生水 真紀夫

Brain damage caused by hypoxic ischemic insult during the perinatal period causes hypoxic ischemic encephalopathies (HIEs). Therapeutic hypothermia is indicated for HIE, but because the therapeutic burden is large for its limited therapeutic effectiveness, another strategy is needed. Progesterone (P4) plays a neuroprotective role through the actions of its metabolite, allopregnanolone (Allo), on P4 receptor, g-aminobutyric acid type A receptors or both. We examined the therapeutic potential of P4 using a newborn ratmodel ofHIE. Fetal rats were exposed to transient ischemic hypoxia by 30-minute bilateral uterine artery clamping on gestational day 18. After spontaneous birth, newborn pups were subcutaneously injected with P4 (0.10 or 0.01 mg), medroxyprogesterone acetate (MPA; 0.12 mg), or Allo (0.10 mg) through postnatal days (PDs) 1 to 9. Brain damage in the rats was assessed using the rotarod test at PD50. The HIE insult reduced the rats-ability in the rotarod task, whichwas completely reversed by P4 and Allo, but not by MPA. Histological examination revealed that the HIE insult decreased neuronal (the cortex and the hippocampal CA1 region) and oligodendroglial cell density (the corpus callosum) through PD0 to PD50. The axon fiber density and myelin sheath thickness in the corpus callosum were also reduced at PD50. The time-course study revealed that P4 restored oligodendroglial cells by PD5, which was followed by neuroprotective action of P4 that lasted long over the injection period. These results suggest that P4 protects the neonatal brain from HIE insult via restoration of oligodendroglial cells.

Brain damage caused by hypoxic ischemic insult during the perinatal period causes hypoxic ischemic encephalopathies (HIEs). Therapeutic hypothermia is indicated for HIE, but because the therapeutic burden is large for its limited therapeutic effectiveness, another strategy is needed. Progesterone (P-4) plays a neuroprotective role through the actions of its metabolite, allopregnanolone (Allo), on P-4 receptor, g-aminobutyric acid type A receptors or both. We examined the therapeutic potential of P-4 using a newborn rat model of HIE. Fetal rats were exposed to transient ischemic hypoxia by 30-minute bilateral uterine artery clamping on gestational day 18. After spontaneous birth, newborn pups were subcutaneously injected with P-4 (0.10 or 0.01 mg), medroxyprogesterone acetate (MPA; 0.12 mg), or Allo (0.10 mg) through postnatal days (PDs) 1 to 9. Brain damage in the rats was assessed using the rotarod test at PD50. The HIE insult reduced the rats' ability in the rotarod task, which was completely reversed by P-4 and Allo, but not by MPA. Histological examination revealed that the HIE insult decreased neuronal (the cortex and the hippocampal CA1 region) and oligodendroglial cell density (the corpus callosum) through PD0 to PD50. The axon fiber density and myelin sheath thickness in the corpus callosum were also reduced at PD50. The time-course study revealed that P-4 restored oligodendroglial cells by PD5, which was followed by neuroprotective action of P-4 that lasted long over the injection period. These results suggest that P-4 protects the neonatal brain from HIE insult via restoration of oligodendroglial cells.

＜文献概要＞Neoadjuvant chemotherapy(NACT)/interval debulking surgery(IDS)で完全切除率は上昇するものの,必ずしもその完全切除手術には良好な予後が伴っていないと指摘されている。重要なことは,NACTの役割が「腫瘍の消失ではなく,腫瘍の縮小であること」を認識しIDSを行うことである。筆者らは,IDS完全切除例における予後を不良にさせる理由の1つに,NACTにより腹腔内の播種巣が消失したように肉眼的に見えるため,IDS時に,見えなくなった腫瘍の取り残しと考えている。また,NACT/IDSのメリットは手術手技を縮小させることで周術期の合併症を下げることではなく,手術手技を縮小させなくても周術期の合併症を下げることであると考えられる。

This is a pooled analysis to evaluate the toxicity and efficacy of carbon-ion radiotherapy (C-ion RT) for inoperable endometrial carcinoma. Eligible patients had previously untreated Stage I-III endometrial carcinoma without para-aortic lymph node metastasis. Total dose to the tumor was 62.4-74.4 Gy [relative biological effectiveness (RBE)] in 20 fractions, and the dose to the gastrointestinal tract was limited to <60 Gy (RBE). Intracavitary brachytherapy was not combined in the present study. Fourteen patients with endometrial carcinoma were analyzed. Ten of the 14 patients were judged medically inoperable, and the others refused surgery. The numbers of patients with Stage I, II and III disease were 1, 9 and 4, respectively. Tumor size was 3.8-13.8 cm in maximum diameter. Median follow-up periods for all patients and surviving patients were 50 months (range, 12-218 months) and 78 months (range, 23-218 months), respectively. Two of three patients receiving 62.4-64.8 Gy (RBE) had local recurrence whereas none of 11 patients receiving 68.0 Gy (RBE) or more had local recurrence. Three patients developed distant metastases and one of them also had local recurrence. The 5-year local control, progression-free survival, overall survival, and cause-specific survival rates were 86%, 64%, 68% and 73%, respectively. No patient developed Grade 3 or higher acute or late toxicity. The present study showed that C-ion RT alone could be a safe and curative treatment modality for inoperable endometrial carcinoma.

Objectives: The present study assessed whether human telomerase reverse transcriptase (TERT) promoter mutations mediate the increased mortality risk observed in patients with ovarian clear cell carcinoma (CCC) and characterized the pathologic features of TERT promoter mutation-associated ovarian CCC. Methods: The TERT promoter region in genomic DNA extracted from paraffin-embedded ovarian CCC specimens (n = 93) was bidirectionally sequenced. Results: A total of 24 TERT promoter mutations were identified among the analyzed CCC cases, of which 11 were known "hotspot" mutations whose frequency was increased in CCC cases with compared to without coexistent adenofibroma (P < .05). In contrast, the 14 (including three novel) identified uncommon site mutations were shown to be associated with a poor progression-free survival rate (P < .01). Conclusions: The identified uncommon TERT promoter mutations exacerbate the poor prognosis characteristic of ovarian CCC cases, and the hotspot mutations appear to be a molecular feature of the adenofibroma-associated form of the disease.

Objective: Double inferior vena cava (IVC) is present in 1.0%–3.0% of the general population and can create clinical problems [1,2]. This anomaly is classified according to the presence and pattern of an interiliac vein; 23% of double-IVC cases do not have an interiliac vein, and variations exist in those with one [3]. Fewreports on retroperitoneal lymphadenectomy in patients with a double IVC exist. Herein, we show retroperitoneal lymphadenectomies in two patients with different double IVC classifications. Methods: We performed an interval debulking surgery, including retroperitoneal lymphadenectomy, in two cases of advanced ovarian cancer with double IVC. The retroperitoneal lymphadenectomy procedure was the same as that for patients with normal IVC. Case 1 involved a 53-year-old female having a double IVC without an interiliac vein. Case 2 involved a 51-year-old female having a double IVC with an interiliac vein from the right common iliac vein to the left IVC. Preoperative enhanced computed tomography revealed double IVC flow pattern in both cases; however, the presence of the interiliac vein in case 2 remained unrecognized. Results: Lymphadenectomy in case 1 was without complications. In case 2, major bleeding from the interiliac vein occurred during lymphatic tissue removal from the front of the sacral region. The bleeding was difficult to stop, and was finally stopped using Tacho Sil®. We then completed lymphadenectomy. Conclusions: During retroperitoneal lymphadenectomy in patients with a double IVC, it is important to determine the presence of an interiliac vein. Furthermore, its flow pattern should be considered with care.

OBJECTIVE: To compare trends in the gestational ages at which single complete hydatidiform moles (CHMs) and partial hydatidiform moles (PHMs) were evacuated, and the rates of postmolar gestational trophoblastic neoplasia (GTN) between 1980 and 2014 at 2 hospitals. STUDY DESIGN: We retrospectively studied 1,334 patients with single CHMs or PHMs. The patients’ medical records were evaluated, and the patients were assigned to 7 periods: group A: 1980–1984, group B: 1985–1989, group C: 1990–1994, group D: 1995–1999, group E: 2000–2004, group F: 2005–2009, and group G: 2010– 2014. RESULTS: The number of postmolar patients gradually declined over the 35-year period. The gestational ages at CHM and PHM evacuation were 12.3±3.7 weeks from 1980–1984 and 9.1±0.91 weeks from 2010–2014, and 12.6±3.7 weeks from 1980–1984 and 10.3±3.4 weeks from 2010–2014, respectively. The GTN rate was fairly constant during the 35-year period (18.9–37.5%). CONCLUSION: The widespread use of ultrasonography has led to earlier CHM and PHM diagnosis and evacuation. The median gestational ages at CHM and PHM evacuation declined, while the rate of GTN after CHM evacuation did not decline over the 35-year period.

We conducted a phase 1/2 study to evaluate the efficacy and safety of carbon ion radiotherapy (C-ion RT) with concurrent chemotherapy for locally advanced uterine cervical adenocarcinoma. Thirty-three patients were enrolled between April 2010 and March 2014. Treatment consisted of C-ion RT with concurrent weekly cisplatin at a dose of 40 mg/m2 . In the phase 1 component, the total dose was escalated from 68.0 Gy (relative biological effectiveness [RBE]) to 74.4 Gy (RBE) to determine the maximum tolerated dose of C-ion RT. In the phase 2 component, the efficacy and safety of C-ion RT with concurrent chemotherapy were evaluated using the dose determined in the phase 1 component. The median follow-up duration was 30 months. Two patients did not receive chemotherapy because of anemia or leukocytopenia immediately prior to commencing treatment; 31 patients were analyzed. None of the patients developed dose-limiting toxicities. The recommended dose (RD) was determined to be 74.4 Gy (RBE). In the phase 2 component, two patients developed Grade 3-4 toxicities in the gastrointestinal tract, due to repeated laser coagulation or peritonitis caused by appendicitis. In the patients treated with the RD, the 2-year local control, progression-free survival, and overall survival rates were 71%, 56%, and 88%, respectively. C-ion RT with concurrent weekly cisplatin was well tolerated in patients with locally advanced uterine cervical adenocarcinoma. Our findings support further investigations into the efficacy of this strategy.

BACKGROUND/AIM: To evaluate the long-term outcomes of carbon-ion radiotherapy (C-ion RT) for locally advanced cervical squamous cell carcinoma (LAC-SqCC) in 2 prospective phase I/II studies. PATIENTS AND METHODS: In the first study, 14 patients were treated with 68.8-72.8 Gy (RBE)/24 fractions. In a subsequent study, 22 patients were treated with 64.0-72.0 Gy (RBE)/20 fractions while limiting the dose to the gastro-intestinal (GI) <60 Gy (RBE). RESULTS: The 10-year local control rates were 92% and 61% for the patients administered a total dose of 72.0-72.8 Gy (RBE) and 64.0-68.8 Gy (RBE), respectively. Two patients in the first study developed grade 3/4 rectal or bladder complications; however, no grade 3 or higher complications occurred in the second study. CONCLUSION: C-ion RT with a higher dose was associated with excellent LC in LAC-SqCC. Long-term safety was confirmed based on the establishment of dose constraints for the GI tract.

OBJECTIVE: Metformin, an antidiabetic drug, inhibits the endometrial cancer cell growth in vivo by improving the insulin resistance; however, its mechanism of action is not completely understood. Protein phosphatase 2A (PP2A) is a serine/threonine phosphatase associated with insulin resistance and type 2 diabetes, and its inhibition restores the insulin resistance. This study investigated the antitumor effect of metformin on endometrial cancer with a focus on PP2A. METHODS: Metformin (1,500-2,250 mg/day) was preoperatively administered to patients with endometrial cancer for 4 to 6 weeks. Expression of the PP2A regulatory subunits, 4 (PPP2R4) and B (PP2A-B), was evaluated using real-time polymerase chain reaction (RT-PCR) and immunohistochemistry (IHC) using paired specimens obtained before and after metformin treatment. The effect of PPP2R4 inhibition with small interfering RNA was evaluated in the endometrial cancer cell lines HEC265 and HEC1B. P values of < .05 were considered statistically significant. RESULTS: Preoperative metformin treatment significantly reduced the expression of PP2A-B, as determined using IHC, and the mRNA expression of PPP2R4, as determined using RT-PCR, in the patients with endometrial cancer. However, metformin could not directly alter the PPP2R4 mRNA levels in the endometrial cancer cell lines in vitro. PPP2R4 knockdown reduced the proliferation and induced the apoptosis by activating caspases 3/7 in HEC265 and HEC1B cells. CONCLUSIONS: Downregulation of the PP2A-B subunit, including PPP2R4, is an important indirect target of metformin. Inhibition of PP2A may be an option for the treatment of endometrial cancer patients with insulin resistance. TRIAL REGISTRATION: This trial is registered with UMIN-CTR (number UMIN000004852).

AIM: The aim of this study was to provide medical terms to describe the condition of a girl who should be evaluated for primary amenorrhea in order to facilitate intervention at an appropriate time. METHODS: We performed a literature and clinical guidelines search for recent practices with regard to menarche and discussed relevant cases that had been experienced by committee members. Additionally, we theoretically reviewed medical terms defined in the Glossary Book of Obstetrics and Gynecology in Japan (Japan Society of Obstetrics and Gynecology, 3rd edition). RESULTS: The committee for the redefinition of primary amenorrhea proposed the introduction of two terms and the deletion of one term that had been defined by the Japan Society of Obstetrics and Gynecology, instead of changing the age definition of primary amenorrhea. 'Delayed menarche' was introduced to describe a condition in which a girl has never experienced cyclic menstruation (menarche) by 15-17 years of age. 'Late menarche' was also introduced to describe a condition in which a girl has experienced menarche at 15 years of age or older. 'Delayed menstruation,' which was defined as a condition in which a girl experiences menarche at 15-18 years of age, was deleted. CONCLUSION: The new terms 'delayed menarche' and 'late menarche' were introduced, and the term 'delayed menstruation' was deleted. The new system might help in the early detection and appropriate treatment of primary amenorrhea.

OBJECTIVE: We evaluated the efficacy and safety of aggressive surgery for advanced ovarian cancer at a non-high-volume center. MATERIALS AND METHODS: We evaluated consecutive patients with stage III/IV ovarian, fallopian, and peritoneal cancer undergoing elective aggressive surgery from January 2008 to December 2012, which encompassed the first 5years after implementing an aggressive surgery protocol. After receiving appropriate training for 9months, a gynecological surgical team began performing multi-visceral resections. Primary debulking surgery was chosen when the team considered that optimal surgery was achievable on the initial laparotomy, otherwise interval debulking surgery was chosen (the protocol treatments). Analysis was performed on an intention-to-treat basis (full-set analysis), and outcomes were compared to those of patients who underwent standard surgery between 2000 and 2007. RESULTS: Of 106 consecutive patients studied, 87 (82%) underwent aggressive surgery per protocol and 19 were excluded. Serous carcinoma was the most common disease (78%), followed by clear cell carcinoma (7%), and 32% of the patients had stage IV disease. The respective median progression-free and overall survival rates increased from 14.6 and 38.1months before implementation, respectively, to 25.0 and 68.5months after implementation, respectively. Complete resection was achieved in 83 of the 106 patients (78%), and the surgical complexity score was high (>8) in 61 patients (58%); although there was no mortality within 12weeks of surgery, major complications occurred in 8 patients. CONCLUSIONS: We confirmed that outcomes improved after implementing aggressive surgery for advanced ovarian cancer, without causing a significant increase in mortality. Factors enhancing survival outcomes are discussed.

OBJECTIVE: Locally advanced ovarian carcinomas may be fixed to the pelvic sidewall, and although these often involve the internal iliac vessels, they rarely involve the external iliac vessels. Such tumors are mostly considered inoperable. We present a surgical technique for complete resection of locally advanced ovarian carcinoma fixed to the pelvic sidewall and involving external and internal iliac vessels. METHODS: A 69-year-old woman presented with ovarian carcinoma fixed to the right pelvic sidewall, which involved the right external and internal iliac arteries and veins and the right lower ureter, rectum, and vagina. We cut the external iliac artery and vein at the bifurcation and at the inguinal ligament to resect the external artery and vein. Then, we reconstructed the arterial and venous supplies of the right external artery and vein with grafts. After creating a wide space immediately inside of the sacral plexus to allow the tumor fixed to pelvic sidewall with the internal iliac vessels to move medially, we performed total internal iliac vessel resection. RESULTS: We achieved complete en bloc tumor resection with the right external and internal artery and vein, right ureter, vagina, and rectum adhering to the tumor. There were no intra- or postoperative complications, such as bleeding, graft occlusion, infection, or limb edema. CONCLUSION: Exfoliation from the sacral plexus and total resection with external and internal iliac vessels enables complete resection of the tumor fixed to the pelvic sidewall.

<sec><title>Introduction</title>Several retrospective or single-centre studies demonstrated the efficacy of transplacental treatment of fetal tachyarrhythmias. Our retrospective nationwide survey showed that the fetal therapy will be successful at an overall rate of 90%. For fetuses with hydrops, the treatment success rate will be 80%. However, standard protocol has not been established. The objective of this study is to evaluate the efficacy and safety of the protocol-defined transplacental treatment of fetal tachyarrhythmias. Participant recruitment began in October 2010. </sec><sec><title>Methods and analysis</title>The current study is a multicentre, single-arm interventional study. A total of 50 fetuses will be enrolled from 15 Japanese institutions. The protocol-defined transplacental treatment is performed for singletons with sustained fetal tachyarrhythmia ≥180 bpm, with a diagnosis of supraventricular tachycardia or atrial flutter. Digoxin, sotalol, flecainide or a combination is used for transplacental treatment. The primary endpoint is disappearance of fetal tachyarrhythmias. The secondary endpoints are fetal death related to tachyarrhythmia, proportion of preterm birth, rate of caesarean section attributable to fetal arrhythmia, improvement in fetal hydrops, neonatal arrhythmia, neonatal central nervous system disorders and neonatal survival. Maternal, fetal and neonatal adverse events are evaluated at 1 month after birth. Growth and development are also evaluated at 18 and 36 months of corrected age. </sec><sec><title>Ethics and dissemination</title>The Institutional Review Board of the National Cerebral and Cardiovascular Center of Japan has approved this study. Our findings will be widely disseminated through conference presentations and peer-reviewed publications. </sec><sec><title>Trial registration number</title>UMIN Clinical Trials Registry UMIN000004270. </sec>

PURPOSE: Obesity and diabetes (DM) are known to increase the risk of endometrial cancer (EC). However, little is known about the prevalence of abnormal glucose metabolism and insulin resistance (IR) in EC patients. We aimed to evaluate the prevalence of abnormal glucose metabolism and IR in EC patients. METHODS: We prospectively enrolled atypical endometrial hyperplasia (AEH) and EC patients who had received planned treatment at Chiba University Hospital, Japan. All patients, except those with a confirmed diagnosis of DM, underwent the 75-g oral glucose tolerance test (OGTT) before treatment. We evaluated the prevalence of obesity, defined as body mass index (BMI) ≥25, IR, abnormal glucose metabolism, and the associations between these three factors and the clinical characteristics of AEH and EC patients. RESULTS: We enrolled 279 patients from April 2009 to March 2015. Of these, 56 had a confirmed diagnosis of DM. Abnormal OGTT results, including impaired fasting glucose (n = 7), impaired glucose tolerance (n = 69), and newly identified DM (n = 33), were noted in 109 patients. Obesity, IR, and abnormal glucose metabolism were observed in 49.8, 51.6, and 59.1% of patients, respectively. Abnormal glucose metabolism was significantly associated with age (P < 0.001), body mass index (P = 0.004), and IR status (P < 0.001) in multivariate analysis. CONCLUSION: Abnormal glucose metabolism, IR, and obesity were highly prevalent in patients with AEH and EC. These results indicate that physicians should consider a patient's metabolic status in the postoperative management of AEH and EC patients.

Nonclassic congenital adrenal hyperplasia (NCAH) is an autosomal-recessive disorder caused by 21-hydroxylase deficiency and manifests as hirsutism and oligomenorrhea due to excess adrenal androgen and progesterone. We report a case of a woman with NCAH who showed continuous high serum progesterone levels in the follicular phase associated with impaired folliculogenesis. NCAH was diagnosed based on high 17-hydroxyprogesterone levels after rapid adrenocorticotropic hormone loading, and three heterozygous missense mutations in CYP21A2, encoding 21-hydroxylase, were identified. Recurrent failure of in vitro fertilization programs occurred because of empty follicles and preterm rupture of leading follicles, and vaginal stenosis with a hypoplastic cervix. Glucocorticoid administration normalized serum progesterone levels, restored folliculogenesis, and stretched the vaginal wall, which contributed to the success of the in vitro fertilization program. The patient delivered at term following blastocyst transfer. Correction of hyperandrogenism and high progesterone levels using glucocorticoids may improve fertility in women with NCAH.

Nonclassic congenital adrenal hyperplasia (NCAH) is an autosomal-recessive disorder caused by 21-hydroxylase deficiency and manifests as hirsutism and oligomenorrhea due to excess adrenal androgen and progesterone. We report a case of a woman with NCAH who showed continuous high serum progesterone levels in the follicular phase associated with impaired folliculogenesis. NCAH was diagnosed based on high 17-hydroxyprogesterone levels after rapid adrenocorticotropic hormone loading, and three heterozygous missense mutations in CYP21A2, encoding 21-hydroxylase, were identified. Recurrent failure of in vitro fertilization programs occurred because of empty follicles and preterm rupture of leading follicles, and vaginal stenosis with a hypoplastic cervix. Glucocorticoid administration normalized serum progesterone levels, restored folliculogenesis, and stretched the vaginal wall, which contributed to the success of the in vitro fertilization program. The patient delivered at term following blastocyst transfer. Correction of hyperandrogenism and high progesterone levels using glucocor-ticoids may improve fertility in women with NCAH.