Large-cell neuroendocrine carcinoma arising in the endometrium: A case report.

Large-cell neuroendocrine carcinoma (LCNEC) of the endometrium is an extremely rare, high-grade malignant tumor. We herein report a case of a rapidly growing LCNEC arising in the endometrium. A 52-year-old woman was referred to Toyooka Hospital (Tooyoka, Japan) due to genital bleeding in February 2016. There had been no abnormalities on a regular gynecological and physical examination 3 months prior to the consultation. Imaging (computed tomography and magnetic resonance imaging) and a pelvic examination revealed a tumor sized 16.9×8.4×7.8 mm occupying the intrauterine cavity and extending into the vaginal cavity. Multiple metastatic pelvic and paraaortic lymph nodes were also identified. Continuous bleeding from the tumor was observed, and a blood examination revealed anemia, which was likely due to that bleeding. Biopsy of the tumor was performed, and large atypical cells were identified. The tumor cells were negative for cytokeratin AE1/AE3 and chromogranin A, but positive for CD56 and synaptophysin. There was also an abundance of Ki-67-positive cells in the tumor, altogether suggesting that the tumor was an LCNEC. The patient succumbed to the disease 36 days after the first consultation. Based on the findings of the present case and previously published cases, LCNECs arising in the endometrium may progress rapidly and are associated with an unfavourable outcome. LCNEC should be included in the differential diagnosis in cases of rapidly growing tumors of the uterine corpus.

Exchange of intraoperative balloon occlusion of the internal iliac artery for the common iliac artery during cesarean hysterectomy in a patient with placenta percreta.

PATIENT: Female, 36 FINAL DIAGNOSIS: Pregnancy - placenta increta Symptoms: - MEDICATION: - Clinical Procedure: Cesarean hysterectomy Specialty: Obstetrics and Gynecology. OBJECTIVE: Unusual clinical course. BACKGROUND: The generally accepted treatment for placenta percreta is cesarean hysterectomy without attempts to detach the placenta. Preoperative internal iliac artery balloon occlusion (IIABO) has been widely performed to minimize blood loss during cesarean hysterectomy for an abnormal attachment of the placenta. Our case is the first reported case of common iliac artery balloon occlusion (CIABO) being more effective than IIABO for reducing blood loss during a cesarean hysterectomy in the same patient. CASE REPORT: We performed cesarean hysterectomy with IIABO in a 36-year-old Japanese female who had placenta percreta. However, there was still a large amount of blood loss. We immediately changed the balloon from the internal iliac artery to the common iliac artery, which visibly reduced the amount of blood loss. We finally achieved cesarean hysterectomy. CONCLUSIONS: CIABO was found to be more effective than IIABO for reducing blood loss during cesarean hysterectomy. Failure of IIABO can be explained by the presence of extensive anastomoses in the pelvic vasculature.

Serial magnetic resonance imaging of placenta percreta with bladder involvement during pregnancy and postpartum: a case report.

Whether to manage placenta previa percreta surgically or conservatively has been a controversial issue. A 30-year-old woman with placenta percreta with bladder involvement was treated conservatively. A planned cesarean section was performed at 33 weeks' gestation. A 1768-g female infant was delivered through a transverse fundal uterine incision with the placenta left inside the uterus. The following morning, a massive postpartum hemorrhage occurred, and was successfully treated with transarterial embolization. The placenta was never expelled and spontaneously disappeared 4 months after surgery. We demonstrate serial magnetic resonance imaging of the placenta percreta during pregnancy and the postpartum period.

Deciduosis can cause remarkable leukocytosis and obscure abdominal pain.

Remarkable leukocytosis with obscure abdominal pain during pregnancy is clinically challenging for obstetricians. A 31-year-old pregnant woman developed persistently elevated white blood cell (approximately 30 000/µL) and C-reactive protein (3.0 mg/dL) with occasional moderate abdominal pain. At 29 gestational weeks, she underwent emergency cesarean section due to suspected abruptio placentae. Hemoperitoneum was observed with extensive hemorrhagic nodules on the peritoneal and omental surfaces. White blood cells rose 87200/µL, and C-reactive protein peaked at 44.9mg/dL after surgery. Pathologically, biopsies showed deciduosis, and decidual cells on the omental surface showed immunohistochemical staining for granulocyte colony-stimulating factor (G-CSF). Serum G-CSF concentration was 339 pg/mL at 28 weeks, and that of ascites was 312 000 pg/mL at cesarean section. G-CSF-producing deciduosis can induce leukocytosis as well as abdominal pain during pregnancy and postpartum.

Advanced papillary serous carcinoma of the uterine cervix: a case with a remarkable response to paclitaxel and carboplatin combination chemotherapy.

Papillary serous carcinoma of the uterine cervix (PSCC) is a very rare, recently described variant of cervical adenocarcinoma. This review, describes a case of stage IV PSCC whose main tumor existed in the uterine cervix and invaded one third of the inferior part of the anterior and posterior vaginal walls. Furthermore, it had metastasized from the para-aortic lymph nodes to bilateral neck lymph nodes. Immnoreactivity for CA125 was positive, whereas the staining for p53 and WT-1 were negative in both the original tumor and the metastatic lymph nodes. Six cycles of paclitaxel and carboplatin combination chemotherapy were administered and the PSCC dramatically decreased in size. The main tumor of the uterine cervix showed a complete response by magnetic resonance imaging (MRI), and on rebiopsy, more than 95% of the tumor cells in the cervix had microscopically disapperared. This is the first report of PSCC in which combination chemotherapy was used and showed a remarkable response.

Management of fetal death with placenta previa.

Management of second- and third-trimester fetal death in the presence of placenta previa is a dilemma for obstetricians. We herein describe a case of fetal death occurring at 23 weeks' gestation in the presence of placenta previa. Three weeks of expectant management failed to reduce uteroplacental blood perfusion evaluated with pulsatility index of the uterine artery. Labor was then induced with gemeprost vaginal pessary following overnight laminaria pretreatment. Vaginal delivery was achieved with total blood loss of 1900 ml. Homologous blood transfusion was obviated owing to autologous blood that had been stored during the waiting period.

Secondary postpartum hemorrhage due to uterine artery pseudoaneurysm rupture in von Willebrand disease.

We here report a case of a 33-year-old woman who experienced secondary postpartum hemorrhage (PPH) due to uterine artery pseudoaneurysm rupture. She had intrauterine balloon tamponade for unexplained primary PPH after spontaneous vaginal delivery, and subsequent angiography showed no abnormal contrast extravasation. However, profuse vaginal bleeding occurred 22 days postpartum. Color Doppler ultrasonography demonstrated an anechoic mass with turbulent flow in the lower uterine segment, corresponding to uterine artery pseudoaneurysm. She was successfully treated with selective uterine arterial embolization. Decreased levels of von Willebrand factor and factor VIII led to the diagnosis of von Willebrand disease. When it is determined that a patient has unexplained PPH or uterine artery pseudoaneurysm, a high index of suspicion and further investigation for underlying bleeding disorders is warranted.

Disseminated intravascular coagulation as the presenting sign of gastric cancer during pregnancy.

Gastric cancer during pregnancy is rare and the outcome is generally poor. A 36-year-old woman in the 28th week of gestation was complicated with disseminated intravascular coagulation (DIC), and she was diagnosed with gastric cancer with bone marrow metastasis. Cesarean delivery followed by sequential methotrexate (100 mg/m2) and 5-fluorouracil (600 mg/m2) chemotherapy was conducted. DIC was successfully managed with blood transfusion and chemotherapy. She has received chemotherapy in the outpatient clinic. This report is the second case of a pregnant woman with DIC as the initial manifestation of advanced gastric cancer. Prompt diagnosis and chemotherapy increases the chances of a relatively favorable outcome even in advanced gastric cancer presenting with DIC due to bone marrow involvement.

Prenatal findings in congenital leukemia: a case report.

We here describe a case of congenital leukemia that ended in intrauterine fetal demise at 30 weeks of gestation. Acute enlargement of the fetal trunk, elevated pulsatility index of the umbilical artery with concomitant decline of pulsatility index of the middle cerebral artery, pleural effusion, and polyhydramnios preceded the fetal death. Diagnosis of congenital myeloid leukemia was suggested by microscopic examination of the placental tissue, revealing immature myeloid precursors filling the lumina of fetal vessels in the umbilical cord and chorionic villi. Extensive vascular involvement of the placenta by leukemic cells was considered to be a primary cause of the fetal death.

Management of retained products of conception with marked vascularity.

Cases of retained products of conception (RPOC) with marked vascularity present a clinical challenge because simple dilation and curettage (D&C) can lead to life-threatening hemorrhage. We describe here two cases of hypervascular RPOC that were successfully managed with two different approaches. Case 1: A 26-year-old woman with history of 3 D&Cs was transported to the emergency room for heavy vaginal bleeding 45 days after a spontaneous abortion. Diagnosis of RPOC with aneurysm-like structure was considered and uterine artery embolization was performed. Four days after the uterine artery embolization, reduction of the vascularity of RPOC was confirmed on color Doppler ultrasonography and D&C was successfully carried out. Case 2: A 37-year-old woman with history of one cesarean section became pregnant after the regular menses. She underwent D&C for missed abortion at 8 weeks' gestation. Seven days after the D&C, sonographically heterogenous mass emerged in the vicinity of the previous cesarean scar. Thereafter, the mass gradually grew larger and diagnosis of hypervascular placental polyp was considered. As the amount of vaginal bleeding was small, expectant management was instituted. Sixty-one days after the first D&C, reduction of the vascularity of RPOC was confirmed on color Doppler ultrasonography and D&C was successfully completed.

Thioredoxin binding protein-2 inhibits excessive fetal hypoglycemia during maternal starvation by suppressing insulin secretion in mice.

Glucose is a major fuel for fetal development. Fetal blood glucose level is mainly dependent on maternal blood glucose concentration, though it is also regulated by fetal insulin level. Thioredoxin binding protein-2 (TBP-2), which is identical to vitamin D3 up-regulated protein (VDUP1) and thioredoxin interacting protein (Txnip), was recently reported to be a key transcriptional factor controlling glucose metabolism. Here, we elucidated the functions of TBP-2 in maintaining blood glucose homeostasis during the fetal period. TBP-2(+/-) female mice were mated with TBP-2(+/-) male mice; beginning 16.5-d post coitum, pregnant mice were fed or fasted for 24 h. Under conditions of maternal starvation, the blood glucose levels of TBP-2(-/-) fetuses were significantly lower than those of TBP-2(+/+) fetuses, corresponding to the elevated plasma insulin levels of TBP-2(-/-) fetuses compared with those of TBP-2(+/+) fetuses. There was no difference between TBP-2(+/+) and TBP-2(-/-) fetuses in terms of their pancreatic beta-cell masses or the expression of placental glucose transporters under conditions of either maternal feeding or fasting. Thus, during maternal fasting, fetal TBP-2 suppresses excessive insulin secretion to maintain the fetus's glucose levels, implying that TBP-2 is a critical molecule in mediating fetal glucose homeostasis depending on nutrient availability.

Cyclic mechanical stretch augments hyaluronan production in cultured human uterine cervical fibroblast cells.

Hyaluronan (HA) a glycosaminoglycan with high affinity for water molecules stimulates local inflammatory reactions. Parturition causes a dramatic increase in the amount of HA fragments in the uterine cervix, thereby contributing to a rapid softening as well as opening of the cervical canal, i.e. cervical ripening. The aim of this study was to investigate the possible involvement of cyclic distension caused by labour in the augmentation of HA production during cervical ripening. Immunohistochemistry and/or RT-PCR detected hyaluronan synthase (HAS)1, 2 and 3 in samples of human cervical tissue obtained from pregnant women. Labour-like cyclic mechanical stretch for 24, 36 and 48 h significantly enhanced the secretion of HA, from cultured human uterine cervical fibroblast (CxF) cells, 128.7, 151.4 and 173.2%, respectively, concomitant with a significant augmentation of HAS1 (36, 48 h), HAS2 (24, 36 and 48 h) and HAS3 (48 h) mRNA expression. Cyclic mechanical stretch for 12, 36 and 48 h increased molecular size of the HA secreted from CxF cells. In conclusion, cyclic mechanical stretch of the uterine cervix caused by the presenting part of the fetus in labour may contribute to the increase in the secretion of HA during the process of cervical ripening.

Role of premature leptin surge in obesity resulting from intrauterine undernutrition.

Intrauterine undernutrition is closely associated with obesity related to detrimental metabolic sequelae in adulthood. We report a mouse model in which offspring with fetal undernutrition (UN offspring), when fed a high-fat diet (HFD), develop pronounced weight gain and adiposity. In the neonatal period, UN offspring exhibited a premature onset of neonatal leptin surge compared to offspring with intrauterine normal nutrition (NN offspring). Unexpectedly, premature leptin surge generated in NN offspring by exogenous leptin administration led to accelerated weight gain with an HFD. Both UN offspring and neonatally leptin-treated NN offspring exhibited an impaired response to acute peripheral leptin administration on a regular chow diet (RCD) with impaired leptin transport to the brain as well as an increased density of hypothalamic nerve terminals. The present study suggests that the premature leptin surge alters energy regulation by the hypothalamus and contributes to "developmental origins of health and disease."

17beta-estradiol up-regulates prostacyclin production in cultured human uterine myometrial cells via augmentation of both cyclooxygenase-1 and prostacyclin synthase expression.

OBJECTIVE: To investigate whether 17beta-estradiol elevates prostacyclin (PGI(2)) production in human myometrial cells in the middle of gestation. METHODS: The concentration of 6-keto-PGF(1alpha), a stable metabolite of PGI(2), in the culture medium was assessed using enzyme-linked immunosorbent assay (ELISA). Western blot analysis and quantitative reverse-transcriptase polymerase chain reaction (RT-PCR) using TaqMan (Applied Biosystems, Foster City, CA) technology were performed to evaluate the expression of cytosolic phopholipase A(2) (cPLA(2)), cyclooxygenase-1 (COX-1), COX-2, and prostacyclin synthase (PGIS) in cultured human myometrial cells prepared from second trimester pregnant women (n = 3) after stimulation with 17beta-estradiol. RESULTS: Treatment with 17beta-estradiol (4-400 nM) dose-dependently elevated PGI(2) secretion from cultured human myometrial cells. Western blot analysis detected cPLA(2) and COX-1 and PGIS protein expression in the cultured human myometrial cells; however, COX-2 protein expression was below the detection sensitivity. Stimulation with 40-nM 17beta-estradiol significantly up-regulated protein and mRNA expression of both COX-1 and PGIS. CONCLUSION: 17beta-Estradiol from placenta may contribute to the augmentation of PGI(2) production in the human myometrium in the middle of gestation via up-regulation of both COX-1 and PGIS expression.

Cyclic mechanical stretch augments both interleukin-8 and monocyte chemotactic protein-3 production in the cultured human uterine cervical fibroblast cells.

Intensive local leukocyte infiltration in the uterine cervix is a characteristic feature in the process of cervical ripening. The infiltrated leukocytes include neutrophils, macrophages and monocytes, which are believed to play important roles in cervical ripening by secreting elastase, matrix metalloproteinase and interleukin-1 (IL-1). Interleukin-8 (IL-8) and monocyte chemotactic protein-3 (MCP-3) belong to the CXC and CC chemokine families, and mediate the chemotaxis of neutrophils and monocytes/macrophages respectively. The aim of the present study was to investigate the possible involvement of IL-8 and MCP-3 in leukocyte chemotaxis in cervical ripening. Immunohistochemistry and RT-PCR detected both IL-8 and MCP-3 expression in human pregnant uterine cervices. Labour-like cyclic mechanical stretch for 48 h significantly elevated both IL-8 (555%) and MCP-3 (360%) secretion from cultured human uterine cervical fibroblast (CxF) cells (P<0.05 for both). Cyclic mechanical stretch for 24, 36 and 48 h significantly increased both IL-8 and MCP-3 mRNA expression in CxF cells (P<0.05 for all). The stretch-induced augmentation of both IL-8 and MCP-3 expression was significantly suppressed by an activator protein-1 (AP-1) inhibitor, curcumin. These data suggest that cyclic mechanical stretch of the uterine cervix by the presenting part of the fetus during labour may augment both IL-8 and MCP-3 production in the uterine cervix via AP-1 activation.

Significant increase in maternal plasma leptin concentration in induced delivery: a possible contribution of pro-inflammatory cytokines to placental leptin secretion.

Maternal plasma leptin concentration is significantly increased during pregnancy. However, its roles in pregnancy, especially in labor, have not been fully clarified. We measured plasma leptin concentrations in pregnant women during the course of induced labor, just after spontaneous vaginal delivery and Cesarean section at term. We also studied the regulation of leptin secretion from term placental tissue and BeWo cells, a trophoblastic cell-line. Plasma leptin concentrations increased significantly during labor (58.9 +/- 9.2 ng/ml) compared to those before labor induction (37.5 +/- 5.8 ng/ml, P<0.05), then decreased 3-6 days postpartum (14 +/- 3 ng/ml, n = 6, P<0.0001) to the levels of normal nonpregnant women. Leptin concentrations within an hour and 24 hours after spontaneous vaginal delivery were significantly higher than those after Cesarean section (P<0.05 for both comparisons). Similarly, leptin mRNA expression in placental tissues obtained after spontaneous vaginal delivery was significantly greater than that in those obtained after Cesarean section without labor (P<0.05). IL-1alpha and TNF-alpha treatment significantly stimulated leptin secretion and leptin mRNA expression in explant culture of human term placental tissue and in BeWo cells as compared with those in vehicle controls (P<0.05, for all comparisons). By contrast, oxytocin and prostaglandin F(2alpha) treatment had no effects on leptin secretion from explant culture of human term placental tissue or from BeWo cells. These data indicate that pro-inflammatory cytokines might stimulate placental leptin secretion, thus finally contributing to the increase in plasma leptin concentration during labor.

Augmented endothelial nitric oxide synthase (eNOS) protein expression in human pregnant myometrium: possible involvement of eNOS promoter activation by estrogen via both estrogen receptor (ER)alpha and ERbeta.

The aim of the present study was to investigate the possible contribution of estrogen to pregnancy-associated modulation of nitric oxide production in the human myometrium during pregnancy. Both endothelial nitric oxide synthase (eNOS) and inducible NOS (iNOS) proteins were clearly expressed in the non-pregnant myometrium and were elevated in the first trimester of pregnancy. Oral contraceptive pills augmented eNOS, but not iNOS, protein expression in the non-pregnant human myometrium. In cultured human myometrial cells, estrogen receptor (ER)alpha and ERbeta expression was extremely low. Therefore, we used either ERalpha or ERbeta expression vector to investigate the effect of 17beta-estradiol treatment on eNOS promoter activity using eNOS promoter/luciferase vector in cultured human myometrial cells. 17beta-estradiol treatment significantly augmented eNOS promoter activity in cells co-transfected with either ERalpha or ERbeta, and this augmentation was dose-dependently suppressed by ICI 182780, an estrogen antagonist. These data suggest the possibility that both ERalpha and ERbeta are involved in the estrogen-associated regulation of eNOS gene expression in the human myometrium.

Expression of nitric oxide synthase isoforms in the human placenta is not altered by labor.

Nitric oxide has various biological activities including smooth muscle relaxation, anti-inflammatory activity, anti-coagulatory activity. As the human placenta is known to express nitric oxide synthases, this study investigated the possible effect of labor on the expression of endothelial nitric oxide synthase (eNOS) and inducible nitric oxide synthase (iNOS) in human placental tissues at term. Both eNOS and iNOS mRNA expression in placental tissues in labor were significantly higher than those in the amnion, chorion laeve, decidua vera and myometrium. The eNOS mRNA and protein expressions in placental tissues in labor (n = 12) were 1.6023 +/- 0.1652 (eNOS/GAPDH, mean +/- SEM) and 12.8 +/- 1.3 arbitrary units (AU), respectively, which were similar to those not in labor (n = 10), 1.5806 +/- 0.2042 (eNOS/GAPDH) and 11.4 +/- 1.8 AU. The iNOS mRNA and protein expressions in the placental tissues in labor were 1.2831 +/- 0.2436 (iNOS/GAPDH) and 10.7 +/- 2.1 AU respectively, similar to those not in labor, 1.9254 +/- 0.8004 (iNOS/GAPDH) and 13.3 +/- 1.8 AU. The guanosine 3',5'-cyclic monophosphate (cGMP) concentration in the placental tissues in labor was 23.6 +/- 1.4 fmol/g wet tissue, similar to that not in labor, 26.1 +/- 2.0 fmol/g wet tissue. These findings suggest that nitric oxide production in the human placenta is maintained during labor.

Resistin is expressed in the human placenta.

The mechanism for decreased insulin sensitivity in pregnant women is not fully clarified. Resistin, a novel peptide hormone, is specifically expressed in the adipose tissue and decreases insulin sensitivity in rodents. In the present study, we demonstrate resistin gene expression in the human placental tissue, mainly in trophoblastic cells. The resistin gene expression in term placental tissue was more prominent than was seen in the first trimester chorionic tissue. In contrast resistin gene expression in adipose tissue was rather weak and remained unchanged by pregnancy. Thus, resistin is a newly isolated placental hormone in humans which may modulate insulin sensitivity during pregnancy.