Aiko Kakigano

Uterine Cervical Cancer Displaying Tumor-Related Leukocytosis : A Distinct Clinical Entity With Radioresistant Feature

BACKGROUND Tumor-related leukocytosis (TRL) is occasionally found in patients with nonhematopoietic malignancies. We investigated the clinical implication of TRL and individualized treatment for TRL-positive cervical cancer, as well as the underlying biological mechanism. METHODS Clinical data from 258 cervical cancer patients treated with definitive radiotherapy were analyzed to investigate the association between TRL and treatment outcome. Clinical samples, cervical cancer cell lines, and a mouse model of cervical cancer were used to examine the mechanisms responsible for TRL in cervical cancer, focusing on the role of tumor-derived granulocyte colony-stimulating factor (G-CSF) and myeloid-derived suppressor cells (MDSCs). All statistical tests were two-sided. RESULTS TRL was statistically significantly associated with younger age (Wilcoxon rank sum test, P = .03), larger tumor size (Wilcoxon rank sum test, P = .006), advanced clinical stage (χ(2) test, P = .01), and shorter overall survival (Cox proportional hazard modeling and Wald tests, P < .001). Among cervical cancer patients, TRL was associated with upregulated tumor G-CSF expression (χ(2) test, P < .001), elevated serum G-CSF levels (Student t test, P = .03), larger spleens (Student t test, P = .045), and increased MDSC frequencies in the blood (Student t test, P < .001) compared with the TRL-negative patients. In vitro and in vivo experiments revealed that tumor-derived G-CSF was involved in the underlying causative mechanism of TRL and MDSCs induced by tumor-derived G-CSF are responsible for the rapidly progressive and radioresistant nature of TRL-positive cervical cancer. The administration of anti-Gr-1 neutralizing antibody or the depletion of MDSCs by splenectomy (n = 6 per group) inhibited tumor growth and enhanced radiosensitivity in TRL-positive cervical cancer xenografts (Wilcoxon rank sum test, P = .008 and P = .02, respectively). CONCLUSIONS TRL is associated with resistance to radiotherapy among cervical cancer patients, and MDSC-targeting treatments may have therapeutic potential in these patients.

Three-dimensional sonography in the differential diagnosis of interstitial, angular, and intrauterine pregnancies in a septate uterus.

Interstitial, angular, and cornual pregnancies and intrauterine pregnancies in an anomalous uterus are separate entities, and the impact of each condition on obstetric outcomes is completely different. However, there is considerable confusion in understanding and managing the natural course of each condition due to a lack of uniform terminology. The single most important factor for differentiating these types of pregnancies is to make an early diagnosis. The differences between interstitial, angular, and cornual pregnancies on 2‐dimensional (2D) sonography are subtle. Although magnetic resonance imaging can be used to differentiate these conditions, it is not preferred as the initial assessment tool because of its limited availability and cost‐effectiveness. Three‐dimensional (3D) sonography has the advantage of providing views of the uterus that cannot be obtained with conventional 2D sonography. We describe 3 cases of interstitial, angular, and intrauterine pregnancies in a septate uterus that were clearly differentiated by 3D sonography. We demonstrate the differences in diagnostic imaging findings and emphasize the importance of 3D sonography in differentiating these entities.

Normalisation of Angiogenic Imbalance after Intra-Uterine Transfusion for Mirror Syndrome Caused by Parvovirus B19

We report a case of mirror syndrome caused by parvovirus B19, which resolved after intra-uterine transfusion. Mirror syndrome is a rare condition characterised by a triad of foetal hydrops, generalized maternal oedema and placentomegaly. Although the mechanism underlying the onset of this syndrome is unknown, it probably shares a common pathophysiologic origin with pre-eclampsia. Our patient showed increased circulating levels of soluble fms-like tyrosine kinase 1 (sFlt-1) and decreased levels of placental growth factor (PlGF), which have also been reported in pre-eclampsia. The sFlt-1/PlGF ratio decreased immediately after intra-uterine transfusion, followed by resolution of both maternal and foetal symptoms. This suggests that the sFlt-1/PlGF ratio may help to predict the post-treatment course of mirror syndrome.

Drug Repositioning for Preeclampsia Therapeutics by In Vitro Screening: Phosphodiesterase-5 Inhibitor Vardenafil Restores Endothelial Dysfunction via Induction of Placental Growth Factor.

We screened a library of 528 approved drugs to identify candidate compounds with therapeutic potential as preeclampsia treatments via their proangiogenic properties. Using human umbilical vein endothelial cells (HUVECs), we assessed whether the screened drugs induced placental growth factor (PIGF) and restored damaged endothelial cell function. Enzyme-linked immunosorbent assays (ELISAs) were carried out to measure levels of PlGF in conditioned media treated with each drug (100 µmol/L) in the drug library. Tube formation assays were performed using HUVECs to evaluate the angiogenic effects of drugs that induced PlGF. We also performed ELISA, quantitative reverse transcription polymerase chain reaction, and tube formation assays after treatment with a range of concentrations of the candidate drug. Of the drugs that induced PlGF, vardenafil was the only compound that significantly facilitated tube formation in comparison with the control cells (P < .01). Treatment with vardenafil at concentrations of 50, 100, and 250 µmol/L increased expression of PlGF in a dose-dependent manner. Vardenafil (250 µmol/L) significantly improved tube formation which was inhibited in the presence of soluble fms-like tyrosine kinase 1 (100 ng/mL) and/or soluble endoglin (100 ng/mL). Production of PlGF from HUVECs in the presence of sera derived from patients with preeclampsia was significantly elevated by administration of vardenafil (250 µmol/L). By assessing drug repositioning through screening a library of approved drugs, we identified vardenafil as a potential protective agent against preeclampsia. The therapeutic mechanism of vardenafil may involve inhibition of the systemic maternal antiangiogenic state that leads to preeclampsia, in addition to its vasodilating effect. As concentrations used are high and unlikely to be useful clinically, further work is needed before testing it in humans.

Maternal Hyperventilation During Labor Revisited: Its Effects on Fetal Oxygenation

To investigate the relationship between maternal hyperventilation and fetal blood gas values and to estimate its possible association with fetal oxygenation, maternal transcutaneous partial pressure of carbon dioxide (tcPCO2) values were analyzed in association with umbilical venous PCO2 (UVPCO2), umbilical venous partial pressure of oxygen (UVPO2), and umbilical venous oxyhemoglobin saturation (UVHbo 2) values. Pregnant women without labor (30.7 ± 3.7 mm Hg, n = 20) showed significantly lower tcPCO2 values compared with nonpregnant women (37.4 ± 4.0 mm Hg, n = 10). Pregnant women in the second stage of labor showed even lower tcPCO2 values compared with pregnant women during the first stage of labor (20.8 ± 5.9 mm Hg vs 28.4 ± 5.0 mm Hg, n = 26). Maternal tcPCO2 values had significant positive correlations with UVPCO2 (r = .78, P < .001), UVPO2 (r = .62, P < .001), and UVHbO2 values (r = .59, P < .001). Maternal hyperventilation had a close relationship with lower UVPCO2, UVPO2, and UVHbo 2 values, which might interfere with optimal fetal cerebral oxygenation.

Imbalance of angiogenic factors and avascular edematous cystic villi in a trisomy 13 pregnancy: A case report

The incidence of pre-eclampsia is significantly higher in trisomy 13 pregnancies than in normal pregnancies. Soluble fms-like tyrosine kinase-1 (sFlt-1), located on chromosome 13, is an anti-angiogenic molecule derived from the placenta and contributes to the pathogenesis of pre-eclampsia. Elevated sFlt-1 and reduced placental growth factor (PlGF) are associated with trisomy 13 pregnancies and may play a pathogenic role in the subsequent development of pre-eclampsia. Here we present a case of a trisomy 13 pregnancy without any signs of pre-eclampsia that showed alterations in circulating angiogenic factors and abnormal placental appearance. The placenta developed edematous changes and contained multiple small cysts. Histology of the placenta confirmed avascular edematous cystic villi and did not show the typical appearance of a partial mole or mesenchymal dysplasia. The sFlt-1/PlGF ratio in maternal serum (134) was much higher than that in gestational age-matched women who were normotensive (2.9-7.2; mean, 5.0). Immunostaining for Flt-1 and endoglin was more intense in our case compared with gestational age-matched controls, and at a similar level to a case of pre-eclampsia. Placental findings that showed avascular edematous cystic villi in our case may be associated with angiogenic imbalance involved in the pathogenesis of pre-eclampsia in trisomy 13 pregnancies.

Maternal carbon dioxide level during labor and its possible effect on fetal cerebral oxygenation: mini review.

During pregnancy, and especially during labor, the maternal carbon dioxide level declines considerably. Maternal carbon dioxide levels show a close relation with fetal carbon dioxide levels. The latter affects fetal cerebral oxygenation by regulating cerebral blood flow and shifting the oxyhemoglobin dissociation curve. In addition, maternal hypocapnia appears to impair placental oxygen transfer. Thus, maternal hyperventilation may interfere with optimal fetal cerebral oxygenation. Here, we provide a brief overview of the literature relevant to this issue.

Current status of non‐invasive prenatal testing in Japan

The purpose of this study was to report the 3‐year experience of a nationwide demonstration project to introduce non‐invasive prenatal testing (NIPT) of maternal plasma for aneuploidy, and review the current status of NIPT in Japan.

Conservative management of placenta percreta

Maternal outcomes after conservative management of placenta percreta are poorly understood.

Fetal cell-free DNA fraction in maternal plasma for the prediction of hypertensive disorders of pregnancy

OBJECTIVE The purpose of this study is to compare the fetal fractions during non-invasive prenatal testing (NIPT) in singleton pregnancies according to gestational age and maternal characteristics to evaluate the utility of this parameter for the prediction of pregnancy complications including gestational diabetes mellitus (GDM) and hypertensive disorders of pregnancy (HDP). STUDY DESIGN This study was a multicenter prospective cohort study. The present data were collected from women whose NIPT results were negative. The relationships between the fetal fractions and the gestational age, maternal weight and height, and incidences of miscarriage, preterm delivery, and pregnancy complications including GDM, HDP and placental abruption were assessed. RESULTS A total of 5582 pregnant women with verified NIPT negative results were registered in the study. The demographic characteristics of the study populations were statistically analyzed, and the women with HDP tended to have a low fetal fraction in samples taken during early gestation. The area under the curve (AUC) in a receiver operating characteristic curve (ROC) analysis was 0.608 for women with HDP. CONCLUSION A low fetal fraction on NIPT might be correlated with future HDP. However, predicting HDP during early pregnancy in women with a low fetal fraction might be difficult.