Kayoko Takahashi

Ambulatory BP monitoring and clinic BP in predicting small-for-gestational-age infants during pregnancy

The significance of ambulatory blood pressure (ABP) monitoring during pregnancy has not been established. We performed a prospective study to elucidate whether ABP measures are associated with small-for-gestational-age birth weight (SGA). We studied 146 pregnant women who were seen for maternal medical checkups or suspected hypertension. ABP monitoring was performed for further assessment of hypertension. The outcome measure was SGA. The subjects were classified by their medical history and ABP as having preeclampsia or gestational hypertension (n=68 cases), chronic hypertension (n=48) or white-coat hypertension (n=30). There were 50 (34.2%) cases of SGA by the fetal growth reference standard. In multivariable logistic regression analyses adjusting for age, body mass index, the presence of prior pregnancy, current smoking habit and the use of antihypertensive medications, 24-h SBP (per 10 mm Hg (odds ratio (OR): 1.74; 95% confidence interval (CI): 1.28–2.38; P<0.001)) was more closely associated with SGA than clinic BP (OR: 1.40; 95% CI: 0.92–2.13; P=0.11). The results were essentially the same if 24-h BP was replaced by awake or sleep SBP. Ambulatory diastolic BP showed the same tendency. However, abnormal circadian rhythm was not associated with the outcome. In conclusion, ambulatory BP monitoring measures performed during pregnancy were more closely associated with SGA than clinic BP.

Development of a mouse model for lymph node metastasis with endometrial cancer.

Controlling lymph node metastasis is currently a key issue in cancer therapy. Lymph node metastasis is one of the most important prognostic factors in various types of cancers, including endometrial cancer. Vascular endothelial growth factor‐C (VEGF‐C) plays a crucial role in lymphangiogenesis, and is implicated to play an important role in lymph node metastasis. To evaluate the role of VEGF‐C in lymph node metastasis, we developed an animal model by using an endometrial cancer cell line, HEC1A. This cell line is not invasive by nature and secretes moderate amounts of VEGF‐C; intrauterine injection of HEC1A cells into Balb/c nude mice resulted in uterine cancer with lymph node metastasis after 8 weeks. To analyze the contribution of VEGF‐C to lymph node metastasis, its corresponding gene was stably introduced into HEC1A cells (HEC1A/VEGF‐C), which then produced more than 10 times the amount of VEGF‐C. The number of lymph node metastases was significantly higher in HEC1A/VEGF‐C cells than in HEC1A cells (3.2 vs 1.1 nodes/animal, respectively). Augmented lymphangiogenesis was observed within tumors when HEC1A/VEGF‐C cells were inoculated. These results indicate that VEGF‐C plays a critical role in lymph node metastasis, in addition to serving as a platform to test the efficacy of various therapeutic modalities against lymph node metastasis. (Cancer Sci 2011; 102: 2272–2277)

Irregular peak‐to‐peak intervals between ascending aortic flows during fetal ventricular tachycardia in long QT syndrome

After delivery, MR imaging revealed that the cyst was located in the left cerebral hemisphere and that there was a solid area in the medial portion of the cyst (Figure 2i–k), suggestive of a cystic CPP. Immediate placement of an Ommaya cerebrospinal fluid reservoir was performed for repeated aspiration of the cyst contents and on the 33rd day after delivery a left parietal craniotomy was performed. Intraoperative findings revealed that the cyst was located in the left cerebral hemisphere, with a papillary tumor situated on the cyst wall, connected to the choroid plexus. Pathological examination confirmed the diagnosis of cystic CPP. The infant’s postoperative course was unremarkable and he was discharged on the 73rd day after delivery without further neurological sequelae. Cystic CPP forming in the cerebral hemisphere is extremely rare, with only two cases reported previously in the literature1–5. CPP is isodense to hyperdense on computed tomography and shows homogeneous enhancement following contrast administration. Cystic CPP manifests as a cystic tumor with or without a mural nodule2,5. If present, the nodule demonstrates enhancement after contrast medium injection6. Prenatally, CPP presents on ultrasound examination as a highly echogenic mass located in one lateral ventricle, adjacent to normal choroid plexus; these findings are necessary for the correct diagnosis7. Tomita et al. reported that in cystic CPP of the cerebral hemispheres the solid part appears in the medial portion5. In our case, ultrasonographic examination detected a medially located solid part with increased echogenicity, similar to that of choroid plexus. This is the first reported case of a confirmed extraventricular intracerebral cystic CPP that showed a marked increase in tumor size prenatally. Cystic CPP should be considered in the differential diagnoses when a cyst with a hyperechogenic solid part is detected in the cerebral hemisphere.

Suppression of lymph node and lung metastases of endometrial cancer by muscle‐mediated expression of soluble vascular endothelial growth factor receptor‐3

Lymph node metastasis is the most important prognostic factor of endometrial cancer. However, effective therapy has not been established against lymph node metastasis. In this study, we explored the efficacy of gene therapy targeting lymph node metastasis of endometrial cancer by suppressing the action of vascular endothelial growth factor (VEGF)‐C through soluble VEGF receptor‐3 (sVEGFR‐3) expression. For this purpose, we first conducted a model experiment by introducing sVEGFR‐3 cDNA into an endometrial cancer cell line HEC1A and established HEC1A/sVEGFR‐3 cell line with high sVEGFR‐3 expression. The conditioned medium of HEC1A/sVEGFR‐3 cells inhibited lymphatic endothelial cell growth in vitro, and sVEGFR‐3 expression in HEC1A cells suppressed in vivo lymph node and lung metastases without inhibiting the growth of a subcutaneously inoculated tumor. To validate the therapeutic efficacy, adeno‐associated virus vectors encoding sVEGFR‐3 were injected into the skeletal muscle of mice with lymph node metastasis. Lymph node and lung metastases of HEC1A cells were completely suppressed by the muscle‐mediated expression of sVEGFR‐3 using adeno‐associated virus vectors. These results suggest the possibility of gene therapy against lymph node and lung metastases of endometrial cancer by using muscle‐mediated expression of sVEGFR‐3.

Ehlers–Danlos type IV in pregnancy with a history of myocardial infarction

Ehlers–Danlos syndrome (EDS) type IV is an autosomal dominantly inherited connective tissue disorder caused by abnormal type III collagen resulting from heterogenous mutations of the type III procollagen gene (COL3A1). The maternal mortality rate per pregnancy in EDS type IV has been reported as 11.5% to 25%. A 30‐year‐old Japanese primiparous woman, with a brother who had suffered a bowel rupture due to EDS type IV, became pregnant. She also suffered from myocardial infarction due to coronary artery dissections at 24 years old, and underwent coronary artery bypass grafting. Due to uncontrollable uterine contractions, beta 2‐stimulants were administered during 18 to 29 weeks of gestation. Therefore, we performed a cesarean section at 29 weeks of gestation to prevent uterine rupture. She and her baby were discharged without any complications. It was revealed that she had the same mutation as her brother, Gly220Trp, in the (Gly‐X‐Y)n repeat of the triple‐helical domain of COL3A1.

Combination therapy of tyrosine kinase receptor inhibitor TSU-68 (SU6668) and paclitaxel inhibits subcutaneous xenografts of endometrial cancer.

TSU-68 is a small-molecular-weight synthetic inhibitor of the tyrosine kinase receptors Flk-1/KDR, PDGFRβ and FGFR1, which are involved in angiogenesis. Using a mouse model in which endometrial cancer was subcutaneously implanted, we investigated the effects of TSU-68 alone or in combination with paclitaxel. We subcutaneously implanted a cell strain of endometrial cancer, HEC1A, into BALB/c nude mice. TSU-68 was orally administered every day, while paclitaxel was intraperitoneally injected once a week, and the rates of subcutaneous tumor proliferation were compared. In a group treated with high-dose (200 mg/kg/day) TSU-68 alone, subcutaneous tumor proliferation was significantly inhibited in comparison with a vehicle-treated control group (p<0.05). In groups treated with low-dose TSU-68 or paclitaxel alone (100 and 10 mg/kg/day, respectively), tumor proliferation was not significantly inhibited. In a low-dose combination therapy group (100 mg/kg/day of TSU-68 + 10 mg/kg/day of paclitaxel), tumor proliferation was significantly inhibited in comparison with the control and low-dose TSU-68 or paclitaxel therapy groups (p<0.01). High-dose monotherapy with TSU-68 inhibited the proliferation of the subcutaneously implanted tumor. Furthermore, a combination of TSU-68 and paclitaxel at a low dose, one at which respective monotherapy was not effective, inhibited tumor proliferation. Combination therapy with the two agents may therefore be useful for treating endometrial cancer.

PP058. The additive effect of plasma levels of sFlt-1/PLGF ratio following the risk classification using both blood pressure levels and uterine artery blood flow impedance in the second trimester on the later occurrence of preeclampsia

INTRODUCTION The multivariate model including circulating levels of soluble fms-like tyrosine kinase 1 (sFlt-1)/placental growth factor (PlGF) ratios, maternal factors, blood pressure (BP) levels and uterine artery (UtA) doppler in the first to second trimester has been reported to be clinically useful to predict PE more accurately. However, the effects of levels of sFlt-1/PlGF ratio after the stratification of women using two major risk factors for PE, BP levels and UtA blood flow imdedance (BFI) have not been evaluated. OBJECTIVES Our aim was to evaluate the additive effect of plasma levels of sFlt-1/PlGF ratio following the risk classification using both mean blood pressure (MBP) levels and the combination of two UtABFI, mean pulsatility index (mPI) and mean notch depth index (mNDI), on the later occurrence of PE. METHODS 1161 women were recruited into a prospective cohort study during 2004 and 2008. Clinical BPs were measured twice during 16 and 23 weeks, UtA doppler was performed twice during 16 and 23 weeks, and the mPI and mNDI was measured. Plasma samples were drawn once at 20-23weeks, and were stored at -20°C until use. The levels of sFlt-1/PlGF ratio were measured by automated electrochemiluminescent immunoassay (Roche Diagnostics K.K.). The cutoff value of mean BP (MBP) was determined as 91.3mmHg using ROC curve, and that of sFlt-1/PlGF ratio was 13.0, the 97.5th percentile of log10(sFlt-1/PlGF) at 20-23 weeks in normal pregnant women. If the mPI was <90th percentile of the gestational-age specific reference range of mPI, or the mNDI was <90th percentile of the gestational-age specific reference range of mNDI, we defined that the UtABFI was low; if the mPI was ⩾90th percentile and the mNDI was ⩾90th percentile, we defined that the UtABFI was high. RESULTS When women were stratified to 4 groups: low BP and low UtABFI, high BP but low UtABFI, high UtABFI but low BP, high BP and high UtABFI, the PPVs were 0.7%, 6.9%, 6.2% and 39.1%, respectively. In women with low BP and low UtABFI, the high sFlt-1/PlGF changed the PPV to 11.1%; the interval from the sampling to the onset of PE in women with high sFlt-1/PlGF ratio was significantly shorter than in those with low sFlt-1/PlGF ratio (mean±SD [weeks]: 5.9±1.5 vs. 16.5±2.1, p<0.01). In women with high BP but low UtABFI, the high sFlt-1/PlGF changed the PPV to 18.2%; the interval from the sampling to the onset of PE in women with high sFlt-1/PlGF ratio was significantly shorter than in those with low sFlt-1/PlGF ratio (8.0±5.7 vs. 12.6±3.7, p<0.05). Although these effects of sFlt-1/PlGF ratio on the occurrence of PE were not confirmed in women with high BP and high UtABFI, PE occurred in all women with three risk factors (5/5), and the interval from the sampling to the onset of PE was6.8±4.1 weeks. CONCLUSION Women with both high BP and high UtABFI, especially those with additional risk of high sFlt-1/PlGF ratio, were the highest risk of PE. In the lowest risk group of low BP and low UtABFI, the addition of sFlt-1/PlGF ratio improved the PPV and the interval from the sampling to the onset of PE. These results clearly indicated the clinical importance of measuring sFlt-1/PlGF ratio in addition to BP levels and UtABFI in all pregnant women in the second trimester.