Spontaneously Resolved Suspected Hemophagocytic Lymphohistiocytosis or Macrophage Activating Syndrome Associated with Neonatal Lupus Erythematosus: A Case Report.

OBJECTIVES: To present a rare case of neonatal lupus erythematosus (NLE) associated with suspected hemophagocytic lymphohistiocytosis (HLH) or macrophage activation syndrome (MAS). CASE PRESENTATION: A female infant weighing 2,995 g was born to a mother without medical history of any disease. At birth, the patient had erythematous papules on her face and trunk. She was admitted at 1 day of age with elevated C-reactive protein levels. The patient was diagnosed with NLE based on the presence of anti-Ro/SSA and anti-La/SSB antibodies. Thereafter, it became clear that the antibody levels in her mother were also elevated. At 20 days of age, the infant showed elevated transaminases, ferritin, triglyceride, and soluble interleukin-2 receptor levels. Although HLH or MAS was suspected, she did not fulfill the diagnostic criteria. Thereafter, these abnormal values spontaneously improved, and the skin rash improved with the use of topical steroids. The patient was discharged at 39 days of age. At 1 year of age, the patient's growth and development were normal. CONCLUSION: NLE should be considered in infants with an unexplained skin rash at birth. When a diagnosis is made, close observation of the infant's clinical features is needed to determine whether they will develop HLH or MAS.

Downregulation of SPARC Expression Enhances the Fusion of BeWo Choriocarcinoma Cells.

Syncytiotrophoblasts, which are formed by the fusion of villous cytotrophoblasts, play an essential role in maintaining a successful pregnancy. Secreted protein acidic and rich in cysteine (SPARC) is a non-structural Ca2+-binding extracellular matrix glycoprotein involved in tissue remodeling and cell proliferation, differentiation, and migration. Previous studies have revealed that SPARC is expressed in villous and extravillous cytotrophoblasts in the first trimester and that RNA interference targeted at SPARC significantly inhibited invasion of human extravillous trophoblast HTR8/SVneo cells. However, the involvement of SPARC in cytotrophoblast fusion remains unknown. This study aimed to investigate the role of SPARC in cytotrophoblast fusion, using the BeWo choriocarcinoma cell line as a model of villous cytotrophoblasts. Immunohistochemical analysis was conducted to assess SPARC expression in normal human placentas using placental tissues obtained during the first and third trimesters of pregnancy. We investigated the effects of SPARC knockdown on trophoblast differentiation markers and cell fusion in BeWo cells using small interfering RNA. Immunohistochemical analysis revealed that SPARC expression was high in the early gestational chorionic villi and low in the late gestational chorionic villi. SPARC knockdown increased the expressions of human chorionic gonadotropin and Ovo-like transcriptional repressor 1; however, glial cells missing transcription factor 1, syncytin-1, and syncytin-2 showed no significant changes. The assessment revealed that SPARC knockdown significantly enhanced cell fusion compared to the non-silencing control. Our data suggest that SPARC plays a vital role in regulating trophoblast fusion and differentiation during placental development.

Liposome-encapsulated progesterone efficiently suppresses B-lineage cell proliferation.

Progesterone suppresses several ancient pathways in a concentration-dependent manner. Based on these characteristics, progesterone is considered a candidate anticancer drug. However, the concentration of progesterone used for therapy should be higher than the physiological concentration, which makes it difficult to develop progesterone-based anticancer drugs. We previously developed liposome-encapsulated progesterone (Lipo-P4) with enhanced anticancer effects, which strongly suppressed triple-negative breast cancer cell proliferation in humanized mice. In this study, we aimed to clarify whether Lipo-P4 effectively suppresses the proliferation of B-lineage cancer cells. We selected six B-cell lymphoma and two myeloma cell lines, and analyzed their surface markers using flow cytometry. Next, we prepared liposome-encapsulated progesterone and examined its effect on cell proliferation in these B-lineage cancer cells, three ovarian clear cell carcinoma cell lines, two prostate carcinoma cell lines, and one triple-negative breast cancer adenocarcinoma cell line. Lipo-P4 suppressed the proliferation of all cancer cell lines. All B-lineage cell lines, except for the HT line, were more susceptible than the other cell types, regardless of the expression of differentiation markers. Empty liposomes did not suppress cell proliferation. These results suggest that progesterone encapsulated in liposomes efficiently inhibits the proliferation of B-lineage cells and may become an anticancer drug candidate for B-lineage cancers.

Construction of the systemic anticancer immune environment in tumour-bearing humanized mouse by using liposome-encapsulated anti-programmed death ligand 1 antibody-conjugated progesterone.

Immune checkpoint inhibitors highlight the importance of anticancer immunity. However, their clinical utility and safety are limited by the low response rates and adverse effects. We focused on progesterone (P4), a hormone produced by the placenta during pregnancy, because it has multiple biological activities related to anticancer and immune regulation effects. P4 has a reversible immune regulatory function distinct from that of the stress hormone cortisol, which may drive irreversible immune suppression that promotes T cell exhaustion and apoptosis in patients with cancer. Because the anticancer effect of P4 is induced at higher than physiological concentrations, we aimed to develop a new anticancer drug by encapsulating P4 in liposomes. In this study, we prepared liposome-encapsulated anti-programmed death ligand 1 (PD-L1) antibody-conjugated P4 (Lipo-anti-PD-L1-P4) and evaluated the effects on the growth of MDA-MB-231 cells, a PD-L1-expressing triple-negative breast cancer cell line, in vitro and in NOG-hIL-4-Tg mice transplanted with human peripheral blood mononuclear cells (humanized mice). Lipo-anti-PD-L1-P4 at physiological concentrations reduced T cell exhaustion and proliferation of MDA-MB-231 in vitro. Humanized mice bearing MDA-MB-231 cells expressing PD-L1 showed suppressed tumor growth and peripheral tissue inflammation. The proportion of B cells and CD4+ T cells decreased, whereas the proportion of CD8+ T cells increased in Lipo-anti-PD-L1-P4-administrated mice spleens and tumor-infiltrated lymphocytes. Our results suggested that Lipo-anti-PD-L1-P4 establishes a systemic anticancer immune environment with minimal toxicity. Thus, the use of P4 as an anticancer drug may represent a new strategy for cancer treatment.

High-progesterone environment preserves T cell competency by evading glucocorticoid effects on immune regulation.

Progesterone (P4) and glucocorticoid (GC) play crucial roles in the immunoregulation of a mother to accept and maintain a semi-allogenic fetus. P4 concentration increases during pregnancy and becomes much higher in the placenta than in the other peripheral tissues, wherein the concentration of cortisol (COR), the most abundant GC and a strong immunosuppressor, remains uniform throughout the rest of the body. Here, we evaluated the effect of a high-P4 environment on pregnant immunity by comparing it with COR. Naïve T cell proportion increased transiently in peripheral blood of pregnant women just after delivery and decreased after one month. T cells stimulated with superantigen toxic-shock-syndrome-1 (TSST-1) in the presence of P4 stayed in the naïve state and did not increase, irrespective of the presence of COR, and reactive T cells could not survive. Treatment of T cells with P4 without T cell receptor (TCR) stimulation transiently suppressed T cell activation and proliferation, whereas the levels remain unaltered if P4 was not given before stimulation. Comparison of the engraftment and response against specific antigens using hu-PBL-NOG-hIL-4-Tg mice showed that P4-pretreated lymphocytes preserved CD62L expression and engrafted effectively in the spleen. Moreover, they produced antigen-specific antibodies, whereas COR-pretreated lymphocytes did not. These results suggest that a high-P4 environment suppresses T cell activation and induces T cell migration into lymphoid tissues, where they maintain the ability to produce anti-pathogen antibodies, whereas COR does not preserve T cell function. The mechanism may be pivotal in maintaining non-fetus-specific T cell function in pregnancy.

Tips and Techniques for Laparoscopic Tubal Reanastomosis: A Case Report.

Tubal reanastomosis or tubal reversal, a surgical method used to reverse tubal sterilization, may be an option for women who for various reasons wish to reestablish their fertility. A 38-year-old Chinese woman, gravida 2, para 2 (both delivered through cesarean section) presented to our outpatient gynecology clinic requesting bilateral tubal recanalization. After other causes of infertility were excluded, laparoscopic tubal reanastomosis was performed. Here, we present our tips and techniques for laparoscopic tubal reanastomosis that rapidly resulted in an intrauterine pregnancy, which delivered at term. Laparoscopic tubal reanastomosis is a well-established procedure with good prognosis, as reported in the literature. For women who wish to become pregnant after tubal sterilization, it is necessary to present the option of surgery as well as in vitro fertilization.

Hypoxia-inducible Factor-1α Suppression in Ovarian Clear-cell Carcinoma Cells by Silibinin Administration.

BACKGROUND/AIM: Advanced ovarian clear-cell carcinoma (CCC) fails to respond to standard chemotherapy, and has a poor prognosis. Since hypoxia-inducible factor-1 (HIF-1) stimulates various genes involved in cancer, we aimed to examine the efficacy of silibinin, an active component of milk thistle belonging to Asteraceae, in suppressing HIF-1 activity, and elucidate the underlying mechanism in human CCC cell lines. MATERIALS AND METHODS: Human ovarian CCC cell lines HAC-2, OVISE, and RMG-1 were treated with 500 µM silibinin for 4 h under normoxic and hypoxic conditions. Using DNA microarray, we analysed genes whose expression modulated more than 2-fold in response to hypoxia, whereas HIF-1α expression was measured using ELISA. RESULTS: Silibinin treatment decreased HIF-1α protein in all cell lines, and eIF4E2 and RPS6 mRNA in HAC-2 and RMG-1 cells. CONCLUSION: Silibinin suppressed HIF-1α protein under hypoxic conditions in CCC cell lines and could be a potential anti-cancer drug.

Acquired Factor XI Deficiency with Lupus Anticoagulant in a Pregnant Woman Diagnosed by the Eruptions and Pain in Fingers.

We report a case of acquired factor XI deficiency with lupus anticoagulant (LA) in a 28-year-old primigravida who presented with finger pain and eruptions on her palms and fingers during the 3rd trimester of pregnancy. The patient complained of pain and reddening of the fingers at 30 weeks of gestation. She was referred to our tertiary center with a diagnosis of preeclampsia and suspected collagen disease at 35 weeks of gestation. Erythema was seen on the fingers and palms, and she presented with pain and cryesthesia on the fingers. Laboratory investigations revealed an activated partial thromboplastin time of 51 s (normal, 23-40 s), although it was normal during the 30th and 34th gestational weeks, LA with an anticardiolipin-beta2-glycoprotein I complex antibody, and low level of clotting XI activity (25 U/mL). On week 37 day 0 of gestation, the patient presented with severe hypertension. An urgent Cesarean section was performed after transfusion of two units of fresh frozen plasma. There was no excessive bleeding during the surgery or the postpartum period. The symptoms on her fingers and palms gradually improved after surgery. Our case indicates that dermatoses of pregnancy may become a starting point for the diagnosis of autoimmune diseases and coagulation abnormalities. When a patient presents with an atypical symptom, as in our case, the possibility of various diseases should be considered.

Retrospective Study of Collection Methods in Laparoscopic Myomectomy.

INTRODUCTION: After a FDA recommendation in April 2014, power morcellation (PM) in laparoscopic myomectomy (LM) has become less common. We now collect a myoma using manual morcellation (MM) from a wound in the umbilical region. In this study, we compared the PM and MM methods. METHODS: The subjects were 69 patients who underwent LM from April 2013 to March 2016 using PM (n = 37) or MM (n = 32). With PM, the myoma was collected using a 4-hole 12-mm parallel trocar in the left lower abdomen. Using MM, an EZ ACCESSTM (2-cm skin incision) was placed on the umbilical region, and the myoma was put in a collection purse and guided into the access hole for MM using scissors under direct vision. RESULTS: None required allogeneic transfusion or a transition to open surgery, and had surgical or post surgical complications. At multiple linear regression analysis, which was adjusted by age, body mass index, and intraoperative blood loss, significant difference was not observed in operation time between the PM and MM groups. CONCLUSION: Manual morcellation was found to be a safe method for collection of myoma that prevents scattering of tissues and does not prolong the operation time.

Atypical Presentation of Duodenal Atresia Concomitant with Type-A Esophageal Atresia in Fetal Life: A Case Report.

Duodenal atresia concomitant with type-A esophageal atresia (DA + TA-EA) is rare. A pronounced enlargement of a closed loop of the upper gastrointestinal tract serves as an early clue for its prenatal detection. We describe an atypical case of DA + TA-EA in which the dilatation of the upper gastrointestinal tract remained mild. Ultrasonographic examination at 28 weeks of gestation showed mild polyhydramnios. Subsequent detailed sonographic and magnetic resonance imaging studies revealed a mildly enlarged stomach and duodenum that resembled a "double bubble," mild ascites, and polydactyly of the right thumb. Fetal abdominal circumference measurements were within normal range. A female neonate born at 36 weeks gestation did not show abdominal distension. DA + TA-EA was diagnosed based on clinical characteristics and X-ray studies of the neonate; the diagnosis was confirmed by surgery. Duodenoduodenostomy and gastrostomy in the first week of life and esophagoesophagostomy at six months of age were performed with satisfactory results, and the infant developed well. Prominent and/or increasing C-shaped fluid collection in the upper abdomen is a highly useful diagnostic sign for DA + TA-EA, but it is not applicable for all fetuses with this disease. Physicians should bear this caveat in mind to avoid diagnostic delays and initiate prompt postnatal therapy.

A novel gene (FAM20B encoding glycosaminoglycan xylosylkinase) for neonatal short limb dysplasia resembling Desbuquois dysplasia.

Desbuquois dysplasia (DBQD) is an autosomal recessive heterogeneous disorder characterized by joint laxity and skeletal changes, including a distinctive monkey-wrench appearance of the femora, advanced carpal ossification, and abnormal patterning of the preaxial digits. Two genes for DBQD (CANT1 encoding calcium-activated nucleotidase-1 and XYLT1 encoding xylosyltransferase-1) have been reported. We propose a novel gene for neonatal short limb dysplasia resembling DBQD, based on the phenotype and genotype of two affected siblings. The affected boy and girl died in early infancy and shortly after birth, respectively. The clinical hallmarks included mid-face hypoplasia, thoracic hypoplasia with respiratory failure, very short stature (approximately -7 SD of birth length) with mesomelic shortening of the limbs, and multiple dislocations of the large joints. Radiological examinations showed prominent lesser trochanter, flared metaphyses of the long bones, and joint dislocations. The affected boy had preaxial digital hypoplasia, and the affected girl showed overlapping and syndactyly of the preaxial digits. Molecular analyses of the girl showed compound heterozygous variants in FAM20B (NM_014864: c.174_178delTACCT p.T59Afs*19/c.1038delG p.N347Mfs*4). FAM20B encodes glycosaminoglycan xylosylkinase, which acts downstream of xylosyltransferase-1. Given the fact that FAM20B deficiency causes skeletal phenotypes in mice and zebrafish, these variants are highly probable to be pathogenic.

Uterine rupture at 26 weeks of pregnancy following laparoscopic salpingectomy with resection of the interstitial portion: a case report.

Uterine rupture in pregnancy can occur in patients with a history of uterine surgery such as myomectomy and Cesarean section. Here, we report a case of spontaneous uterine rupture that occurred in the early third trimester in a pregnant woman who had previously undergone laparoscopic removal of the right fallopian tube and interstitial portion for treatment of interstitial pregnancy. The patient presented with sudden onset of abdominal pain at 26 weeks of gestation. Detailed ultrasonography and magnetic resonance imaging led to diagnosis of uterine rupture. In emergency laparotomy, the fetus was delivered by Cesarean section, the placenta and membranes were removed, and the uterus was preserved with closure of the rupture and wound. This case highlights the importance of close follow-up of a pregnant patient who has previously had a uterine incision. The case also raises the question of whether the prevalence of uterine rupture may increase as more patients are treated with laparoscopic surgery of the uterus.

Surgical management of vulvar lymphangioma circumscriptum: two case reports.

OBJECTIVE: To evaluate the efficacy of major labiaectomy as a surgical management of vulvar lymphangioma circumscriptum, we report two cases of this rare clinical entity. CASE REPORTS: Two female patients, aged 56 and 68 years, presented with persistent edema of the lower limbs, papule-like condyloma of the labia majora, and lymph oozing from these papules of the vulva, which had developed 24 and 10 years, respectively, after radical hysterectomy with adjuvant pelvic radiation therapy for cervical cancer. After major labiaectomy was performed, symptoms in the first case, of extensive resected skin margin, improved clearly, in the second case, vulvar lymphangioma circumscriptum was more severe than in the first case, and a small amount of lymph oozing occurred from residual papules of the labia majora. In both cases, histology revealed lymphangioma circumscriptum of the vulva. CONCLUSION: Major labiaectomy is an effective therapy for vulvar lymphangioma circumscriptum. Particularly, in the case which was extensive and deep resected skin margin, symptoms such as papules of the labia majora and lymph oozing from these papules of the vulva associated with lymphangioma seemed to be clearly improved.

Laparoscopic cystectomy of ovarian teratoma in anti-NMDAR encephalitis: 2 case reports.

We present 2 case reports of anti-N-methyl-d-aspartate receptor (NMDAR) encephalitis that was successfully treated via laparoscopic ovarian cystectomy. In both cases, resection of an ovarian teratoma resulted in eventual full recovery. Although adnexectomy has been reported for tumor resection in anti-NMDAR encephalitis, we chose ovarian cystectomy to preserve ovarian function. The efficacy of cystectomy is equivalent to that of adnexectomy. This suggests that ovarian adnexectomy may not be necessary in anti-NMDAR encephalitis with ovarian teratoma.

Expression of ovary-specific acidic protein in steroidogenic tissues: a possible role in steroidogenesis.

Ovary-specific acidic protein (OSAP) is a novel molecule discovered from a genomic project designed to identify ovary-selective genes in mice. Whereas public databases suggest extraovarian expression of OSAP, its tissue distribution has not yet been well documented. Thus, the expression profile of mouse and human OSAP was determined by quantitative real-time RT-PCR using RNAs isolated from various tissues. The results demonstrate that the human and mouse OSAP expression profiles are similar; OSAP is prominently expressed in steroidogenic tissues with the highest level of expression observed in the adrenal gland. Placenta served as an exception and possessed minimal level of OSAP mRNA. Immunohistochemical studies show that mouse OSAP localizes almost exclusively to the steroid-producing cells of the ovary, adrenal gland, and testis. Consistent with predictions made by several subcellular localization algorithms, dual labeling studies in Y-1 mouse adrenocortical cells indicate OSAP resides in the mitochondria. Because of its abundant expression in steroidogenic cells and mitochondrial localization, a role for OSAP in steroidogenesis was determined. OSAP silencing by specific small interfering RNAs significantly inhibits 8-bromoadenosine-cAMP-induced progesterone production in Y-1 cells. Reduction in OSAP levels results in mitochondrial fragmentation and a decrease in the cellular content of mitochondrial DNA, indicative of decreased mitochondrial abundance. Lastly, 8-bromoadenosine-cAMP does not regulate OSAP protein expression in Y-1 cells as is the case for other steroidogenic components known to be induced by cAMP. Collectively these results suggest that OSAP is involved in steroidogenesis, potentially through its ability to maintain mitochondrial abundance and morphology.

Prenatal diagnosis of retroperitoneal teratoma: a case report and review of the literature.

We report a case of retroperitoneal teratoma diagnosed prenatally by serial sonographic examinations in the third trimester. A 29-year-old woman was referred for sonographic evaluation at 33 weeks' gestation because of a fetal intra-abdominal mass. Our initial sonographic image suggested a neuroblastoma. Repeat ultrasound images demonstrated an increase in size of the tumor, while the content of the tumor became predominantly solid with areas of calcification. Teratoma should be considered on detection of any cystic or mixed semisolid mass, especially when calcification is present. The fetus was prenatally diagnosed with retroperitoneal teratoma. After birth at 39 weeks, the tumor was removed and histological analysis revealed an immature retroperitoneal teratoma. Intensive monitoring of the changes in ultrasound images of the tumor should provide ground for a precise antenatal diagnosis.

Pseudoaneurysm of the uterine artery after laparoscopic myomectomy.

OBJECTIVE: To describe a case of uterine pseudoaneurysm after laparoscopic myomectomy in a 36-year-old woman. DESIGN: Case report. SETTING: University hospital. PATIENT(S): A 36-year-old woman, 3 months after laparoscopic myomectomy, presenting with an intrauterine hypoechoic lesion measuring 5 cm in diameter. INTERVENTION(S): Uterine pseudoaneurysm was diagnosed by color Doppler ultrasound. MAIN OUTCOME MEASURE(S): Complete resolution of the pseudoaneurysm. RESULT(S): Spontaneous thrombosis was observed in the pseudoaneurysm. At 6-month follow-up, the uterus appeared normal. CONCLUSION(S): Our case presents the possibility of delayed occurrence of uterine pseudoaneurysm after laparoscopic myomectomy.

Occipital scalp hemangioma: prenatal sonographic and magnetic resonance images.

Fetal scalp hemangioma in the occipital region is extremely rare and its accurate diagnosis is essential for perinatal management. We present a case of occipital scalp hemangioma diagnosed by prenatal sonography and magnetic resonance imaging (MRI). An echogenic mass measuring 29 mm x 23 mm x 30 mm was found in the occipital region by sonography at 20 weeks of gestation. Color-flow Doppler sonography depicted vascularity only at the periphery of the mass. The MRI results indicated that the extracranial mass exhibited a heterogeneous appearance of predominantly hyperintensity on T1- and hypointensity on T2-weighted images without evidence of fat signals, suggesting a soft tissue lesion containing blood products. Based on sonographic and MRI findings, the fetus was diagnosed to have occipital scalp hemangioma. Postmortem examination revealed cavernous hemangioma with hemorrhage. The MRI was a valuable adjunct to sonography for prenatal evaluation of an occipital lesion.

The periphery of the human fetal adrenal gland is a site of angiogenesis: zonal differential expression and regulation of angiogenic factors.

CONTEXT: Although the inner fetal zone (FZ) of the mid-gestation human fetal adrenal (HFA) produces dehydroepiandrosterone sulfate, the function of the outer definitive zone (DZ) remains less clear. We have proposed that the DZ phenotype is that of a pool of progenitor cells, many of which are mitotically active. Recently, we studied HFA expression of a family of vascular endothelial cell-specific angiogenic factors, the angiopoietins (Angs), and demonstrated that Ang2 was localized predominantly in the periphery of the gland. Ang1 stabilizes, whereas Ang2 destabilizes, vessels, increasing responsiveness to angiogenic stimuli such as vascular endothelial growth factor (VEGF)-A and fibroblast growth factor (FGF)-2. OBJECTIVE: Our objective was to test the hypothesis that the periphery of the HFA is a site of angiogenesis. DESIGN: Studies were conducted involving RNA, frozen sections, and primary cell cultures from midgestation HFAs. MAIN OUTCOME MEASURES: Immunofluorescence, laser capture microdissection, and real-time quantitative RT-PCR were used. RESULTS: Double immunostaining demonstrated that proliferating endothelial cells were limited to the DZ and DZ/FZ border. Ang2 mRNA was primarily expressed in the DZ, whereas Ang1 mRNA was primarily in the FZ. VEGF-A and FGF-2 mRNA levels were higher in the DZ. FGF-2 (10 ng/ml) induced Ang2 mRNA by 4-fold in both zones of cells (P < 0.01, at 24 h), but not Ang1 or VEGF-A mRNA. CONCLUSION: Data suggest that angiogenesis occurs at the periphery of the HFA. The DZ-predominant expression of Ang2 may be explained, in part, by the parallel pattern of FGF-2 expression.

Rapid growth of malignant melanoma in pregnancy.

Malignant melanoma during pregnancy is a difficult problem as a variety of risks to both the mother and fetus must be weighed. We describe a rapidly progressive malignant melanoma diagnosed during pregnancy. There are no standarized guidelines for treatment; each case requires an individualized approach. We review the literature and present an algorithm to aid in approaching such patients.