical resection of their primary tumor and/or metastatic lesions from 1994 to 2015 at the Okayama University Hospital. Results: By the GSEA, prominent signatures enriched in CRCs with BRAF V600E mutation vs. wild-type were EMT-related processes (EMT and myogenesis). Additionally, CRC with BRAF V600E mutation strongly associated with inactivation of Wnt signaling and intestinal differentiation-related genes. Among the differentially expressed genes between CRCs with BRAF V600E mutation versus wild-type, Wnt-antagonist, Secreted frizzled-related proteins (SFRPs) were significantly upregulated in CRCs with BRAF V600E mutation. As SFRPs are well known to be inactivated in CRCs by promoter hypermethylation, and up to 80% of CRCs are methylated in the promoter region of the SFRP2 gene, we focused and analyzed SFRP2 promoter methylation status in 782 stage II-IV CRCs of our cohort by a modified highly sensitive assay for bisulfite DNA followed by fluorescence-based PCR, as we previously reported (JNCI 2009). SFRP2 methylation was observed in 498 (64.2%) stage II-IV CRCs. Interestingly, SFRP2 unmethylated CRCs with genetic mutation in the KRAS/BRAF genes demonstrated significantly poorer outcome in RFS compared with SFRP2 methylated CRCs with genetic mutations in the KRAS/BRAF genes (5-years RFS rate were 46.8% vs 72.1%; P = 0.015, Hazard ratio 2.06 [95% CI, 1.12 to 3.69]; P = 0.021). Conclusion: Our results suggest that SFRP2 methylation status could be a potential prognostic biomarker for stage II-IV CRCs, especially with genetic mutations in the KRAS/BRAF genes. Citation Format: Kazuya Yasui, Takeshi Nagasaka, Toshiaki Toshima, Takashi Kawai, Kunitoshi Shigeyasu, Yoshiko Mori, Junko Haraga, Keiichiro Nakamura, Yuzo Umeda, Hiroshi Tazawa, Ajay Goel, Toshiyoshi Fujiwara. Gene expression profiles in BRAF V600E mutant colorectal cancer and association with SFRP2 methylation status [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5711. doi:10.1158/1538-7445.AM2017-5711

Background: Endometrial cancer accounts for the second percentage of Lynch syndrome related tumors following colorectal cancer. Inactivation of MSH2 was frequently observed in endometrial cancer with microsatellite instability (MSI) or mismatch repair complex deficiency (dMMR). With respect to MSH2 deficiency (dMSH2), not like MLH1 deficiency, most of dMSH2 were caused by germline mutations in the MSH2 gene or germline EpCAM deletions. Meanwhile, heritable germline epimutations in MSH2 have been reported in a few Lynch syndrome families that lacked germline mutations in the MSH2 gene. We previously provided evidence for frequent MSH2 hypermethylation in Lynch syndrome colorectal tumors with dMSH2 and MSH2 methylation may serve as the “second hit” at the wild-type allele. Materials and Methods: In this study, we analyzed MSH2 promoter methylation status, as well as MLH1 methylation status, and expression status of the mismatch repair proteins (MLH1, MSH2, PMS2, and MSH6) by immunohistochemistry in a cohort of 138 endometrial cancer tissues surgically resected at Okayama University Hospital. DNA was extracted from formalin-fixed, paraffin-embedded tissue, analyzed MSI status by four mononucleotide markers and both MLH1 and MSH2 promoter methylation status by a fluorescent quantitative bisulfite PCR assay. Results: Endometrial cancers displaying MSI or dMMR were observed in 40 (29.0%) or 41 cases (29.7%), respectively. Endometrial cancers with MSH2 deficiency were observed in eight (5.8%) of 138 tumors (19.5% of dMMR). MSH2 promoter methylation was present in 7 cases (5.1% in 138 tumors), and significantly correlated with dMSH2 (P=0.0041, Fisher's exact probability test). Then, we also examined the family history of first-degree relatives retrospectively. In this cohort, although patients with MMR deficiency were significantly associated with family history of Lynch syndrome related tumor (P Conclusions: In this study, we demonstrated that MSH2 methylation significantly correlated with dMSH2 and may have strong relation with family history of Lynch syndrome related tumor, taking a role as “second hit” to the MSH2 gene. Citation Format: Junko Haraga, Takeshi Nagasaka, Keiichirou Nakamura, Tomoko Haruma, Takeshi Nishida, Akihiro Nyuya, Kazuya Yasui, Hisashi Masuyama, Toshiyoshi Fujiwara, Yuji Hiramatsu. Clinicopathological significance of endometrial cancer with MSH2 deficiency [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4277. doi:10.1158/1538-7445.AM2017-4277

Placental mesenchymal dysplasia (PMD) rarely complicates with pregnancy. A 30-year-old woman, gravida 3, para 3, presenting with placentomegaly, was referred to our department at 18 weeks of gestation. An ultrasonography revealed a normal fetus with a large multicystic placenta, measuring 125 × 42 × 80 mm. The border between the lesion and normal region was not clear. Color doppler revealed little blood flow in the lesion. Magnetic resonance imaging revealed normal fetus and a large multicystic placenta. Serum human chorionic gonadotropin level was 20124.97 U/L, which was normal at 20 weeks of gestation. Thus, placental mesenchymal dysplasia rather than hydatidiform mole with coexistent fetus was suspected. Then, routine checkup was continued. Because she had the history of Cesarean section, an elective Cesarean section was performed at 37 weeks of gestation, and 2520 g female infant with apgar score 8/9 was delivered. The baby was normal with no evidence of Beckwith-Wiedemann syndrome. Placenta of 20 × 16 × 2 cm, weighing 720 g, was bulky with grape like vesicles involving whole placenta. Microscopic examination revealed dilated villi and vessels with thick wall which was lacking trophoblast proliferation. Large hydropic stem villi with myxomatous struma and cistern formation were seen. PMD was histopathologically confirmed.