Immunosuppressive therapy before and during pregnancy may improve obstetric outcomes in pregnancy complicated by dermatomyositis with anti-MDA-5 antibody positivity: A case report.

Dermatomyositis (DM) is one of the most common autoimmune rheumatic diseases affecting women of childbearing age. Pregnancy may lead to exacerbation of DM, especially of DM with anti-melanoma differentiation-associated gene (MDA) 5 antibody positivity, leading to a poor obstetric outcome. Here, we report consecutive pregnancies complicated by DM with anti-MDA-5 antibodies. A 32-year-old pregnant woman, gravida 3 para 1, presented with fetal growth restriction. Emergency cesarean section was performed because of non-reassuring fetal status at 28 weeks of gestation. Two days postpartum, the patient's hand eczema had worsened and she was diagnosed with DM with MDA-5 antibody positivity. Immunosuppressive therapy using corticosteroids combined with tacrolimus was immediately started, suppressing the DM symptoms. Eighteen months later, she became pregnant again but was then negative for anti-MDA-5 antibodies while continuing immunosuppressive therapy. During pregnancy, the titer of the antibody gradually increased, peaked in the second trimester and declined to near normal range through the third trimester. A male infant weighing 2418 g was delivered at 38 weeks of gestation. Our case demonstrates that controlling of DM activity using immunosuppressive treatment before and during pregnancy may be beneficial to obstetric outcomes.

Oral Gonadotropin-Releasing Hormone Antagonist Relugolix Has the Same Effect as Gonadotropin-Releasing Hormone Agonist Injections in Terms of Preparation for Transcervical Resection Myomectomy.

For preparing the optimal condition in transcervical resection (TCR) surgery, gonadotropin-releasing hormone (GnRH) agonist has been utilized. Recently, an oral GnRH antagonist (relugolix) is available and acts directly on GnRH receptor, avoiding flare up and reducing blood E2 levels rapidly. We retrospectively compared the oral GnRH antagonist (n = 14) effect to that of subcutaneous GnRH agonist (n = 19) for the pretreatment of endometrium in TCR myomectomy. Endometrial thickening was determined by intraoperative videos. The color tone of the endometrium in the normal part was assessed by digital image processing. The median duration of the first GnRH agonist injection and the surgery was 67 days (21-136 days), which is significantly longer than that of the oral GnRH antagonist group, 18.5 days (7-157 days P < 0.01). Both the GnRH agonist and antagonist groups did not exhibit prominence in the endometrium. The GnRH antagonist group showed the same degree of whiteness in the normal endometrium as the GnRH agonist group. The oral GnRH antagonist administration could rapidly atrophy the endometrium and create an optimal surgical field for TCR in a short period.

Perinatal outcomes associated with the positional relationship between the placenta and the adenomyosis lesion.

INTRODUCTION: Although various perinatal complications have been reported to be increased in the pregnant patients with adenomyosis, it is not clear what type of patients with adenomyosis is more likely to cause obstetric complications. In this study, we focused on the positional relationship between the placenta and adenomyosis lesion in evaluating perinatal prognosis of pregnant patients with adenomyosis. MATERIAL AND METHODS: This retrospective cohort study was carried out between 1 January 2005 and 31 December 2019 in a single institution. Adenomyosis was diagnosed by magnetic resonance imaging (MRI) and/or transvaginal ultrasonography (TVUS). To evaluate the influence of adenomyosis on perinatal outcomes, we classified the positional relationship between the placenta and the adenomyosis lesion into two groups and examined the perinatal prognosis of the patients with adenomyosis by analyzing their clinical records. Group I (n = 9) was defined when the placenta was not overlaid on adenomyosis lesion. Group II (n = 11) was defined when a part of the placenta was overlaid on adenomyosis lesion. RESULTS: Twenty pregnant patients with adenomyosis were analyzed. There were no differences in clinical backgrounds between group I and group II. There was a significant increase in the obstetric morbidity in group II than that of Group I(group I: 6.3%, 4/63 vs group II: 18.6%, 26/77; P < 0.001). In group II, fetal growth restriction (FGR) was more frequent (0%, 0/9 vs 45.5%, 5/11; P = 0.042) and the birth weight was significantly lower than that in group I (2951.1 g ± 326.5 g vs 2318.9 ± 656.1 g; P = 0.037). There was a trend of lighter weight of the placenta in group II (550.6 ± 66.5 g vs 437.5 ± 117.8 g; P = 0.063) and the volume of bleeding during delivery was a higher trend in group II than that in group I (845.1 ± 367.1 g vs 1356 ± 604.8 g; P = 0.083). Group II was furtherly subdivided into group IIa (less than half the major axis of the placenta overlaid on adenomyosis lesion) and group IIb (more than half the major axis of placenta overlaid on adenomyosis lesion). The obstetric morbidity tended to be higher in group IIb than in group IIa (group IIa: 22.9%, 8/35 vs group IIb: 42.9%, 18/42); P = 0.09). In group IIb, the frequency of FGR was significantly higher (group IIa: 0%, 0/5 vs IIb: 83.3%, 5/6; P = 0.020) and the birth weight was significantly lower than those in group IIa (2656.8 ± 231.9 g vs 2037 ± 780.1 g; P = 0.040). All cases of FGR, hypertensive disorder of pregnancy (HDP), and oligohydramnios were observed in group IIb. CONCLUSION: Placental localization near adenomyosis may increase the risk of perinatal complications.

CD206+ macrophage is an accelerator of endometriotic-like lesion via promoting angiogenesis in the endometriosis mouse model.

In endometriosis, M2 MΦs are dominant in endometriotic lesions, but the actual role of M2 MΦ is unclear. CD206 positive (+) MΦ is classified in one of M2 type MΦs and are known to produce cytokines and chemokines. In the present study, we used CD206 diphtheria toxin receptor mice, which enable to deplete CD206+ cells with diphtheria toxin (DT) in an endometriosis mouse model. The depletion of CD206+ MΦ decreased the total weight of endometriotic-like lesions significantly (p < 0.05). In the endometriotic-like lesions in the DT group, a lower proliferation of endometriotic cells and the decrease of angiogenesis were observed. In the lesions, the mRNA levels of VEGFA and TGFß1, angiogenic factors, in the DT group significantly decreased to approximately 50% and 30% of control, respectively. Immunohistochemical study revealed the expressions of VEGFA and an endothelial cell marker CD31 in lesions of the DT group, were dim compared to those in control. Also, the number of TGFß1 expressing MΦ was significantly reduced compared to control. These data suggest that CD206+ MΦ promotes the formation of endometriotic-like lesions by inducing angiogenesis around the lesions.

Inhibition of receptor activity-modifying protein 1 suppresses the development of endometriosis and the formation of blood and lymphatic vessels.

Neuroimmune interactions are involved in the development of endometriosis. Here, we examined the role of a neuropeptide, calcitonin gene-related peptide (CGRP), and its receptor, receptor activity-modifying protein (RAMP) 1, in growth of endometrial tissues and the formation of blood and lymphatic vessels in a mouse ectopic endometrial transplantation model. Endometrial fragments from donor wild-type (WT) mice transplanted into the peritoneal wall of recipient WT mice grew with increased density of blood and lymphatic vessels. When tissues from RAMP1-deficient (RAMP1-/- ) mice were transplanted into RAMP1-/- mice, implant growth and angiogenesis/lymphangiogenesis were decreased. CGRP was up-regulated in dorsal root ganglia, and CGRP+ nerve fibres were distributed into the implants from the peritoneum. RAMP1 was co-expressed with CD11b (macrophages) and S100A4 (fibroblasts), but did not co-localize with blood vessel endothelial cell marker CD31 or lymphatic vessel endothelial hyaluronan receptor (LYVE)-1. Cultured with CGRP, macrophages up-regulated vascular endothelial growth factor (VEGF)-A, VEGF-C and VEGF-D, whereas fibroblasts up-regulated VEGF-C, but not VEGF-A or VEGF-D, in a RAMP1-dependent manner. CGRP receptor antagonist CGRP8-37 inhibited growth of and angiogenesis/lymphangiogenesis within endometrial tissue implants. These results suggest that RAMP1 signalling is crucial for growth and angiogenesis/lymphangiogenesis in endometrial tissue. Blockade of RAMP1 is a potential tool for the treatment of endometriosis.

Lymphangiogenesis induced by vascular endothelial growth factor receptor 1 signaling contributes to the progression of endometriosis in mice.

Lymphangiogenesis is related to the growth of endometriosis. Here, we examined whether vascular endothelial growth factor (VEGF) receptor 1 (VEGFR1) signaling plays a role in lymphangiogenesis during endometriosis. Endometrial fragments from wild-type (WT) mice transplanted into the peritoneal wall of host WT mice (WT→WT) developed well and displayed enhanced lymphangiogenesis associated with increases in mRNA levels of VEGF-C and VEGF-D. Compared with WT mice, the implant size and lymphangiogenesis were reduced, when endometrial fragments from mice lacking the VEGFR1 tyrosine kinase (TK) domain (TK-/-) were transplanted into host TK-/- mice (TK-/-→TK-/-). Treatment of WT→WT mice with the VEGFR3 kinase inhibitor suppressed the size of implants and lymphangiogenesis. Immunofluorescence analyses demonstrated that VEGF-C and VEGF-D were expressed in both CD11b+ and S100A4+ cells. TK-/-→TK-/- mice had lower numbers of CD11b+ and S100A4+ cells than WT→WT mice. When isolated bone marrow (BM)-derived macrophages or culture murine fibroblasts were stimulated with placental growth factor (PlGF), a specific agonist of VEGFR1, the levels of VEGF-C and VEGF-D were increased in a VEGFR1-dependent manner. These results suggest that VEGFR1 signaling in macrophages and fibroblasts contributes to the growth of endometrial implants and lymphangiogenesis.

IL-33 Exacerbates Endometriotic Lesions via Polarizing Peritoneal Macrophages to M2 Subtype.

In endometriosis, M2 macrophages (MΦ) are dominant and promote the development of endometriosis lesions. However, the factor(s) which induces M2 MΦ are unknown. In the present study, we focused on interleukin (IL)-33, known as an alarmin and investigated its expression and its role in endometriosis, especially from the point of the relevance with MΦ. The expression of IL-33 in endometriosis lesions was examined by immunohistochemistry. The cystic fluid of ovarian cysts/tumors was obtained and used to measure IL-33 concentration. Endometriotic stromal cells (ESC) and MΦ derived from patients were used for in vitro experiments. IL-33 was detected in the epithelium and stromal cells of endometriotic lesions. The mean IL-33 concentration in the cystic fluid of endometriomas was significantly higher than that in non-endometriomas (2.2 ng/ml vs. 0.02 ng/ml, P < 0.01). IL-1ß induced IL-33 mRNA expression in ESC via p38 MAPK activation. With IL-33 stimulation, peritoneal MΦ polarized to M2 MΦ and produced IL-1ß mRNA with a 2.2-fold increase, which was negated with soluble ST2, a decoy receptor of IL-33. IL-33, derived from endometriotic lesions, stimulated MΦ to produce IL-1ß, which results in increasing IL-33 production in ESC. This cycle may continue to exacerbate the endometriotic lesions.

Quantitative analysis of ovarian cysts and tumors by using T2 star mapping.

AIM: The aim of this study was to investigate the efficacy of T2 star (T2*) mapping in diagnosing ovarian cysts/ tumors. METHODS: Pelvic magnetic resonance examinations including T2*WI were performed before surgery in 35 patients. The region of interest, consisted of a 10 mm2 diameter circle, was set as much as possible inside ovarian tumors/cysts to measure T2*values, and mean T2* values were compared in ovarian cyst/tumor types, retrospectively. Diagnoses of 40 ovarian cysts/tumors were determined by pathological reports, in which 17 were endometriomas, 13 were mature cystic teratomas, 6 were mucinous cystadenomas and 4 were serous cystadenomas. RESULTS: The average T2* values of endometrioma was 56.8 ± 8.7 ms (mean ± SEM), which was significantly lower than that of mucinous cystadenoma (334.2 ± 58.5 ms, mean ± SEM) or serous cystadenoma (237.0 ± 45.4 ms, mean ± SEM). There was no difference in T2* values between endometrioma and mature cystic teratoma (64.1 ± 22.6 ms, mean ± SEM). Receiver operating characteristics curve analysis revealed that optimal cut-off value for differential diagnosis of endometrioma and mucinous or serous cystadenoma was 149.2 ms as T2* value, which has an area under the curve of 0.95 (sensitivity = 92.4%, specificity = 78.6%). CONCLUSION: T2* values were useful to diagnose various types of ovarian cyst/tumor.

VEGF Receptor 1-Expressing Macrophages Recruited from Bone Marrow Enhances Angiogenesis in Endometrial Tissues.

Angiogenesis is critical in maintenance of endometrial tissues. Here, we examined the role of VEGF receptor 1 (VEGFR1) signaling in angiogenesis and tissue growth in an endometriosis model. Endometrial fragments were implanted into the peritoneal wall of mice, and endometrial tissue growth and microvessel density (MVD) were determined. Endometrial fragments from wild-type (WT) mice grew slowly with increased angiogenesis determined by CD31+ MVD, peaking on Day 14. When tissues from WT mice were transplanted into VEGFR1 tyrosine kinase-knockout mice, implant growth and angiogenesis were suppressed on Day 14 compared with growth of WT implants in a WT host. The blood vessels in the implants were not derived from the host peritoneum. Immunostaining for VEGFR1 suggested that high numbers of VEGFR1+ cells such as macrophages were infiltrated into the endometrial tissues. When macrophages were deleted with Clophosome N, both endometrial tissue growth and angiogenesis were significantly suppressed. Bone marrow chimera experiments revealed that growth and angiogenesis in endometrial implants were promoted by host bone marrow-derived VEGFR1+/CD11b+ macrophages that accumulated in the implants, and secreted basic fibroblast growth factor (bFGF). A FGF receptor kinase inhibitor, PD173047 significantly reduced size of endometrial tissues and angiogenesis. VEGFR1 signaling in host-derived cells is crucial for growth and angiogenesis in endometrial tissue. Thus, VEGFR1 blockade is a potential treatment for endometriosis.

Ultrasonic findings of fetal axillary lymphangioma with intralesional hemorrhage.

We report a case of an axillary lymphangioma in a fetus delivered at 30 weeks' gestation with suspected intralesional hemorrhage based on the ultrasonic findings. In the ultrasonic examination at 15 weeks' gestation, the fetus was found to have a multilocular mass spreading from the axilla to the chest wall, which was diagnosed as an axillary lymphangioma. Chromosome analysis by amniocentesis showed a normal karyotype, and no other malformations were observed. At 29 weeks, the mass had increased in size, and color Doppler ultrasound examination revealed that the middle cerebral artery peak systolic velocity (MCA-PSV) reached 80.2 cm/s [1.86 MoM (multiples of the median)]. Intralesional bleeding was suspected because of the multiple images of hemorrhage in which sites of blood spouting in a pulsatile fashion were detected within the mass. Cordocentesis at 30 weeks revealed that fetal hemoglobin concentration was 5.1 g/dL. An emergency Cesarean section was performed. A female weighing 2810 g, including the mass, was delivered, and the blood hemoglobin level was 5.9 g/dL at birth. Blood transfusion, fine-needle aspiration of the fluid in the mass, intralesional injection of OK-432, and partial excision of the lymphangioma were performed after birth. Ultrasonic examination proved useful in the diagnosis of intralesional bleeding in this lymphangioma.

Guidelines for obstetrical practice in Japan: Japan Society of Obstetrics and Gynecology (JSOG) and Japan Association of Obstetricians and Gynecologists (JAOG) 2014 edition.

The 'Clinical Guidelines for Obstetrical Practice, 2011 edition' were revised and published as a 2014 edition (in Japanese) in April 2014 by the Japan Society of Obstetrics and Gynecology and the Japan Association of Obstetricians and Gynecologists. The aims of this publication include the determination of current standard care practices for pregnant women in Japan, the widespread use of standard care practices, the enhancement of safety in obstetrical practice, the reduction of burdens associated with medico-legal and medico-economical problems, and a better understanding between pregnant women and maternity-service providers. The number of Clinical Questions and Answers items increased from 87 in the 2011 edition to 104 in the 2014 edition. The Japanese 2014 version included a Discussion, a List of References, and some Tables and Figures following the Answers to the 104 Clinical Questions; these additional sections covered common problems and questions encountered in obstetrical practice, helping Japanese readers to achieve a comprehensive understanding. Each answer with a recommendation level of A, B or C was prepared based principally on 'evidence' or a consensus among Japanese obstetricians in situations where 'evidence' was weak or lacking. Answers with a recommendation level of A or B represent current standard care practices in Japan. All 104 Clinical Questions and Answers items, with the omission of the Discussion, List of References, and Tables and Figures, are presented herein to promote a better understanding among English readers of the current standard care practices for pregnant women in Japan.

Effects of campaign for postpartum vaccination on seronegative rate against rubella among Japanese women.

BACKGROUND: Japan experienced two rubella outbreaks in the past decade (2004 and 2012-2013), resulting in 10 and 20 infants with congenital rubella syndrome (CRS), respectively. This study was performed to determine whether the seronegative rate was lower in multiparous women than in primiparous women in Japan. METHODS: Hemagglutination inhibition (HI) test results during pregnancy were analyzed retrospectively in 11048 primiparous and 9315 multiparous women who gave birth at six hospitals in northern Japan in the 5-year study period (January 2008 through December 2012). Women with HI titer <  1:8 were defined as susceptible to rubella. RESULTS: The seronegative rate was significantly lower in multiparous than primiparous women aged 30 - 31 years (2.3% [22/967] vs. 4.5% [66/1454], P  =  0.0036), 36 - 37 years (3.4% [55/1601] vs. 5.7% [79/1389], P  =  0.0030), and overall women (3.8% [350/9315] aged 34.7  ±  5.2 vs. 5.4% [597/11048] for 33.2  ±  5.9, P  <  0.001). The susceptible fraction size did not differ largely according to hospital, ranging from 3.5% to 6.3%. Those for each year did not change markedly; 4.5% [150/3369], 5.2% [221/4268], 4.4% [195/4412], 4.6% [186/4056], and 4.6% [195/4258] for 2008, 2009, 2010, 2011, and 2012, respectively. Those for teenagers were consistently high: 22.7% [5/22], 20.7% [6/29], 20.6% [7/34], 13.0% [3/23], and 23.5% [4/17] for 2008, 2009, 2010, 2011, and 2012, respectively. CONCLUSIONS: The seronegative rate was significantly lower in multiparous than primiparous women. However, Japanese rubella vaccination programs were insufficient to eliminate CRS.

Transversus abdominis plane block provides postoperative analgesic effects after cesarean section: additional analgesia to epidural morphine alone.

AIM: The aim of our study was: (i) to investigate whether transversus abdominis plane (TAP) block confers additional analgesic effects to epidural morphine alone; and (ii) to determine plasma levels of local anesthetics after TAP block in post-cesarean women. MATERIAL AND METHODS: The subjects were parturients undergoing cesarean section under combined spinal-epidural anesthesia. Morphine (2 mg) was administered to the epidural space close to the end of surgery. Women who desired TAP block were allocated to the TAP group. Women who did not undergo TAP block were allocated to the control group. In the TAP group, 20 mL of either 0.375% ropivacaine or 0.3% levobupivacaine was infused to both sides of the transversus abdominis plane after surgery. All patients were placed on a patient-controlled i.v. analgesia regimen with morphine after surgery. Time to the first morphine request and amount of morphine consumption within 24 h after surgery were compared in patients with and without TAP block. Plasma concentrations of local anesthetics were determined at 15, 30 and 60 min after TAP block. RESULTS: Forty and 54 patients were allocated to the control and TAP group, respectively. The median time to the first morphine request was longer (555 vs 215 min), and the median cumulative morphine consumption within 24 h was lower (5.3 vs 7.7 mg) in the TAP group than in the control group. The maximum median concentrations of ropivacaine and bupivacaine after TAP block were 784 and 553 ng/mL, respectively. CONCLUSION: TAP block had additional analgesic effects to epidural morphine alone.

[Emergency cesarean section].

There are abundant cases of obstetric emergencies demanding prompt intervention. Emergency cesarean sections are classified into stable, urgent and immediate surgeries, although there is significant overlap between three groups. Stable emergency cesarean sections are performed in patients with stable maternal and fetal physiology, but who need surgery before unstability occurs. Urgent cesarean sections refer to situations in which maternal and/or fetal physiology is unstable, whereas the immediate cesarean section is used for life-threatening condition such as sustained fetal bradycardia, maternal cardiopulmonary arrest. In most cases the key to proper management is the prompt communication between obstetricians and anesthesiologists. Anesthesiologists must have a clear understanding of certain obstetric emergencies. In the event of sustained fetal bradycardia caused by placental abruption, cord prolapse, uterine rupture etc, delivery by immediate cesarean section within 25 minutes improve long-term neonatal neurologic outcome. Although cardiopulmonary arrest in pregnancy is very uncommon, peripartum cesarean section should be considered within 5 minutes not only for maternal resuscitation but for neonatal survival. Only a well-coordinated teamwork of all involved specialities will guarantee optimal prognosis of mother and fetus.

The inducible prostaglandin E synthase mPGES-1 regulates growth of endometrial tissues and angiogenesis in a mouse implantation model.

Endometriosis is one of the most common gynecological diseases in women of reproductive age. Although cyclooxygenase (COX)-2 inhibitors are effective in the treatment of endometriosis, the adverse cardiovascular effects associated with these inhibitors have limited their use. Microsomal prostaglandin E synthase-1 (mPGES-1) is an inducible enzyme downstream of COX-2 in prostaglandin E(2) biosynthesis. Previously, we developed mPGES-1 knockout mice (mPGES-1(-/-)) and have identified for the first time the roles of ectopic lesion- and host-associated mPGES-1 in angiogenesis and the growth of endometrial tissues. When mPGES-1(-/-) endometrial fragments were implanted into wild type (WT) mice (mPGES-1(-/-)→WT), or WT fragments implanted into mPGES-1(-/-) mice (WT→mPGES-1(-/-)), the growth of the implants was suppressed at days 14 and 28 after implantation, compared toWT→WT transplantation. An even greater degree of suppression was observed in mPGES-1(-/-) endometrial fragments implanted into mPGES-1(-/-) mice (mPGES-1(-/-)→mPGES-1(-/-)). After WT-WT implantation, mPGES-1 expression was localized at the border of the implanted endometrial tissues. Microvessel density, determined by CD31 immunostaining, was markedly suppressed in the mPGES-1(-/-) endometrial fragments implanted into mPGES-1(-/-) mice, with some suppression also observed in the mPGES-1(-/-)→WT and WT→mPGES-1(-/-) groups. The expression of vascular endothelial growth factor (VEGF-A) was significantly reduced in mPGES-1(-/-) endometrial tissues implanted into mPGES-1(-/-) mice at days 14 and 28, in comparison to the WT→WT group. These results suggested that mPGES-1 enhanced angiogenesis and growth of the endometrial implant, and indicate that mPGES-1 may be a good therapeutic target for endometriosis.

Clinical significance of human papillomavirus genotype by linear array assay in Japanese women with uterine cervical lesions and type 16 physical status by in situ hybridization.

The aim of this study was to clarify the relation of human papillomavirus (HPV) genotypes and physical status in the cervical neoplasm of Japanese patients with the grade of the disease. Human papillomavirus genotype was detected using a linear array genotyping assay. Human papillomavirus status, diffuse or punctate signal pattern, was studied by biotynyl-tyramide-based in situ hybridization for positive cases of HPV-16. Human papillomavirus types 16, 52, 58, and 31, in descending order of frequency, were prevalent. The rates of HPV infection in patients with cervical intraepithelial neoplasia (CIN) or squamous cell carcinoma (SCC) were significantly higher than those in patients without cervical lesions. The frequency of HPV single infection in SCC was higher than that in CIN1 or CIN2. In an unspecified-risk HPV, types 66 and 70 were found in SCC and 62, 71, and 82 were detected in CIN3. The diffuse pattern was more frequent in CIN, and the punctate pattern was more frequent in SCC. Human papillomavirus types 16, 52, 58, and 31 were frequently detected in Japanese women with cervical neoplasias, and several unspecified-risk HPVs might be high-risk types. A single infection of HPV and a punctate signal pattern seemed to be closely correlated with cervical carcinogenesis.

Abscopal effect of radiation on toruliform para-aortic lymph node metastases of advanced uterine cervical carcinoma--a case report.

The case of a 69-year-old woman with advanced uterine cervical carcinoma with toruliform para-aortic lymph node metastases that showed an abscopal effect of radiation therapy (effect out of irradiated field) is reported. The patient was admitted to our University Hospital in March 2005, and treated with radiation therapy only for the primary pelvic lesions without chemotherapy because of her severe economic status. After the treatment, not only did the cervical tumor in the irradiated field disappear, but the toruliform para-aortic lymph node swelling outside the irradiated field also spontaneously disappeared. The patient is still alive and well without relapse. This case is the first clinical demonstration of an abscopal effect in advanced uterine cervical carcinoma.

Phase II study of radiation therapy combined with weekly nedaplatin in locally advanced uterine cervical carcinoma: Kitasato Gynecologic Radiation Oncology Group (KGROG 0501).

In order to evaluate the safety and efficacy of chemoradiotherapy using nedaplatin for locally advanced uterine cervical carcinoma in Japanese patients, we have started a single-institute phase II trial. Eligibility criteria include: (i) pathologically proven squamous cell carcinoma or adenocarcinoma, (ii) clinical FIGO stage Ib, IIa, or IIb with bulky tumor (> 40 mm) or pelvic lymph node swelling, or (iii) clinical FIGO stage IIIa, IIIb and IVa, (iv) no para-aortic lymph node swelling. A combination of external beam radiation and high dose rate intracavitary irradiation is given. Nedaplatin (30 mg/m2) is intravenously infused on a weekly basis for five times. The primary endpoint is 3-year overall survival, and the secondary endpoints are tumor response, 2-year overall survival, 3-year progression-free survival, acute adverse events, protocol treatment compliance, and late adverse events. We plan to recruit 45 patients within 3 years.

Recruitment of a prostaglandin E receptor subtype, EP3-expressing bone marrow cells is crucial in wound-induced angiogenesis.

E-type prostaglandins have been reported to be proangiogenic in vivo. Thus, we examined prostaglandin receptor signaling relevant to wound-induced angiogenesis. Full-thickness skin wounds were created on the backs of mice, and angiogenesis in wound granulation tissues was estimated. Wound closure and re-epithelization in EP3 receptor knockout mice (EP3-/-) were significantly delayed compared with their wild-type (WT) mice, whereas those in EP1-/-, EP2-/-, and EP4-/- were not delayed. Wound-induced angiogenesis estimated with CD31 immunohistochemistry in EP3-/- mice was significantly inhibited compared with that in WT mice. Immunoreactive vascular endothelial growth factor (VEGF) in wound granulation tissues in EP3-/- mice was markedly less than that in WT mice. Wound closure in WT mice was delayed significantly by VEGF neutralizing antibody compared with control IgG. Wound-induced angiogenesis and wound closure were significantly suppressed in EP3-/- bone marrow transplantation mice compared with those in WT bone marrow transplantation mice. These were accompanied with the reductions in accumulation of VEGF-expressing cells in wound granulation tissues and in mobilization of VEGF receptor 1-expressing leukocytes in peripheral circulation. These results indicate that the recruitment of EP3-expressing cells to wound granulation tissues is critical for surgical wound healing and angiogenesis via up-regulation of VEGF.

Regulation of membrane-associated prostaglandin E2 synthase 1 in pregnant sheep intrauterine tissues by glucocorticoid and estradiol.

This study was designed to determine the regulatory effect of glucocorticoid and estradiol on expression of ovine intrauterine membrane-associated prostaglandin E(2) synthase 1 (mPTGES1) in late gestation and at labor. For gestational and labor groups, 16 pregnant ewes from 95-147 d gestational age (dGA) and four pregnant ewes at spontaneous term labor were used. The fetal glucocorticoid group, 14 pregnant ewes at 123-125 dGA with fetuses, was divided into the following groups: after sham adrenalectomy (n = 5), adrenalectomy (n = 4), and adrenalectomy with fetal cortisol replacement to late gestation levels (n = 5). For the maternal glucocorticoid group, nine pregnant ewes were treated with saline (n = 4) and three courses of maternal dexamethasone (n = 5). For the estradiol group, 10 pregnant ewes at 119-121 dGA were treated with sesame oil (n = 5) or estradiol (n = 5) to produce labor levels of estradiol in maternal plasma. Endometrial, myometrial, and placental mRNA and proteins were analyzed by Northern and Western blot and immunocytochemistry for mPTGES1. Data were analyzed by Student's t test and ANOVA. There was a significant increase of placental mPTGES1 in late gestation. Glucocorticoids, given to the mother or fetus, significantly stimulated mPTGES1 in placenta. mPTGES1 was elevated only in the endometrium during spontaneous term labor and after estradiol treatment. The mPTGES1 was localized in the myometrial smooth muscle cells, endometrial stromal cells, and placental trophoblast cells. Our study suggested that increased expression of placental mPTGES1 throughout late gestation might result from the increased fetal and maternal circulating glucocorticoids, whereas elevated maternal plasma estradiol concentration might be responsible for the induced mPTGES1 expression in the endometrium during labor.