生水 真紀夫

Background: Metformin, widely used in the treatment of type 2 diabetes mellitus, reduces the risk of cancer and relapse after treatment. Fertility-sparing treatment for endometrial cancer (EC) with progestin is associated with a high chance of disease regression, and the high relapse rate continues to be a problem. We assessed the efficacy of metformin in preventing recurrence after medroxyprogesterone acetate (MPA) as fertility-sparing treatment for atypical endometrial hyperplasia (AEH) and EC. Patients and methods: This phase II study enrolled 17 patients with AEH and 19 patients with EC limited to the endometrium (age, 20-40 years). MPA (400 mg/day) and metformin (750-2250 mg/day) were administered for 24-36 weeks to achieve a complete response (CR). Metformin was administered until conception, even after MPA discontinuation. The primary end point was relapse-free survival (RFS) after remission.We analyzed all efficacy end points in the full analysis set. Results: The body mass index was ≥25 kg/m2 in 27 patients (mean, 31 kg/m2 range, 19-51 kg/m2), and the homeostasis model assessment for insulin resistance index was ≥2.5 in 24 patients (mean, 4.7 range, 0.7-21). Two patients showed progression at 12 weeks [6% 95% confidence interval (CI) 2-18]. At 36 weeks, 29 (81% 95% CI 65-90) patients achieved CR, and 5 (14% 95% CI 6-29) patients achieved partial response. During a median follow-up of 38 months (range, 9-66 months) after remission, relapse was confirmed in three of the patients who had achieved CR (relapse rate, 10%). The 3-year estimated RFS rate was 89%. No patients experienced severe toxicity. Conclusions: Metformin inhibited disease relapse after MPA therapy. The combination of metformin and MPA in EC treatment should be studied further.

AIMS: The carcinogenesis of ovarian clear cell carcinoma (CCC) has been hypothesized to comprise two different pathways: an adenofibroma-carcinoma sequence and an endometriosis-carcinoma sequence. However, the difference in the genetic basis of these two pathways remains unclear. Recent studies have suggested that an ARID1A mutation and the loss of the corresponding protein, BAF250a, are frequent events in CCC. Herein, we investigated the difference in the loss of BAF250a expression in adenofibroma-related CCC and endometriosis-related CCC. METHODS AND RESULTS: In total, 93 cases of surgically treated CCC were evaluated. The presence of adenofibroma and endometriosis associated with carcinoma was determined by reviewing haematoxylin and eosin-stained slides for each case. BAF250a expression in carcinoma was examined immunohistochemically. The loss of BAF250a expression was detected in carcinomas in 50 of 93 (54%) cases, including five of 18 (28%) with adenofibroma alone, 30 of 45 (67%) with endometriosis alone, eight of 18 (44%) with both conditions and seven of 12 (58%) with neither condition. The loss of BAF250a expression was significantly less frequent in CCC cases with adenofibroma than in cases with endometriosis (P = 0.01, Fisher's exact test). CONCLUSIONS: The action of ARID1A in carcinogenesis differs between adenofibroma-related CCC and endometriosis-related CCC.

妊娠中に症状を呈する腰椎椎間板ヘルニアは1万人に1例と稀である.保存的治療により軽快することが多いが,ときに手術が必要となることがある.今回,妊娠中に手術を施行した症例を経験したので報告する.患者は32歳,1経妊1経産.31歳時,腰痛に対して牽引治療歴あり.妊娠21週に右腰痛と右足の跛行が出現し,その後増悪して疼痛管理が困難となったため,妊娠29週に当院転院となった.右L5/S1の腰椎椎間板ヘルニアと診断された.運動麻痺・膀胱直腸障害は認めなかった.保存的治療が奏功せず手術適応と判断した.文献検索の結果,妊娠中の腹臥位,全身麻酔下の手術は安全に施行されていた.妊娠31週3日,腹臥位,全身麻酔下に腰椎後方椎間板ヘルニア摘出術を施行した.手術は四点支持での手術台を使用し,腹部は弾性包帯で支持し,母児ともに安全に施行できた.術後16日目(33週5日)に杖歩行にて退院し,妊娠39週5日に3,052gの児を経腟分娩した.術後半年の時点で右足底の触覚・痛覚障害が軽度残存している.妊娠中に,腹臥位で全身麻酔下に腰椎椎間板ヘルニア手術を合併症なく行うことができた.術後,症状は軽快し,正常分娩となった.(著者抄録)

Ovarian pregnancy is a rare subtype of ectopic pregnancy, and its mechanisms have not been clarified. We report a case of ovarian pregnancy that supports a blastocyst migration mechanism. An infertile woman became pregnant after a single blastocyst transfer following in vitro fertilization during a fresh non-donor cycle. Transvaginal ultrasound revealed a gestational sac-like structure containing an active fetus that was located adjacent to the corpus luteum of the right ovary. Laparoscopy identified a red, swollen implantation site in the ovary, which was completely removed by wedge resection without damaging the remaining parenchyma. This case demonstrated that a fresh blastocyst transferred into the endometrial cavity migrated through the fallopian tube, implanted on an ovarian surface, and formed an ovarian pregnancy.

[目的]子宮体がん検診の対象者を閉経前の女性に広げるにはどのような基準が適切か、細胞診採取器具による採取組織診(簡易組織診)が診断精度改善に有用か検討した。[方法]45歳以下の子宮内膜異型増殖症及び子宮体癌患者で同意の得られた症例を対象に、リスク因子を確認しbody mass indexを計測した。糖尿病既往例を除き、全例75g糖負荷試験(OGTT)を施行した。また、細胞診標本と簡易組織診の診断精度を比較した。[結果]肥満・インスリン抵抗性・糖代謝異常・不妊・多嚢胞性卵巣症候群の頻度が高く、全体の73%がいずれかのリスク因子を有していた。細胞診は簡易組織診と比較して、子宮体癌の検出感度は同等だが、子宮内膜異型増殖症の検出感度が有意に低かった。[結論]閉経前でも、リスク因子を有する場合は内膜組織診の適応と考えられた。閉経前での子宮内膜検査は、細胞診採取器具での組織採取が有用であった。(著者抄録)

AIM: The aim of this study was to examine the current status and management of secondary infertility following cesarean section in Japan. MATERIAL AND METHODS: A two-step questionnaire survey was performed in 1092 facilities, including teaching hospitals and artificial reproductive technology clinics, registered with the Japan Society of Obstetrics and Gynecology. In our questionnaires, we obtained data about symptoms, clinical findings, diagnostic methods, and pregnancy outcomes. Treatments were sorted into three groups, namely typical infertility treatment (group A), conservative treatment (group B), and operative treatment (group C). RESULTS: Of the 1092 facilities, 616 (56%) sent back reply forms to the first questionnaire; 56 (32%) of 176 facilities answered the second questionnaire, and 189 cases were able to be analyzed after completion of the two questionnaires. The commonest symptom was abnormal uterine bleeding during the follicular phase (91 cases; 48% of the 189 eligible cases), and the commonest clinical finding was fluid pooling in the area of cesarean scar dehiscence during the ovulatory phase (142 cases; 75%). The most commonly used diagnostic method was transvaginal ultrasound (153 cases, 81%). The pregnancy rate was 33% in group A, 50% in group B, and 60% in group C. In patients with abnormal uterine bleeding, painful symptoms and fluid pooling at the cesarean scar dehiscence, the pregnancy rate was significantly higher in group C (64%) than in group A (16%; P = 0.0063). CONCLUSIONS: We recommend operative treatment for secondary infertility following cesarean section with painful symptoms and fluid pooling at the site of cesarean scar dehiscence.

BACKGROUND: To achieve optimal cytoreduction for advanced-stage ovarian cancer, modified posterior exenteration is the most frequently performed bowel surgery. We assessed the extents of tumor spreading in the rectosigmoid wall and pelvic side wall in modified posterior exenteration specimens during primary debulking surgery (PDS) and interval debulking surgery (IDS) following neoadjuvant chemotherapy, and compared the validity of selecting this surgical procedure in the patients undergoing PDS with that in the patients undergoing IDS. METHODS: Clinicopathological data from consecutive patients who had undergone a modified posterior exenteration for primary ovarian, tubal, and peritoneal cancer at our institution between April 2008 and March 2013 was retrospectively reviewed. RESULTS: A total of 75 patients (38 in PDS and 37 in IDS) were included in this study. Tumor involvement of the rectosigmoid was histopathologically confirmed in 65% of the specimens. Though the extent of tumor spreading in the rectosigmoid was deeper in PDS than in IDS, the frequency of tumor involvement of the rectosigmoid in patients who had undergone modified posterior exenteration during PDS was equivalent to that in the IDS group. Lateral tumor spreading to the side wall(s) was histopathologically confirmed in 53% of the patients in whom a pelvic side wall resection had been performed. CONCLUSIONS: During both PDS and IDS for ovarian cancer presenting with tumor involvement of the cul-de-sac, close inspection and palpation by gynecologic oncologists may enable the extent of tumor spreading in the pelvis to be estimated, enabling valid decisions as to whether an en bloc resection of the pelvic tumors together with the rectosigmoid and the pelvic side wall might or might not be appropriate.

26歳女。低カリウム血症を伴う高血圧の精査を主訴とした。22歳時に骨盤内滑膜肉腫で左卵管切除術を受けたが、術後化学療法に抵抗し、再発の度に低カリウム血症と血圧上昇を来たしていた。CTで骨盤内に充実性部分を伴った最大径13cm大の嚢胞性腫瘤が多発し、生検と染色体検査でSYT-SSX1による滑膜肉腫と診断した。内分泌学的検査でプロレニン高値を認め、プロレニン産生腫瘍と診断した。腫瘍の病勢が強くコントロールできず、発症後約6年で死亡した。摘出腫瘍のレニン発現解析を行ったところ、免疫染色で多数の(プロ)レニン陽性細胞を認め、real-time RT-PCRでも(プロ)レニンの高発現を認め、(プロ)レニン産生腫瘍と確定診断した。また、プロレニン受容体の高発現とWint/βカテニンシグナルの活性化を認めた。SYT-SSXを背景とした滑膜肉腫58例のマイクロアレイのデータベースを用いて腫瘍の進展と予後に及ぼす影響を検討したところ、(プロ)レニンが滑膜腫瘍の転移や予後に関係している可能性が示唆された。

In developed countries, endometrial cancer (EC) is the most common malignancy among women. Unopposed estrogen therapy, obesity, nulliparity, diabetes mellitus and arterial hypertension have been linked to an increased risk of EC. However, the molecular mechanisms of EC oncogenesis and metastasis have not yet been fully elucidated. Our recent studies of microRNA (miRNA) expression signatures revealed that the microRNA-1/133a (miR‑1/133a) cluster is frequently downregulated in various types of human cancers. However, the functional role of the miR‑1/133a cluster in EC cells is still unknown. Thus, the aim of this study was to investigate the functional significance of the miR‑1/133a cluster and its regulated molecular targets, with an emphasis on the contributions of miR‑1/133a to EC oncogenesis and metastasis. We found that the expression levels of miR‑1 and miR‑133a were significantly reduced in EC tissues. Moreover, restoration of mature miR‑1 or miR‑133a miRNAs significantly inhibited cancer cell migration and invasion, suggesting that these clustered miRNAs act as tumor suppressors. Prediction of miRNA targets revealed that phosphodiesterase 7A (PDE7A) was a potential target gene regulated by both miR‑1 and miR‑133a. PDE7A was confirmed to be overexpressed in EC clinical specimens and silencing of PDE7A significantly inhibited cancer cell migration and invasion. Our data demonstrated that downregulation of the miR‑1/133a cluster promoted cancer cell migration and invasion via overexpression of PDE7A in EC cells. Elucidation of the molecular networks regulated by tumor-suppressive miRNAs will provide insights into the molecular mechanisms of EC oncogenesis and metastasis.

© 2015 by IGCS and ESGO. Objectives It has been established that concurrent chemoradiotherapy (CCRT) is efficacious for cervical cancer, but adherence is unsatisfactory among elderly patients. To improve adherence, we have developed and initiated a daily low-dose cisplatin-based CCRT regimen. Here, we retrospectively evaluated the use of CCRT, especially for elderly patients. Methods The study included a total of 53 patients who were 70 years or older, had stage IB-IVA cervical cancer, and were initially treated with daily CCRT. The daily CCRT comprised pelvic external beam radiotherapy (2 Gy/d × 25) with daily low-dose cisplatin (8.0 mg/m 2 per day) and either low- or high-dose-rate intracavitary brachytherapy. Results The median age was 72 years (range, 70-85 years). The median follow-up duration was 32 months (range, 2-104 months). The 3-year overall survival rate was 79.0%. Daily cisplatin chemotherapy was successfully completed in 32 (60.4%) of the 53 patients. Grade 3 or 4 neutropenia was observed in 19 patients (36%). A late complication of grade 3 rectal hemorrhage occurred in 3 patients who received high-dose-rate brachytherapy. All primary tumors responded to daily CCRT; complete response was observed in 43 patients (91.5%) and partial response was observed in 4 patients (8.5%). Conclusions Daily CCRT in patients 70 years and older had acceptable compliance and safety. Daily CCRT is suggested to be a good treatment option for elderly patients who have advanced cervical cancer and require concurrent cisplatin.

We investigated the first site of distant failure after carbon ion radiotherapy (C-ion RT) for locally advanced cervical cancer in three clinical trials. A total of 91 cases were enrolled in the three trials (Protocol 9702, 9704 and 9902). Histologically, 36 cases had squamous cell carcinoma (SqCC) and 55 cases had adenocarcinoma (AC), including 13 with adenosquamous cell carcinoma. The number of cases with Stage IIB, IIIB and IVA disease was 21, 59 and 11, respectively. Of the 91 cases, 42 had positive pelvic lymph nodes (PLNs). The median tumor size was 6.0 cm (range, 3.0–12.0 cm). The median follow-up duration for all cases was 40 months (range, 7–181 months). A total of 40 cases developed distant failure as the first site of failure: 13 of 36 (36.1%) SqCC cases had distant failure, with 9 of them with para-aortic lymph node (PALN) failure; 27 of 55 (44.0%) AC cases had distant failure, and 23 of them had distant failure excluding PALN metastasis. Distant failure rates of SqCC cases who had positive and negative PLNs before C-ion RT were 61.1% and 11.1%, respectively (P = 0.0045). Those of AC cases were 54.2% and 45.2%, respectively (P = 0.507). In conclusion, there were high rates of distant failure after C-ion RT in AC cases regardless of PLN status, and there were high rates of distant failure after C-ion RT, especially PALN failure, in SqCC cases with positive PLNs.

Metformin is a diabetes drug with anticancer properties. Several studies have investigated the effects of metformin combined with chemotherapeutic agents, with controversial results. This study evaluated the efficacy of combined metformin/cisplatin treatment in an endometrial cancer cell line. Ishikawa cells were treated with metformin, cisplatin or both types of treatment. Cell proliferation was evaluated by quantification and colorimetric and thymidine incorporation assays, cell cycle progression was assessed by flow cytometry, and apoptosis by the caspase-3 activity assay. The effects of metformin and cisplatin used in combination were assessed under normoxic (21% O2) and hypoxic (1% O2) conditions. Mitochondrial morphology was examined using the MitoTracker dye, while function was assayed by lactate production. Discrepant results were obtained from the different assays of cell proliferation, with the value obtained from the colorimetric assay being higher than that from cell counts after drug treatment. Combined treatment with metformin (≥2 mM) and cisplatin (1 µM) had additive anti-proliferative effects on cells under normoxic conditions. However, the additive effect of metformin was attenuated under hypoxia. Metformin caused morphological and functional changes in mitochondria, which appeared shortened after exposure to metformin, while the connections between individual mitochondria appeared weaker. Additionally, decreased MitoTracker staining was observed after an 8-h exposure to metformin. The colorimetric assay did not accurately determine the effects of metformin and cisplatin on cell proliferation. The additive effects of metformin on cisplatin-induced inhibition of cell proliferation were attenuated under hypoxic conditions, while metformin compromised mitochondrial structure and function. Additional studies are needed to determine the efficacy of this drug combination in vivo.

UNLABELLED: To evaluate the efficacy and the toxicity of prophylactic extended-field carbon-ion radiotherapy (C-ion RT, Protocol 0508) for locally advanced squamous cell carcinoma of the uterine cervix in phase I / II clinical trial. Between May 2006 and January 2012, 26 patients of Protocol 0508 were treated with C-ion RT. The numbers of patients with stage IIB, IIIB, and IVA disease were 13, 11, and 2, respectively. Twenty patients had pelvic lymph node metastases. Median tumor size was 6.1 cm (range, 4.0–10.0 cm). The treatment consisted of extended-field irradiation of 39.0 gray equivalents (GyE) in 13 fractions, and additional 15.0 GyE in 5 fractions was given to the gross tumor volume (GTV) and surrounding tissues. With regard to local boost, 18.0 GyE in 2 fractions was given to GTV only. Total dose to the cervical tumor was 72.0 GyE over 20 fractions. The median follow-up period was 37 months. Twenty-one patients had grade 1 or 2 acute gastrointestinal toxicity, but all patients completed the treatment on schedule. There were no grade 3 or higher late complications, with 8 patients having grade 1 or 2 toxicities, 1 had grade 2 gastrointestinal toxicity and 2 had grade 2 genitourinary toxicity. Four patients (15.4%) developed local recurrence, and 8 patients (30.8%) had distant metastases. The 2-year local control rate, progression-free survival rate and overall survival rate were 83.6%, 61.5% and 73.1%, respectively. There were no severe acute or late complications in this trial. Prophylactic extended-field C-ion RT for locally advanced squamous cell carcinoma of the uterine cervix was a safe treatment. Although the number of patients in this study was small, the results support further investigations to confirm the therapeutic efficacy and to avoid or reduce toxicity. TRIAL REGISTRATION: UMIN-CTR UMIN000016169.

BACKGROUND: Because there is limited information on fetal bradyarrhythmia associated with congenital heart defects (CHD), we investigated its prognosis and risk factors. METHODS AND RESULTS: In our previous nationwide survey of fetal bradyarrhythmia from 2002 to 2008, 38 fetuses had associated CHD. Detailed clinical data were collected from secondary questionnaires on 29 fetuses from 18 institutions, and were analyzed. The 29 fetuses included 22 with isomerism, 4 with corrected transposition of the great arteries (TGA) and 3 with critical pulmonary stenosis; 14 had complete atrioventricular block (AVB), 8 had second-degree AVB, and 16 had sick sinus syndrome; 5 died before birth, and 10 died after birth (5 in the neonatal period). Neonatal and overall survival rates for fetal bradyarrhythmia with CHD were 66% and 48%, respectively. Pacemaker implantation was needed in 17 cases (89%). Beta-sympathomimetics were administered in utero in 13 cases and were effective in 6, but were not associated with prognosis. All cases of corrected TGA or ventricular rate ≥70 beats/min survived. A ventricular rate <55 beats/min had significant effects on fetal myocardial dysfunction (P=0.02) and fetal hydrops (P=0.04), resulting in high mortality. CONCLUSIONS: The prognosis of fetal bradyarrhythmia with CHD is still poor. The type of CHD, fetal myocardial dysfunction, and fetal hydrops were associated with a poor prognosis, depending on the ventricular rate.

BACKGROUND: Metformin, an antidiabetic drug, decreases the incidence of various cancers in diabetic patients. Metformin-induced inhibition of cancer cell proliferation has been confirmed in vitro but not in humans. Because endometrial cancer is associated with insulin resistance, the authors investigated whether a diabetes-therapeutic metformin dose inhibits cancer cell growth in patients with endometrial cancer. METHODS: A dose of metaformin was administered (1500-2250 mg/day) to 31 patients with endometrial cancer preoperatively for 4 to 6 weeks. Cell proliferation was assessed in patient tissues using immunohistochemical and Western blot analyses and DNA synthesis was measured in serum using a thymidine uptake assay. All statistical tests were 2-sided. P values of < .05 were considered statistically significant. RESULTS: Preoperative metformin treatment decreased DNA synthesis in sera and significantly reduced the Ki-67 (mean proportional decrease, 44.2%; 95% confidence interval [95% CI], 35.4-53.0 [P < .001]) and topoisomerase IIα (mean proportional decrease, 36.4%; 95% CI, 26.7-46.0 [P < .001]) labeling indices. Levels of phospho-ribosomal protein S6 and phospho-extracellular signal-regulated kinase 1/2 (ERK1/2) were found to be significantly decreased and phospho-adenosine monophosphate-activated protein kinase and p27 levels were significantly increased. Preoperative metformin use caused significant decreases in circulating factors, including insulin, glucose, insulin-like growth factor 1, and leptin. DNA synthesis-stimulating activity in patient sera was significantly decreased during metformin administration. CONCLUSIONS: An antidiabetic dose of metformin inhibited endometrial cancer cell growth in vivo, an effect likely due to its effect on humoral factor(s). This translational study provides considerable rationale to initiate large clinical trials.