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Ovarian serous cystadenofibroma is a relatively rare subtype of serous cystadenoma classified as ovarian benign epithelial tumor. We report a rare case of ovarian serous cystadenofibroma with scattered lesions in pelvic cavity, like malignant disseminations. The patient was 22 years old, gravida 0, para 0. In the laparoscopic surgery, numerous hard yellowish-white solid masses of various sizes were present in the bilateral ovaries. Grossly similar masses were scattered in the fimbria of the fallopian tubes, peritoneum, and great omentum. Because the intraoperative rapid histological diagnosis was benign tumor, surgery was completed for only tumor excision. Postoperative histopathological diagnosis is serous cystadenofibroma. Similar pathological findings were noted in the scattered lesions in the peritoneum and great omentum. No malignant or borderline malignant finding was observed. Because of a benign disease, careful treatment taking fertility preservation into consideration is necessary, especially for young patients.

Secondary debulking surgery(SDF)for gynecologic malignancies may improve prognosis. However, recurrent lesions may be invasions of the intestinal tract and observed peritoneal dissemination. SDF can be safely carried out by performing cooperative surgery with a gastroenterological surgeon and gynecologists. Precise cooperation is indispensable for the operation, especially when it comes to aspects such as the contact method and perioperative management at that time. In our hospital, if the gynecologist suspects other organs invasion during a preoperative examination, they contact the gastroenterological surgeon in an elective manner. If other organs invasion is not clear during a preoperative examination or bowel injury occurs during surgery, the gastroenterological surgeon would be contacted urgently. To ensure smooth cooperation, it is necessary to run regular joint conferences. By sharing in planned and combining the expertise of all the department of interest, it is possible to perform highly curative and safe surgery.

Background: It remains unclear whether the end-of-life (EOL) treatment/environment impacts on survival after anticancer treatment in terminally ill women with ovarian carcinoma (OC). Objective: The...

Background. Lower-limb lymphedema (LLL) is a chronic and progressive complication of gynecologic cancer treatment, including pelvic lymphadenectomy. This study aims to investigate the therapeutic effect of goreisan, a traditional Japanese medicine, which has been used for hydrostatic modulation on patients with LLL. Methods. Patients diagnosed with LLL in our hospital in 2018 were included and principally treated with complex decongestive therapy (CDT), including elastic clothing and lymph drainage. The patients who received a combination therapy of CDT and goreisan (CDT-G group) were prescribed goreisan extract granules, with a dose of 7.5 g per os daily in three doses. Patients who were not prescribed goreisan received CDT alone (CDT group). The severity of lymphedema was evaluated by the estimated limb volume calculated by limb circumferences and the ratio of extracellular water (ECW) to total body water (TBW). Results. Nineteen women with LLL after pelvic lymphadenectomy were included in the study. The number of patients in the CDT and CDT-G groups was 8 and 11, respectively. There were no statistically significant differences between the CDT and CDT-G groups in terms of patient characteristics and severity of LLL before treatment. Reduction in ECW/TBW in the CDT-G group (in the whole body and the affected lower limb) after the intervention was significantly more remarkable than that in the CDT group. Conclusions. Goreisan-based Japanese herbal therapy may be effective in patients with LLL after retroperitoneal lymphadenectomy.

Background Ubiquitin-associated protein 2-like (UBAP2L) has been demonstrated to be associated with the progression of multiple types of cancer. However, the function of UBAP2L in uterine cervical cancer remains unclear. Materials and methods Between 2005 and 2015, 84 patients who underwent surgery were included in this study. The patients were stratified into two groups on the basis of immunohistochemical staining for UBAP2L, and survival analysis was performed. Moreover, loss-of-function analysis was performed using the cervical cancer cell lines CaSki and SiHa. Results Based on immunohistochemistry, the overall survival in patients with low UBAP2L expression was significantly longer than that of those with high UBAP2L expression (p=0.045). The in vitro experiment revealed that knockdown of UBAP2L remarkably inhibited cell proliferation in both live cell imaging and the MTS assay. Conclusion Patients with high UBAP2L expression had unfavorable prognosis and UBAP2L appears to play an important role in proliferation.

Plasma-activated medium (PAM) is a novel chemotherapy that induces reactive oxygen species (ROS) and cell death in a wide range of cancer cell types, suggesting that PAM may be a promising therapeutic option for cancer treatment. However, dose response experiments suggest that PAM sensitivity is cell line specific. We examined the sensitivities of three glioblastoma cell lines to PAM, and found a wide variation in cell killing that was linked to differences in PAM induced ROS and apoptosis. These results indicate that the PAM sensitivity of glioblastoma cells, and potentially cancer cells more generally, is heterogeneous and likely to be dependent on the regulation of apoptosis and antioxidant pathways in target cells.

Background Photodynamic therapy (PDT) is known as a minimally invasive treatment for cancer. 5-Aminolevulinic acid (ALA) is a precursor of the photosensitizing agent protoporphyrin IX (PpIX). Patients with ovarian clear-cell carcinoma (CCC) have poorer prognoses than those of patients with other histological CCC types. We evaluated the efficacy of ALA-PDT on CCC cells in vitro. Methods We used seven human CCC cell lines to measure the cytotoxicity of ALA-PDT. PpIX production in cancer cells was measured using a micro-plate reader. Quantitative real-time PCR was performed to assess the mRNA levels of genes involved in the accumulation of PpIX in cancer cells. Additionally, we measured the enhancement in cytotoxicity with the use of an ABCG2 inhibitor. Results We found that three cell lines were highly sensitive to ALA-PDT. In contrast, one cell line was resistant to ALA-PDT. The cytotoxicity of ALA-PDT varied among CCC cell lines. The IC50 values of ALA-PDT for the CCC cell lines had a wide range (30–882 μM). The cytotoxicity of ALA-PDT was correlated with the intracellular PpIX accumulation. The cell lines sensitive to ALA-PDT expressed PEPT1 (an ALA uptake transporter). The cell line resistant to ALA-PDT expressed ABCG2 (a PpIX export transporter). In the resistant cell line, a combination treatment with both ALA and an ABCG2 inhibitor resulted in the promotion of cytotoxic sensitivity. Conclusion The present study revealed the efficacy of ALA-PDT against CCC with chemoresistance in vitro.

The objective of this study was to estimate the frequency of possible occult metastasis through long-term survival analyses in patients with clear cell carcinoma (CCC) who had undergone complete resection. During the period of 1990-2015, 799 patients with stage I-IV CCC were identified in the TOTSG database. Of these, a total of 528 patients without a residual tumor were enrolled in the study and classified into four groups: Group 1: FIGO stage IA-IB (N=104), Group 2: FIGO stage IC1 (N=170), Group 3: FIGO stage IC2/IC3 (N=98), and Group 4: FIGO stage II-III (no residual tumor: N=156). Cumulative incidences of recurrence (CIR) and death (CID) were examined. The median age was 54, ranging from 29-87. The 5-year CIR / CID of each group were as follows: Group 1 (7.3% / 3.8%), Group 2 (14.3% / 10.2%), Group 3 (37.7% / 18.4%), and Group 4 (46.5% / 33.8%), respectively {P

Aim Medroxyprogesterone acetate (MPA) is used to preserve fertility in patients with Grade 1 endometrial cancer without myometrial invasion (G1EA) and those with atypical endometrial hyperplasia (AEH). However, the efficacy of retreatment with MPA has not been sufficiently established for patients who experience recurrence but wish to retain their fertility. This study aimed to show the effectiveness of MPA treatment and retreatment for AEH and G1EA. Methods A total of 39 patients received MPA treatment between 2005 and 2015, including nine with G1EA and 30 with AEH. The patients received high-dose (600 mg/day) MPA for 26 weeks. If a complete response was not achieved, MPA treatment was continued. After complete remission, if there was a recurrence, the patient was offered a choice of a hysterectomy or retreatment with MPA. The gynecologic and obstetric outcomes were retrospectively analyzed. Results The median age was 34 years, and the median body mass index was 23.3 kg/m2. The median follow-up period was 52 months. Complete response rates for the initial treatment were 89% for G1EA and 93% for AEH. Recurrence occurred in 88% of patients with G1EA (7/8) and 50% of those with AEH (14/28). Seven patients with G1EA and 11 with AEH received MPA retreatment, and 100% and 92% of these achieved a complete response. During the study period, a total of 14 pregnancies were recorded with 10 live births. Conclusion MPA can be effective for G1EA and AEH treatment even when they recur.

// Jun Sakata 1 , Fumi Utsumi 1 , Shiro Suzuki 1 , Kaoru Niimi 1 , Eiko Yamamoto 2 , Kiyosumi Shibata 3 , Takeshi Senga 4 , Fumitaka Kikkawa 1 and Hiroaki Kajiyama 1 1 Department of Obstetrics and Gynecology, Graduate School of Medicine, Nagoya University, Nagoya, Japan 2 Department of Healthcare Administration, Graduate School of Medicine, Nagoya University, Nagoya, Japan 3 Department of Obstetrics and Gynecology, Banbuntane Hotokukai, Fujita Health University, Fujita, Japan 4 Division of Tumor Biology, Graduate School of Medicine, Nagoya University, Nagoya, Japan Correspondence to: Hiroaki Kajiyama, email: kajiyama@med.nagoya-u.ac.jp Keywords: epithelial ovarian carcinoma, epithelial-mesenchymal transition, ZEB1, chemoresistance, metastasis Received: June 07, 2017 Accepted: July 25, 2017 Published: August 10, 2017 ABSTRACT ZEB1, a member of the zinc-finger E-box binding homeobox family, is considered to play a crucial role in cancer progression and metastasis. In the current study, we investigated the role of ZEB1 in metastasis and chronic chemoresistance of epithelial ovarian carcinoma (EOC) cells. Using several EOC and acquired paclitaxel (PTX)-resistant EOC cell lines, we investigated whether silencing ZEB1 led to a reversal of the chemoresistance and metastatic potential in vitro and in vivo . Subsequently, the expression of ZEB1 in EOC tissues and its association with the oncologic outcome were investigated. According to the immunohistochemical staining of EOC tissues, as the positivity of ZEB1 expression was increased, the overall survival of EOC patients became poorer ( P = 0.0022 for trend). Additionally, cell migration and invasion were significantly decreased by ZEB1 silencing in both PTX-sensitive and PTX- resistant cells. Although PTX-sensitivity was not changed by silencing ZEB1 in parental EOC cells, the depletion of ZEB1 made the PTX-resistant EOC cells more sensitive to PTX treatment. In an animal model, mice injected with ZEB1-silencing PTX-resistant cells survived for longer than the control cell-injected mice. Although the intravenous injection of PTX did not affect the tumor weight of shCtrl cells, the tumor weight of shZEB1 cells was significantly reduced by PTX treatment. The current data indicate the possible involvement of ZEB1 in the metastasis and paclitaxel resistance of EOC, and suggest that targeting this molecule may reverse the malignant potential and improve the oncologic outcome for EOC patients.

Aim Women with ovarian cancer (OC) often experience relapse and receive further repetitive chemotherapy. The objective of this study was to overview the remaining survival time after the final chemotherapy and to examine influential clinicopathologic indicators in those patients. Methods The medical charts of deceased OC patients who had died of the disease between 2003 and 2012 were retrospectively reviewed. We investigated post-cancer-treatment survival (PCS) defined as the interval between the date of the final chemotherapy and death. Results In all, 77 patients were enrolled. Three patients (3.9%) had received chemotherapy in the last 2 weeks. Eight (10.4%), 28 (36.4%), and 44 (57.2%) patients had received chemotherapy in the last 30, 60, and 90 days, respectively. There were no differences in either survival after recurrence or overall survival between the shorter (

The therapeutic effects of non-thermal plasma are expected in the medical fields, including hemostasis, vascularization, prevention of organ adhesion, and cell proliferation. Cancer is an internal enemy arising from normal tissue in the body. The prognosis of metastatic and recurrent cancers is still poor despite advances in medicine. To apply non-thermal plasma in cancer treatment is now on going. The mechanism of the proliferation-inhibitory effect of plasma is reactive nitrogen oxide species/reactive oxygen species production in cells. There are a number of problems to be overcome, such as existence of intrinsic reactive oxygen species/reactive nitrogen species scavengers and the shallow infiltration of plasma on tumor surface. The current reviews makes referral to the study results of plasma therapy clarified so far, the possibility of its application in the future.

Occasionally, ovarian tumors are found to have originated from non-ovarian organs as metastatic lesions since the ovary is a common site of metastasis from many cancers. The aim of the current study was to estimate the long-term oncologic outcome of patients with metastatic mucinous ovarian carcinoma (MmOC) in comparison with those with primary mucinous ovarian carcinoma (PmOC) at an advanced stage. The data of one hundred and sixty-seven patients with mucinous ovarian cancer, including 91 patients with MmOC from the digestive organs and 76 patients with stage III–IV PmOC, were retrospectively analyzed. The prognostic significances of clinicopathologic factors were evaluated employing both uni- and multivariable analyses. Pathological slides were evaluated based on centralized pathological review. The median age of patients with PmOC and MmOC was 55 (18–81) and 51 years (30–82), respectively. With follow-up of a total of 167 patients, 145 patients (86.8%) developed recurrence. In addition, 122 patients (73.0%) died of the disease. Regardless of the residual tumor status, patients with PmOC did not a show a significantly poorer OS than those with MmOC. Furthermore, in a Cox multivariable hazard model, after adjustment for various clinicopathologic confounders, a gastric cancer (GC)-originated tumor and larger residual tumor were significant predictors of poorer OS [GC (vs. PmOC): HR (95% CI) 2.205 (1.303–3.654), P = 0.0036]. The oncologic outcome of patients with MmOC was extremely poor; however, it was almost the same as that of those with PmOC. We should recognize MmOC derived from gastric carcinoma as a highly aggressive malignancy.

Aim Radical trachelectomy (RT) is a widely used fertility-sparing treatment for patients with early cervical cancer (CCA). RT, however, is an investigational treatment, and its gynecological and obstetric efficacy are being investigated. We retrospectively assessed the efficacy of abdominal RT (ART) as a fertility-sparing surgery. Methods From 2010 to 2014, patients with stage IA2–IB1 CCA (tumor ≤2 cm) who wished to preserve their fertility underwent ART. The major outcomes were mortality, recurrence, pregnancy complications, and obstetric outcome. Results Twenty-eight patients received ART. Adjuvant chemotherapy was performed in seven patients because of lymphovascular space invasion. During the median follow-up of 43 months, no recurrences occurred. Twelve women attempted to conceive, and eight of them became pregnant. A total of five children were born, and one baby was full term. Three cases of second trimester, and one case of third trimester preterm births were recorded. Conclusions Fertility was preserved after ART in a moderate number of patients. The pregnancy and birth rates after ART have been improving, and increasing the full-term birth rate is the next goal. In addition, development of further types of minimally invasive surgery for CCA can be expected.

Background Elderly patients with uterine cervical cancer reportedly have a poorer prognosis than younger patients. Until now, the benefit of concurrent chemoradiotherapy (CCRT) for elderly patients has been considered limited. Methods We retrospectively analyzed 49 women with cervical cancer aged >70 years primarily treated with radiotherapy (RT) or CCRT in our institute between 2003 and 2014. Treatment compliance, toxicity, and survival benefit were analyzed. Results A total of 49 patients were identified in this retrospective analysis. Twenty patients with a median age of 75.4 years (range 70–77) were treated with CCRT and 29 patients with a median age of 77.9 years (range 70–89) underwent RT. In the CCRT group, 14 patients (70%) completed CCRT consisting of radiotherapy and 5 courses of cisplatin plus 5-fluorouracil including patients requiring a dose reduction of chemotherapy. The median overall survival (OS) in the CCRT and RT groups was 66.9 and 60.1 months, respectively (p = 0.156). The most common grade 3/4 acute toxicity was hyponatremia (35.0%), followed by neutropenia (15.0%) and diarrhea (10.0%) in the CCRT group, while this was anemia (17.2%) followed by radiation enteritis (10.3%) in the RT group. Conclusions CCRT was well tolerated in elderly patients with cervical cancer. Careful attention should be paid to the different characteristics of treatment-related toxicities in this group compared with younger patients.

Based on a number of recent reports, plasma exerts anti-proliferative and apoptotic effects on various cancer cells. Besides a direct effect on the cells, the proliferation of normal and tumorous mammalian cells was reported to be downregulated by indirect plasma-exposed medium through the generation of reactive oxidative species. We demonstrated that plasma-activated medium (PAM) also had an anti-tumor effect on even acquired chemoresistant OC cells. Furthermore, the aqueous plasma displayed an anti-tumor effect against clear-cell carcinoma, which is natively chemo-refractory OC, and we confirmed that the efficacy is selective for tumor cells rather than normal mesothelial cells. The adhesion potency to type-I-collagen-coated dishes was significantly lower in both chemosensitive and chemoresistant cells pretreated with PAM than that of non-stimulated cells (P

Non-thermal atmospheric pressure plasma has been widely studied in recent years in many fields, including cancer treatment. However, its efficiency for inducing apoptosis sometimes varies depending on the cell species and experimental conditions. The aim of this study was to elucidate what causes these differences in responses to plasma treatment. Using four ovarian cancer cell lines, the cell density had a markedly negative impact on the proliferation inhibition rate (PIR) and it was more obvious in OVCAR-3 and NOS2 cells. Furthermore, TOV21G and ES-2 cells were drastically sensitive to plasma‑activated medium (PAM) compared with the other two cell lines. We demonstrated that the proportion of reactive oxygen species and cell number had a marked impact on the effect of PAM against ovarian cancer cells. Additionally it was suggested that the morphological features of cells were also closely related to the sensitivity of cancer cells to the plasma treatment.

There is an intensive need for the development of novel drugs for the treatment of epithelial ovarian cancer (EOC), the most lethal gynecologic malignancy due to the high recurrence rate. TP53 mutation is a common event in EOC, particularly in high-grade serous ovarian cancer, where it occurs in more than 90% of cases. Recently, PRIMA-1 and PRIMA‑1MET (p53 reactivation and induction of massive apoptosis and its methylated form) were shown to have an antitumor effect on several types of cancer. Despite that PRIMA-1MET is the first compound evaluated in clinical trials, the antitumor effects of PRIMA-1MET on EOC remain unclear. In this study, we investigated the therapeutic potential of PRIMA-1MET for the treatment of EOC cells. PRIMA-1MET treatment of EOC cell lines (n=13) resulted in rapid apoptosis at various concentrations (24 h IC50 2.6-20.1 µM). The apoptotic response was independent of the p53 status and chemo-sensitivity. PRIMA‑1MET treatment increased intracellular reactive oxygen species (ROS), and PRIMA-1MET-induced apoptosis was rescued by an ROS scavenger. Furthermore, RNA expression analysis revealed that the mechanism of action of PRIMA‑1MET may be due to inhibition of antioxidant enzymes, such as Prx3 and GPx-1. In conclusion, our results suggest that PRIMA-1MET represents a novel therapeutic strategy for the treatment of ovarian cancer irrespective of p53 status and chemo-sensitivity.

Malignant transformations of mature cystic teratomas (MCT) are extremely rare and most of them are squamous cell carcinomas (SCC). Therefore no effective postoperative treatment has been established. In this article, we report two cases in which radiotherapy was effective for SCC arising from MCT. Case 1 was a 64-year-old woman with stage IIA of this tumor. After primary surgery, chemotherapy and interval debulking surgery were performed. She received radiotherapy for relapsed tumors, and has been well for 36 months since the initial diagnosis. Case 2 was a 37-year-old woman with stage IIB of this tumor. After primary debulking surgery, she received chemoradiotherapy for a residual tumor and has been well for 27 months since the surgery. Although there is no established therapy, radiotherapy or concurrent chemoradiotherapy might have beneficial effects on this tumor, similarly to those on SCC from other tissue.

Cancer treatment using non-thermal atmospheric pressure plasma is a brand new and challenging approach for cancer therapy. Conventional cancer therapies are surgery, radio-therapy, and chemo-therapy. We propose plasma-therapy as the fourth cancer therapy. Plasma cancer therapy involves direct plasma treatment of cancers including melanomas, head and neck cancer, pancreatic cancer and liver metastasis, and indirect plasma treatment of cancers by using plasma irradiated solutions such as plasma-activated medium (PAM). We have been recently studying plasma cancer therapy using target cancers such as ovarian cancers, brain tumors, gastric cancers and skin cancers. We have developed a plasma source with ultrahigh electron density, which we have applied to these cancer cells. In addition, we found that plasma-irradiated medium itself can kill these cancer cells. This medium was termed plasma-activated medium (PAM). In vitro and in vivo studies have suggested that PAM is an important tool for cancer therapy especially for disseminated cancers that are currently untreatable. Although many dramatic therapeutic effects of plasma therapy on cancer cells have been reported, the molecular mechanisms of the anti-tumor effects of plasma remain to be elucidated. The greatest challenge for plasma medical science is to understand the complex system that mediates plasma inputs resulting in physiological outputs such as cell death of cancer cells and proliferation of normal cells. Intracellular molecular mechanisms of PAM are also being intensively studied in order to understand the mode of action of PAM. In this review, we summarize the latest understanding of plasma cancer treatments.

In cervical cancer, para-aortic lymph nodes are common sites of metastasis. The purpose of the study was to evaluate the clinical benefits of prophylactic irradiation as postoperative therapy. A retrospective cohort study was conducted during 2001–2015 at a single institution. Patients with a high risk of para-aortic lymph nodes recurrence were eligible for this study, and we identified patients who had pelvic lymph node metastasis and underwent radical surgery and concurrent chemo-radiotherapy. As a result, 33 and 46 patients were included in the treatment (prophylactic irradiation) and non-treatment groups, respectively. Baseline differences between the two groups were adjusted with the inverse probability of treatment weighting using propensity scores composed of the independent variables including age, stage, tumor size, pathological findings, lymph node status, and pathological subtypes. In the 68-month median follow-up period (range 6–178 months), 25 patients experienced recurrence, and 17 patients were dead. After adjustment with the inverse probability of treatment weighting, the recurrence rates tended to decrease in the treatment group, but there was no significant difference between the two groups [treatment vs. non-treatment, 29.4% and 44.3%, respectively; hazard ratio, 0.593 (95% CI 0.320–1.099); P = 0.097]. However, adjusted para-aortic lymph nodes recurrence rates were not significantly different [treatment vs. non-treatment, 7.8% and 11.4%, respectively; odds ratio, 0.660 (95% CI 0.187–2.322); P = 0.558]. Moreover, Kaplan–Meier curves showing post-recurrence survival revealed no significant difference between the two groups (P = 0.141). Prophylactic para-aortic lymph nodes irradiation did not reduce the risk of recurrence.

Malignant ovarian germ cell tumors usually occur in young women. Until the 1970s, before establishment of systemic chemotherapy, malignant ovarian germ cell tumors had a very poor prognosis. Recently, prognosis has improved, and fertility-sparing treatment is being adopted in patients who desire to become pregnant. However, the number of malignant ovarian germ cell tumor survivors who actually became pregnant remains unknown.The present study aimed to clarify the reproductive outcomes in malignant ovarian germ cell tumor survivors by using data from a multicenter database and an additional survey on reproductive outcomes.The study used the Tokai Ovarian Tumor Study Group database on ovarian cancer patients. We assessed the database from 1986 through 2016 and selected malignant ovarian germ cell tumor patients40 years of age who received fertility-sparing treatment. Questionnaires on reproductive outcomes were sent to the registered facilities. The following data were collected and used in this study: age, date of onset, surgical procedure, chemotherapy regimen, tumor type, International Federation of Gynecology and Obstetrics stage, survival outcome and period, number of pregnancies and childbirths, marital status, childbearing desire, method of pregnancy, gestational weeks at delivery, birthweight of the baby, obstetric complications, and menstrual status after fertility-sparing treatment.A total of 110 malignant ovarian germ cell tumor patients who received fertility-sparing treatment were identified. The median follow-up period was 10.4 years. Five patients were excluded because of death or loss of fertility after treatment for recurrence. Thus, 105 patients were finally included. The additional survey revealed that 42 of 45 patients who desired childbirth became pregnant. The total number of pregnancies was 65, and 56 babies were born to 40 malignant ovarian germ cell tumor survivors.The reproductive outcomes of malignant ovarian germ cell tumor survivor are promising with fertility-sparing treatment. Malignant ovarian germ cell tumor survivors can become pregnant and give birth if they desire.

Kinesin family member 20A (KIF20A), which is involved in cytokinesis and intracellular transportation, has been recently reported to be upregulated in several malignancies and may contribute to chemotherapeutic resistance. We examined the distribution and expression of KIF20A in clear-cell carcinoma (CCC) of the ovary to elucidate its clinical significance and molecular mechanism. Paraffin sections from ovarian CCC tissues (N=43) were immunostained with KIF20A antibody, and the staining intensities were semi-quantitatively evaluated. Furthermore, we investigated whether silencing of KIF20A contributes to the proliferation-inhibitory potential using CCC cells. During the observational period, 18 patients (41.9%) developed recurrence. The median time to recurrence was 11.5 months. Patients in the high KIF20A expression group showed poorer progression-free survival (PFS) and overall survival (OS) than those in the low expression group (P=0.0443 and P=0.0478, respectively). In multivariable analyses, KIF20A expression was also a significantly independent indicator of PFS and a marginally significant indicator of OS [PFS: HR (high vs. low), 5.488; 95% CI, 1.410–24.772 (P=0.0136); OS: HR, 2.835; 95% CI, 0.854–11.035, (P=0.0897)]. In in vitro studies, the ovarian CCC cell proliferation was significantly decreased by KIF20A silencing or in the presence of KIF20A inhibitor in CCC cells. Cell cycle G2/M arrest and a higher apoptosis-induced fraction were more frequently observed in si-KIF20A-transfected CCC cells than in the control cells. Although the present study was preliminary, these data indicate the possible involvement of KIF20A in the proliferation of CCC, suggesting that targeting this molecule may contribute to reversing the malignant potential consequently affecting the oncologic outcome of CCC patients.

// Nobuhisa Yoshikawa 1, * , Toshiya Teshigawara 1, * , Yoshiki Ikeda 1 , Kimihiro Nishino 1 , Jun Sakata 1 , Fumi Utsumi 1 , Kaoru Niimi 1 , Ryuichiro Sekiya 2 , Shiro Suzuki 1 , Michiyasu Kawai 3 , Kiyosumi Shibata 2 , Fumitaka Kikkawa 1 and Hiroaki Kajiyama 1 1 Department of Obstetrics and Gynecology, Nagoya University Graduate School of Medicine, Nagoya, Japan 2 Department of Obstetrics and Gynecology, Fujita Health University Banbuntane Hotokukai Hospital, Nagoya, Japan 3 Department of Obstetrics and Gynecology, Toyohashi Municipal Hospital, Toyohashi, Japan * These authors have contributed equally to this work Correspondence to: Nobuhisa Yoshikawa, email: n-yoshikawa@med.nagoya-u.ac.jp Hiroaki Kajiyama, email: kajiyama@med.nagoya-u.ac.jp Keywords: malignant transformation; mature cystic teratoma; fertility-sparing surgery; oncological outcome; reproductive outcome Abbreviations: MT-MCT (malignant transformation arising from mature cystic teratoma of the ovary), FSS (fertility-sparing surgery), OS (overall survival), DFS (disease-free survival), EOC (epithelial ovarian cancer) Received: February 20, 2018 Accepted: May 19, 2018 Published: June 08, 2018 ABSTRACT Background: The purpose of this study was to evaluate the long-term clinical outcome of young women with malignant transformation arising from mature cystic teratoma of the ovary (MT-MCT) by comparing radical surgery and fertility-sparing surgery (FSS). Patients and methods: All patients treated with radical surgery or FSS for MT-MCT in multiple institutions were registered in this analysis. Univariate and multivariate analyses were performed to evaluate clinical outcome, including overall survival (OS) and disease-free survival (DFS). Results: From 1986 to 2016, 62 patients with MT-MCT were treated in our group. The median follow-up period was 38.0 (2.0-227.9) months, and the median age was 54 (17-82) years old. Multivariate analysis revealed that only advanced stage was significantly correlated with poorer prognosis of patients [hazard ratio (HR) for death: 6.58, 95% confidence interval (CI): 1.82–24.78, P = 0.0048; HR for recurrence: 5.59, 95% CI: 1.52–21.83, P = 0.01]. Of a total of 13 women with stage I-II disease at less than 45 years old, 7 were treated with FSS, and there was no recurrence except for in one woman with stage II MT-MCT. There was no significant difference in long-term oncological outcome between radical surgery and FSS. Conclusion: FSS may be indicated for patients with stage I MT-MCT, who hope to preserve fertility, as no relapse was found after FSS.

Uterine sarcomas are some of the most malignant and aggressive tumor types among the gynecologic malignancies, and they are associated with a high rate of recurrence and a poor prognosis. Due to their rarity and diversity, the optimal treatment for recurrent uterine sarcomas has not yet been elucidated. The aim of the present study was to investigate the potential of secondary cytoreductive surgery (SCS) for patients with recurrent uterine sarcomas. A total of 18 patients with recurrent uterine sarcomas were retrospectively identified at the Department of Obstetrics and Gynecology, Nagoya University (Nagoya, Japan) between January 2002 and December 2015. This included 8 patients with leiomyosarcoma, 6 with carcinosarcoma, 3 with endometrial stromal sarcoma and 1 with adenosarcoma. All patients underwent primary debulking surgery as the initial treatment. In summary, 9 patients were treated with SCS when they experienced their first recurrence, and the other 9 patients were treated with non-SCS methods, including chemotherapy or radiotherapy. In the SCS group, 5/9 patients had confined pelvic recurrences, 3 patients had extra-pelvic diseases, including pulmonary metastasis, and one patient had intra- and extra-pelvic recurrence. The 3-year overall survival (OS) rates were 77.8 and 11.1% in the SCS and non-SCS groups, respectively. The patients who underwent SCS experienced a significantly longer OS time compared with those in the non-SCS group (P=0.006). In addition, the disease-free survival after second-line therapy was significantly longer in the SCS group than in the non-SCS group (P=0.0496). These findings suggest that resection of recurrent uterine sarcomas may be beneficial for the improvement of patient survival. Prospective studies with sufficient statistical power are warranted for further evaluation of the effect of SCS.

The aim of the present study was to estimate the post-recurrence survival (PRS) of patients with relapsed uterine cervical cancer (RUCC). In addition, clinicopathological indicators that influenced PRS were investigated. Between 1998 and 2014, of 740 patients with cervical cancer, 165 patients experienced recurrence (recurrence rate, 22.3%), and 83 patients succumbed to the disease within a median follow-up of 34.3 months. A total of 151 stage Ib-IV patients who experienced recurrence after initial treatment for cervical cancer at our institute were analyzed. Uni- and multivariate analyses were performed using the Kaplan Meier method, and Cox regression model. The median age was 55 years (range, 20–88 years). In all, 80 patients succumbed to the disease. The median PRS time of all the patients was 28.4 months. The 1-, 3-, and 5-year PRS rates of patients were 75.1, 41.9, and 32.1%, respectively. In addition, the median survival period in patients who had received surgery as an initial treatment was significantly longer compared with that in patients who had not previously undergone surgery (36.7 vs. 23.3 months, respectively; P=0.0338). Following the univariate analysis, the median PRS in patients with in- and out-field recurrence was 12.6, and 45.9 months, respectively (P

We have been developing novel ultrahigh density atmospheric pressure plasma sources and succeeded in the selective killing ovarian cancer cells against normal ones. Furthermore, we have found out the plasma-activated medium (PAM) also killed glioblastoma brain tumor cells selectively against normal ones and the chemical products in the PAM have long lifetime healing effects. To clarify the mechanism, interactions of plasma with the organism and the medium where the organism belongs were investigated on the viewpoint of intracellular molecular mechanism.

Non-thermal atmospheric pressure plasma has been proposed as a new therapeutic tool for cancer treatment. Recently, plasma-activated medium (PAM) has been widely studied in various cancer types. However, there are only few reports demonstrating the anti-tumour effects of PAM in an animal model reflecting pathological conditions and the accompanying mechanism. Here we investigated the inhibitory effect of PAM on the metastasis of ovarian cancer ES2 cells in vitro and in vivo. We demonstrated that ES2 cell migration, invasion and adhesion were suppressed by PAM at a certain PAM dilution ratio, whereas cell viability remained unaffected. In an in vivo mouse model of intraperitoneal metastasis, PAM inhibited peritoneal dissemination of ES2 cells, resulting in prolonged survival. Moreover, we assessed the molecular mechanism and found that MMP-9 was decreased by PAM. On further investigation, we also found that PAM prevented the activation of the MAPK pathway by inhibiting the phosphorylation of JNK1/2 and p38 MAPK. These findings indicate that PAM inhibits the metastasis of ovarian cancer cells through reduction of MMP-9 secretion, which is critical for cancer cell motility. Our findings suggest that PAM intraperitoneal therapy may be a promising treatment option for ovarian cancer.

Vascular endothelial growth factor (VEGF) inhibitors have been utilized for the treatment against advanced or recurrent cervical carcinoma as a novel therapeutic modality. However, the expression level of VEGF in post-radiotherapy relapsed/persistent cervical cancer remains to be elucidated. The aim of the present study was to investigate the expression of VEGF and associated molecules using tumor samples from patients with post-radiotherapy relapsed/persistent cervical cancer. From a database of 826 patients who were treated at our institution between 2003 and 2015, eight patients with post-radiotherapy relapsed/persistent cervical cancer were identified, and 20 patients who underwent initial surgery alone were used as a control. Using samples from these patients, the expression levels of VEGF-A, VEGF receptor-1 (VEGFR-1) and hypoxia inducible factor-1α (HIF-1α) were immunohistochemically categorized as negative or weakly, moderately, or strongly positive according to the size of the staining area, and intensity. In carcinoma cells, the expression levels of VEGF-A, VEGFR-1 and HIF-1α were significantly higher in post-radiotherapy relapsed/persistent cervical cancer compared with control patients (P=0.0003, 0.0003, and 0.0001, respectively). In stroma cells, similar tendencies with statistical significance were observed (P=0.0014 and P

Several previous studies have revealed that the expression of zinc finger E-box binding homeobox 1 (ZEB1) in solid malignancies has an important significance on the clinical outcome of patients. However, the association between ZEB1 expression and survival in patients with epithelial ovarian carcinoma (EOC) remains unclear. The objective of the present study was to examine the extent of ZEB1 expression in EOC using immunohistochemical staining and investigate its association with patient outcome. A total of 40 patients with EOC initially treated with cytoreductive surgery and systematic chemotherapy were enrolled. ZEB1 expression was immunohistochemically categorized as negative, weak, moderate and strong according to the size of the staining area, and intensity. Subsequently, the associations between ZEB1 expression and recurrence/progression-free survival (RFS) rate were examined. The median age of patients in the current study was 54 years old (range, 22-72 years old). Among these patients, 15 (37.5%) exhibited International Federation of Gynecology and Obstetrics stage I disease, and 10 (25.0%), 13 (32.5%), and 2 (5%) had stage II, III, and IV disease, respectively. No patients with negative expression of ZEB1 experienced recurrence. In addition, ZEB1 expression was identified to be a significant predictor of a poorer RFS rate compared with negative expression (negative vs. weak, moderate and strong, P=0.0126). Furthermore, multivariate analyses revealed that moderate and strong ZEB1 expression levels were significant prognostic indicators of a poorer RFS rate in patients with EOC (hazard ratio, 2.265; 95% confidence interval, 1.072-8.021; P=0.0349). Confining analysis to patients with the clear-cell/mucinous histological type, those with moderate/strong ZEB1 expression demonstrated a significantly poorer RFS rate (P=0.0025). Positive ZEB1 expression may be an indicator to predict unfavorable RFS in patients with EOC.

Non-thermal atmospheric pressure plasma is a novel approach for wound healing, blood coagulation, and cancer therapy. A recent discovery in the field of plasma medicine is that non-thermal atmospheric pressure plasma not only directly but also indirectly affects cells via plasma-treated liquids. This discovery has led to the use of non-thermal atmospheric pressure plasma as a novel chemotherapy. We refer to these plasma-treated liquids as plasma-activated liquids. We chose Ringer’s solutions to produce plasma-activated liquids for clinical applications. In vitro and in vivo experiments demonstrated that plasma-activated Ringer’s lactate solution has anti-tumor effects, but of the four components in Ringer’s lactate solution, only lactate exhibited anti-tumor effects through activation by non-thermal plasma. Nuclear magnetic resonance analyses indicate that plasma irradiation generates acetyl and pyruvic acid-like groups in Ringer’s lactate solution. Overall, these results suggest that plasma-activated Ringer’s lactate solution is promising for chemotherapy.

Non-thermal plasma in the medical field is a novel approach having various beneficial applications, such as sterilization, blood coagulation, tissue regeneration and cancer treatment. Recently, plasma-activated medium (PAM) has been widely studied in various types of cancer such as brain, lung, breast, gastric and ovarian cancer, due to its antitumor effect by inducing apoptosis and DNA damage. [1] We previously demonstrated that PAM showed selective cytotoxicity towards cancer cells, whereas normal cells remained unaffected. Moreover, PAM was shown to exert antitumor effects in acquired/natively chemo-resistant ovarian cancer cells. In vivo study, we also demonstrated the antitumor effects of PAM in a subcutaneous tumor formation xenograft mouse model. [2] In the clinic, peritoneal metastasis is quite an issue for ovarian cancer patients and it is also a big obstacle for treatment. However, this model may not reflect the pathological conditions of ovarian cancer, with numerous micrometastatic disseminations in the peritoneal cavity. In this study, we selected between the two ovarian cancer cell lines ES2 and SKOV3, which could stably show tumor formation in vivo, and decided to use ES2 for the following in vivo experiments because ES2 was more sensitive than SKOV3 to the effects of PAM. We examined whether PAM therapy affects survival in a mouse model of intraperitoneal injection. Six-week-old female BALB/c nude mice were intraperitoneally injected with ES2 cells and then the mice were treated with PAM or non-plasma-irradiated medium as a control once a day for a total of 3 days. As shown in the figure, Survival analysis was performed using the Kaplan–Meier method, indicating that the survival rates were poorer in the control group than in the PAM therapy group (P Download : Download high-res image (81KB) Download : Download full-size image Overall survival

Ovarian cancer is among the most malignant gynecologic cancers since peritoneal dissemination often occurs at the diagnosis of these patients. The 5-year survival rate is less than 50%. Recently, non-equilibrium atmospheric pressure plasma (NEAPP) has been introduced in medical field. We have already demonstrated the cytotoxic effect of the direct plasma exposure to ovarian cancer cells. However, it is difficult to expose cancer cells to plasma gas intraperitoneally. Thus, we established the system of plasma-activated medium (PAM) to treat ovarian cancer indirectly instead of a direct exposure to plasma [1]. In our previous works, it was demonstrated that PAM significantly inhibited proliferation ability of ovarian cancer cells, with fibroblast cells remaining unaffected though. Both in vitro and in vivo study had confirmed the cytotoxic effect of PAM to ovarian cancer. However, it still remains unknown whether PAM can affect metastasis of ovarian cancer cells, which is the fatal problem of ovarian cancer patients [2]. In this study, we tried to investigate PAM’s anti-metastasis effect in vitro and the underneath mechanism. Firstly, we performed wound-healing and transwell assay on ES2, one of ovarian cancer cell lines. We found that the cell migration and invasion abilities were significantly inhibited by PAM. Secondly, we established a co-culture system by seeding ES2 cells onto monolayer of peritoneal mesothelial cells, which models the initial step of ovarian cancer cells metastasis in human peritoneal cavity, and it was found that PAM significantly repressed ES2 cells to implant onto mesothelial cells. Moreover, mechanism study showed both mRNA and protein levels of MMP-9 were inhibited by PAM. And PAM significantly inhibited the phosphorylation of JNK1/2 MAPK and p38 MAPK (figure 1), which indicated that inhibition of MMP-9 was dependent on MAPK pathway [3]. In summary, it is indicated in this work that PAM presents efficient inhibitory effect towards ovarian cancer cells metastasis in vitro. Moreover, PAM’s anti-metastasis effect is implemented by repressing the activation MAPK pathway, resulting in de-activation of downstream target MMP-9, thus leading to suppression of cell migration and invasion. In the near future, it might be a new clinical strategy for metastatic ovarian cancer patients to choose PAM therapy via intaperitoneal treatment. Download : Download high-res image (86KB) Download : Download full-size image Fig. 1

Objectives: The aim of this study was to identify the patterns of recurrence and their significance in patients with endometrial carcinoma (EMCA). Patients and Methods: After a search of the medical records from single institutions, a total of 49 patients with relapsed endometrial carcinoma were retrospectively evaluated. Various clinical information was examined, including the site of recurrence, detection procedure, and presence or absence of any symptom at the time of recurrence. Furthermore, the postrecurrence survival analysis was based on the Kaplan-Meier method. Results: The median follow-up period of all patients was 39.4 months (5.8 - 293.1). In all, twenty-five (51.0%) patients experienced recurrence within 12 months after the final treatment. At the time of recurrence, 15 (30.6%) and 34 (69.4%) patients were symptomatic and asymptomatic, respectively. Among the 34 asymptomatic patients, recurrence was detected by CT scan in 14 (28.6%), tumor markers alone in 14 (28.6%), and pelvic examination/ultrasound scan in 5 (10.2%). There was no relapsed case detected by vaginal vault cytology alone. The 5-year postrecurrence survival rates in symptomatic and asymptomatic patients were 57.5 and 36.6 months, respectively (P = 0.2973). After recurrence, 12 patients underwent debulking surgery, and 37 received salvage chemotherapy or radiotherapy. The postrecurrence survival of patients receiving surgery did not differ from that of those with chemotherapy/radiotherapy (P = 0.9198). Conclusion: Although imaging studies and tumor marker measurement contributed to the early detection of recurrence, they did not necessarily improve the prognosis postrecurrence.

Women with ovarian cancer (OC) often experience relapse and receive further repetitive chemotherapy. The objective of this study was to overview the remaining survival time after the final chemotherapy and to examine influential clinicopathologic indicators in those patients.The medical charts of deceased OC patients who had died of the disease between 2003 and 2012 were retrospectively reviewed. We investigated post-cancer-treatment survival (PCS) defined as the interval between the date of the final chemotherapy and death.In all, 77 patients were enrolled. Three patients (3.9%) had received chemotherapy in the last 2 weeks. Eight (10.4%), 28 (36.4%), and 44 (57.2%) patients had received chemotherapy in the last 30, 60, and 90 days, respectively. There were no differences in either survival after recurrence or overall survival between the shorter (75 days) and longer (≥75 days) PCS groups. On the other hand, patients in the shorter PCS group had significantly fewer chances of referral to a hospice or home-care than those in the latter group (P = 0.035). In multivariable analysis, a poorer performance status, an elevated white blood cell count, and a higher C-reactive protein value were significantly correlated with a shorter PCS (P = 0.004, 0.006 and 0.027, respectively).Half of the patients received chemotherapy within 75 days of death and we did not identify any survival benefit in patients who received chemotherapy near the end of life. We should provide information to patients about their prognosis and discuss the timing of withdrawal from chemotherapy from the early stage of their recurrence.

Radical trachelectomy (RT) is a widely used fertility-sparing treatment for patients with early cervical cancer (CCA). RT, however, is an investigational treatment, and its gynecological and obstetric efficacy are being investigated. We retrospectively assessed the efficacy of abdominal RT (ART) as a fertility-sparing surgery.From 2010 to 2014, patients with stage IA2-IB1 CCA (tumor ≤2 cm) who wished to preserve their fertility underwent ART. The major outcomes were mortality, recurrence, pregnancy complications, and obstetric outcome.Twenty-eight patients received ART. Adjuvant chemotherapy was performed in seven patients because of lymphovascular space invasion. During the median follow-up of 43 months, no recurrences occurred. Twelve women attempted to conceive, and eight of them became pregnant. A total of five children were born, and one baby was full term. Three cases of second trimester, and one case of third trimester preterm births were recorded.Fertility was preserved after ART in a moderate number of patients. The pregnancy and birth rates after ART have been improving, and increasing the full-term birth rate is the next goal. In addition, development of further types of minimally invasive surgery for CCA can be expected.

We previously reported that plasma-activated medium (PAM) selectively kills glioblastoma brain tumor cells by downregulating the signaling molecule, the serine-threonine kinase AKT. AKT kinase plays a key role in survival and proliferation by acting as a hub mol- ecule in the signaling network to inhibit apoptosis. The pathways that contain AKT and that are affected by PAM are unclear. In this study of glioblastoma brain tumor cells, phosphoryla- tion of AKT at both Ser473 and Thr308 was downregulated by PAM, suggesting that upstream signaling by the mammalian target of rapamycin complex 2 (mTORC2) and phosphatidylino- sitol-3 kinase (PI3K)/ 3-phosphoinositide-dependent protein kinase-1 (PDK1) were affected by PAM. Furthermore, the extracellular regulated kinase (ERK) signaling pathway, which is parallel to the AKT signaling pathway, was downregulated by PAM, and the mTORC1 sig- naling pathway, which is a major downstream signaling pathway of AKT and ERK, was also downregulated by PAM. In addition, CD44, a cell membrane-bound receptor that promotes both the AKT pathway and the ERK pathway, was downregulated by PAM. Taken together, these results suggest that PAM completely downregulates the survival and proliferation signal- ing network in glioblastoma brain tumor cells.

Ovarian clear cell carcinoma (CCC) is a histological type of epithelial ovarian cancer that is less responsive to chemotherapy and associated with a poorer prognosis than serous and endometrioid carcinoma. Non-thermal atmospheric pressure plasma which produces reactive species has recently led to an explosion of research in plasma medicine. Plasma treatment can be applied to cancer treatment to induce apoptosis and tumor growth arrest. Furthermore, recent studies have shown that a medium exposed to plasma also has an anti-proliferative effect against cancer in the absence of direct exposure to plasma. In this study, we confirmed whether this indirect plasma has an anti-tumor effect against CCC, and investigated whether this efficacy is selective for cancer cells. Non-thermal atmospheric pressure plasma induced apoptosis in CCC cells, while human peritoneal mesothelial cells remained viable. Non-thermal atmospheric pressure plasma exhibits selective cytotoxicity against CCC cells which are resistant to chemotherapy.

It remains unknown whether the end-of-life (EOL) environment influences survival after anticancer treatment, particularly for gynecologic malignancy.The study's objective was to clarify whether the survival time varied depending on where patients spend the EOL.This retrospective study included patients who received initial oncologic treatment but died due to cancer recurrence and/or progression. The subjects were a cohort of 181 gynecologic malignant tumor cases in a single institution from 2002 to 2008. Measurement was of postcancer treatment survival (PCS), defined as the time interval between the last date of anticancer treatment after recurrence/progression and death from the disease, analyzed on stratification by type of supportive care or where patients spent the EOL.The median survival time was 26.1 (1.0-306.4) months. The distribution of the carcinoma type was as follows: 28.7% of patients with cervical (N=52), 27.6% with endometrial (N=50), and 43.1% with ovarian (N=79) cancer. The median PCS was 13.3 weeks. Patients in the hospice/home care group showed a significantly more favorable PCS than those in the hospital group (log rank: P=0.029). On multivariate analysis, the age (60 versus ≥60) and site of supportive care (hospital versus hospice/home care) retained their significance as independent prognostic factors of poor PCS (age: HR=0.679, 95% CI, 0.496-0.928, P=0.0151; site of supportive care: HR=0.704, 95% CI, 0.511-0.970, P=0.0319).Our current data could be hypothesis generating; it is possible that the EOL environment is a crucial prognostic factor for survival after anticancer treatment.

Epithelial ovarian carcinoma (EOC) is the leading cause of cancer-related death in women in Western countries. Once patients experience recurrence, complete cure is almost impossible. We elucidated the effect of nonequilibrium atmospheric pressure plasma on the growth of EOC, particularly in plasma-activated medium (PAM). Furthermore, we examined the role of reactive oxygen species (ROS) or their scavengers in chronic antineoplastic-resistant EOC cells. As a result, we showed PAM induced the antitumor effect of EOC cells in vitro and in vivo, even in chemoresistant cells. To apply the plasma treatment for advanced or recurrent EOC, we suggest adopting indirect plasma therapy instead of direct plasma considering intraperitoneal administration in the future. However, there are several problems under investigation, including intracellular mechanism of antitumor effect by PAM and adverse event in vivo.

PurposeNonequilibrium atmospheric pressure plasma (NEAPP) therapy has recently been focused on as a novel medical practice. Using cells with acquired paclitaxel/cisplatin resistance, we elucidated effects of indirect NEAPP-activated medium (NEAPP-AM) exposure on cell viability and tumor growth in vitro and in vivo.MethodsUsing chronic paclitaxel/cisplatin-resistant ovarian cancer cells, we applied indirect NEAPP-exposed medium to cells and xenografted tumors in a mouse model. Furthermore, we examined the role of reactive oxygen species (ROS) or their scavengers in the above-mentioned EOC cells.ResultsWe assessed the viability of NOS2 and NOS3 cells exposed to NEAPP-AM, which was prepared beforehand by irradiation with NEAPP for the indicated time. In NOS2 cells, viability decreased by approximately 30% after NEAPP-AM 120-sec treatment (PConclusionWe demonstrated that plasma-activated medium also had an anti-tumor effect on chemo-resistant cells in vitro and in vivo. Indirect plasma therapy is a promising treatment option for EOC and may contribute to a better patient prognosis in the future.

Compared with other epithelial ovarian carcinoma subtypes, ovarian clear cell carcinoma (OCCC) has been recognized to show chemoresistance. Therefore, new treatment modalities are required for patients with OCCC that is refractory to chemotherapy. The carcinoembryonic antigen glypican-3 (GPC3) is expressed by approximately half of OCCC and is a promising immunotherapeutic target. The purpose of this study was to evaluate the effect of GPC3 peptide vaccine against refractory OCCC patients. We conducted a phase II trial with a GPC3-derived peptide vaccine in OCCC patients. Immunological responses were analyzed by ex vivo IFNγ ELISPOT assay. We also evaluated control subjects, who received best supportive care without vaccinations during the same period. Thirty-two patients with refractory OCCC were enrolled between July 2010 and September 2015, and underwent GPC3 peptide vaccination. Fifteen patients were vaccinated less than six times because their general condition progressively deteriorated, and 17 patients were vaccinated at least six times. Three patients showed a partial response as the best overall response. The GPC3 peptide vaccine induced a GPC3-specific CTL response in 15 out of 24 patients who had PBMCs collected three times or more. The prognosis of palliative care patients without GPC3 peptide vaccinations was significantly poorer than that of those with GPC3 peptide vaccinations (post cancer-treatment survival: p = 0.002). Although the disease control rate was not high, our results suggest that GPC3 peptide vaccinations may hold a significant impact to prolong survival of patients with refractory OCCC, allowing them to maintain quality of life with no serious toxicities.

Epithelial ovarian cancer (EOC) is the leading cause of cancer-related death in women in Western countries. Once patients experience recurrence, complete cure is almost impossible. Nonequilibrium atmospheric pressure plasma (NEAPP) therapy has recently been focused on as a novel medical practice. We have elucidated the effect of nonequilibrium atmospheric pressure plasma on the growth of EOC, particularly in plasma-activated medium (PAM). In our recent report, we examined the role of reactive oxygen species (ROS) or their scavengers in chronic antineoplastic-resistant EOC cells. As a result, PAM exerted the antitumor effect of EOC cells in vitro and in vivo, even in chemoresistant cells. There are several problems under investigation, including intracellular mechanism of antitumor effect by PAM and adverse event in vivo. Through recent results about plasma in cancer treatment, PAM therapy is a promising treatment option for EOC and may contribute to a better patient prognosis in the future.