Efficacy and safety of controlled-release dinoprostone vaginal delivery system (PROPESS) in Japanese pregnant women requiring cervical ripening: Results from a multicenter, randomized, double-blind, placebo-controlled phase III study.

AIM: To evaluate the efficacy and safety of dinoprostone vaginal insert (PROPESS) in pregnant post-term Japanese women requiring cervical ripening. METHODS: This randomized, double-blind, placebo-controlled study included 114 pregnant Japanese women at term (41 weeks of gestation) requiring cervical ripening (baseline Bishop score (BS) ≤ 4). The primary end-point was the proportion of subjects with successful cervical ripening defined as BS ≥ 7 or vaginal delivery in 12 h. The secondary end-points were changes in BS, proportion of women with vaginal delivery, proportion of women receiving mechanical cervical ripening procedure and use of oxytocic drugs. RESULTS: PROPESS administration for a maximum of 12 h showed significantly higher successful cervical ripening rate (47.4% vs 14.3%, respectively; treatment contrast [TC]: 33.1%; P = 0.0002). The median time from administration to vaginal delivery was significantly shorter in the PROPESS group than in the placebo group (26.18 h vs 33.02 h; OR 2.51; 95% CI [1.60-3.92]; P < 0.0001). In the PROPESS group, the dosage of uterotonic drugs, such as oxytocin, decreased, and the number of patients who used these drugs also decreased. CONCLUSION: PROPESS administration for a maximum of 12 h was an effective and well-tolerated treatment for pregnant Japanese women post-term requiring cervical ripening.

Dynamics of effector and naïve Regulatory T cells throughout pregnancy.

Regulatory T (Treg) cells are a specialized subset of T cells possessing immunosuppressive functions indispensable for the maintenance of self-tolerance and pregnancy. However, how functional Treg cells dynamically change and are engaged in feto-maternal tolerance during human pregnancy is still unclear. Recent studies have shown that functionally distinct and immunosuppressive subsets of Treg cells, i.e., effector Treg (eTreg) and naïve Treg (nTreg) cells, can be delineated by combinations of molecular markers and that their proportions differ in normal and disease states. In this study, we examined how the proportion of eTreg and nTreg cells in peripheral blood changes in the 1st, 2nd, and 3rd trimesters of pregnancy and the postpartum period. During the 2nd trimester the proportion of eTreg cells was reduced while nTreg cells was increased. This pattern was maintained throughout the 3rd trimester of pregnancy. The kinetics of eTreg reduction highly correlated with migration of eTreg cells into feto-maternal interface while stable nTreg proportion paralleled with their expression of the anti-apoptotic molecule Bcl-2 and production of thymic emigrant naïve Treg cells. These results suggest that further studies on divergence of functional Treg proportions will be helpful for predicting instability of pregnancy.

Tyrosine kinase inhibitor imatinib augments tumor immunity by depleting effector regulatory T cells.

This report addresses whether small molecules can deplete FoxP3-expressing regulatory T (T reg) cells, thereby augmenting antitumor immunity. Imatinib, a tyrosine kinase inhibitor of oncogenic BCR-ABL protein expressed by chronic myelogenous leukemia (CML) cells, possesses off-targets including LCK expressed in T cells. We showed that imatinib-treated CML patients in complete molecular remission (CMR) exhibited selective depletion of effector T reg (eT reg) cells and significant increase in effector/memory CD8+ T cells while non-CMR patients did not. Imatinib at CML-therapeutic concentrations indeed induced apoptosis specifically in eT reg cells and expanded tumor antigen-specific CD8+ T cells in vitro in healthy individuals and melanoma patients, and suppressed colon tumor growth in vivo in mice. Mechanistically, because of FoxP3-dependent much lower expression of LCK and ZAP-70 in T reg cells compared with other T cells, imatinib inhibition of LCK further reduced their TCR signal intensity, rendering them selectively susceptible to signal-deprived apoptotis. Taken together, eT reg cell depletion by imatinib is instrumental in evoking effective immune responses to various cancers.

Are naïve T cells and class-switched memory (IgD- CD27+) B cells not essential for establishment and maintenance of pregnancy? Insights from a case of common variable immunodeficiency with pregnancy.

The disruption of adaptive immune response has adverse effects on the establishment and maintenance of pregnancy. The adaptive immune system is regulated by several types of immune cells. However, there is limited information about cell hierarchy in the adaptive immune response to the establishment and maintenance of pregnancy in women. The assessment of the outcome of pregnancy in primary immunodeficiency diseases could help in understanding the cell hierarchy in the adaptive immune system during pregnancy. Common variable immunodeficiency (CVID) is a heterogeneous adaptive immune system disorder characterized by primary hypogammaglobulinemia. A few studies have previously reported the assessment of the T and B cell subpopulations in CVID patients. However, an assessment of the subpopulations of T and B cells and the outcome of pregnancy in women with CVID has not been reported till date. Most CVID patients show a general decrease in the expression of CD27 in B cells. The assessment of pregnancy and the subpopulations of T and B cells in CVID women with severe reduction in the naïve T and switched B cells could help understand whether these cells are essential for the establishment and maintenance of pregnancy in women.

Severe micrognathia with 21 trisomy assessed prenatally by performing three-dimensional computed tomography.

Severe micrognathia can lead to death shortly after birth without a proper resuscitation. However, it is difficult to develop an effective resuscitation strategy without a prenatal diagnosis of the severity of micrognathia. In the present case, we used fetal three-dimensional computed tomography (3D-CT) to assess the severity of micrognathia. Its images clearly demonstrated bony framework of mandible and suggested that mandibular hypoplasia was too severe to allow for oral intubation. We therefore decided that the ex utero intrapartum treatment (EXIT) procedure would be more appropriate to establish the airway at birth. The prenatal 3D-CT is useful to evaluate the mandibular anatomy in utero if the severity of the micrognathia is not confirmed by the ultrasound or magnetic resonance imaging (MRI).

Laparoscopic excisional surgery for growing teratoma syndrome of the ovary: case report and literature review.

Growing teratoma syndrome (GTS) is rare clinical phenomenon occurring as a sequelae of a malignant germ cell tumor. We present the case of a 20-year-old woman who developed GTS after undergoing fertility-sparing surgery and chemotherapy for an immature teratoma. She underwent left salpingo-oophorectomy, right ovarian cystectomy, and disseminated tumor reduction during her primary surgery. The postsurgical histology report identified the tumor as an immature teratoma, grade 3, International Federation of Gynecology and Obstetrics (FIGO) stage IIIb. She subsequently received 3 cycles of chemotherapy consisting of bleomycin, etoposide, and cisplatin. At 17 months after the chemotherapy, follow-up computed tomography (CT) scan revealed an enlarged mass in her right paracolic gutter and a small peritoneal lesion in the pouch of Douglas. Her serum alpha-fetoprotein level was not elevated. These findings were compatible with GTS, but it was difficult to rule out a recurrent immature teratoma. Diagnostic exploratory laparoscopic surgery revealed the enlarged tumors that had been detected by the CT scan. Although there were multiple tumors in the pouch of Douglas, we were able to resect all of them laparoscopically. Histological diagnosis of the surgically resected specimens was of a mature teratoma, and so we concluded that this tumor was a GTS. Our experience suggests that laparoscopic surgery is an effective alternative diagnostic and therapeutic approach in cases suspicious of GTS where the disease is disseminated to the peritoneum.

Clear cell adenocarcinoma of the peritoneum: a case report and literature review.

Clear cell adenocarcinoma (CCC) is generally thought to originate from ovarian, endometrial, or renal tissue. A CCC of the peritoneum (CCAP) is an extremely rare medical condition and is associated with a poor prognosis. To date, only 10 cases of CCAP have been reported, of which half resulted in death or recurrence within 6 months after initial treatment because CCAP is commonly resistant to multiple drugs. In this report, we present a case of CCAP of the pouch of Douglas coexisting with an endometriosis and we offer a review of the related literature.

An Arthrobacter spp. bacteremia leading to fetal death and maternal disseminated intravascular coagulation.

A 34-year-old parous woman developed high fever and threatened preterm labor after a 1-day trip, for which she was receiving prenatal care at a hospital. Three days after onset, at 24 4/7 weeks of gestation, she was transferred to our hospital in an emergency. Soon after the woman's arrival at our hospital, the infant was spontaneously stillborn via a transvaginal delivery. Laboratory tests revealed severe maternal disseminated intravascular coagulation with renal and liver insufficiency. Histopathologic examination of the placenta revealed vast fibrin deposition and remarkable neutrophilic infiltration in the intervillous space, suggesting a rare bacterial infection caused by Arthrobacter spp. The bacteria were predominantly detected in the placenta and maternal blood serum by common bacterial 16S rRNA sequencing after polymerase chain reaction amplification. We report the first case, to our knowledge, of bacteremia with Arthrobacter spp., which may lead to maternal disseminated intravascular coagulation and intrauterine fetal death.

A large retroperitoneal cystic venous malformation mimicking bilateral ovarian cystic tumors.

INTRODUCTION: Retroperitoneal cysts are a rare disease. Most retroperitoneal cysts of vascular origin have been reported as hemangiomas. However, according to the recent classification of vascular anomalies accepted by the International Society for Study of Vascular Anomalies (ISSVA), these previously reported retroperitoneal hemangiomas should rather have been classified as vascular malformations. CASE REPORT: A 65-year-old woman visited our hospital complaining of a sense of unexplained abdominal fullness. Magnetic resonance imaging suggested a uterine leiomyoma and bilateral ovarian cystic tumors. However, abdominal surgery revealed normal bilateral ovaries, but huge cystic masses in the retroperitoneum. Postoperative histological diagnosis of the retroperitoneal cysts demonstrated that they were venous malformations. CONCLUSION: This is a rare case in which large cystic retroperitoneal venous malformations were preoperatively diagnosed as ovarian cystic tumors. Retroperitoneal hemangiomas should be renamed as vascular malformations following the ISSVA classification.