西澤 春紀

Abstract Purpose In the context of in vitro fertilization–embryo transfer (IVF–ET), factors other than egg quality may be key determinants of treatment success, in particular, maternal factors related to uterine endometrial receptivity and unidentified factors. We therefore aimed to analyze the metabolome and microbiome in IVF–ET patients who did and did not achieve pregnancy. Methods Cervicovaginal mucus was collected from patients undergoing IVF–ET. Metabolite analysis was conducted by liquid chromatography‐mass spectrometry and the microbiota were determined by the polymerase chain reaction using universal 16S‐rRNA gene bacterial primers by MiSeq sequencing. Patients were classified as pregnant (N = 10) or nonpregnant (N = 13). Metabolic pathways were examined by MetaboAnalyst. Results Three metabolic pathways, including alanine‐aspartate–glutamate metabolism, arginine biosynthesis, and cysteine‐methionine metabolism, were commonly decreased at the time of embryo transfer irrespective pregnant outcomes. Notably, pyruvate was decreased in the pregnant group. Amino acid metabolites showed inverse correlations with the presence of anaerobic microbiota in the nonpregnant group. Conclusions Metabolism decreased during embryo transplantation, with a notable decrease in pyruvate metabolism, particularly in patients who became pregnant. The behavior of metabolites in the pregnant and nonpregnant groups suggests that metabolome analysis in the cervicovaginal mucus may be a diagnostic marker for predicting pregnancy.

OBJECTIVES: Nectin-4 is a cell adhesion molecule with vital functions at adherens and tight junctions. Cumulative evidence now indicates that the NECTIN4 gene is overexpressed in a variety of cancers, and that the nectin-4 protein is both a disease marker and therapeutic target in a subset of these cancers. We previously demonstrated that NECTIN4 is overexpressed in placenta during pre-eclamptic pregnancy, which is one of the most serious obstetric disorders. METHODS: Nectin-4 protein levels were measured in maternal sera from pregnant women with pre-eclampsia and its related disorder, unexplained fetal growth retardation. RESULTS: Maternal serum concentrations of nectin-4 were significantly elevated in pre-eclamptic women compared with those with an uncomplicated normotensive pregnancy. However, no increase was observed in pregnancies with unexplained fetal growth retardation. Serum nectin-4 levels were higher in cases with early-onset pre-eclampsia that generally showed more severe clinical symptoms, but levels were not correlated to other clinical indicators of disease severity. CONCLUSIONS: Nectin-4 is a potential new diagnostic and predictive biomarker for severe pre-eclampsia.

BACKGROUND: FLT1 is one of the significantly overexpressed genes found in a pre-eclamptic placenta and is involved with the etiology of this disease. METHODS: We conducted genome-wide expression profiling by RNA-seq of placentas from women with pre-eclampsia and those with normotensive pregnancy. RESULTS: We identified a lncRNA gene, MG828507, located ~80 kb upstream of the FLT1 gene in a head-to-head orientation, which was overexpressed in the pre-eclamptic placenta. MG828507 and FLT1 are located within the same topologically associated domain in the genome. The MG828507 mRNA level correlated with that of the FLT1 in placentas from pre-eclamptic women as well as in samples from uncomplicated pregnancies. However, neither the overexpression nor knockdown of MG828507 affected the expression of FLT1. Analysis of pre-eclampsia-linking genetic variants at this locus suggested that the placental genotype of one variant was associated with the expression of MG828507. The MG828507 transcript level was not found to be associated with maternal blood pressure, but showed a relationship with birth and placental weights, suggesting that this lncRNA might be one of the pivotal placental factors in pre-eclampsia. CONCLUSION: Further characterization of the MG828507 gene may elucidate the etiological roles of the MG828507 and FLT1 genes in pre-eclampsia in a genomic context.

Objectives: Alterations in the vaginal bacterial flora reflect the status of various obstetric conditions and are associated with mechanisms that underlie certain pregnancy-associated complications. These changes are also a predictive biomarker for clinical outcomes of these adverse events. Methods: We examined the vaginal microbiome in samples from pregnant Japanese women with preterm labor. Results: The microbiota composition in preterm delivery (PD) samples differed from those of control or threatened preterm delivery (TPD) samples in principal component analysis. An increase in Firmicutes and a decrease in Actinobacteria were significantly associated with PD only (both P<0.01). In the Firmicutes phylum, Lactobacillus tended to be abundant, and the abundance of L. iners and L. crispatus was especially high, whereas the L. gasseri population was low in PD samples. Longitudinal analysis showed that the abundance of L. iners decreased after commencing tocolytic treatment in TPD samples compared with before treatment, but it remained high in PD samples. Conclusions: The vaginal microbiome may be a useful prognostic indicator of preterm labor and a monitoring tool for tocolytic treatment to prevent preterm birth.

PURPOSE: Since chromosomal abnormalities can be detected in more than half of miscarriages, cytogenetic testing of the product of conception (POC) can provide important information when preparing for a subsequent pregnancy. Conventional karyotyping is the common diagnostic method for a POC but can be problematic due to the need for cell culture. METHODS: We here conducted shallow whole-genome sequencing (sWGS) using next-generation sequencing (NGS) for alternative POC cytogenomic analysis. Since female euploidy samples can include 69,XXX triploidy, additional QF-PCR was performed in these cases. RESULTS: We here analyzed POC samples from miscarriages in 300 assisted reproductive technology (ART) pregnancies and detected chromosomal abnormalities in 201 instances (67.0%). Autosomal aneuploidy (151 cases, 50.3%) was the most frequent abnormality, consistent with prior conventional karyotyping data. Mosaic aneuploidy was detected in seven cases (2.0%). Notably, the frequency of triploidy was 2.3%, 10-fold lower than the reported frequency in non-ART pregnancies. Structural rearrangements were identified in nine samples (3%), but there was no case of segmental mosaicism. CONCLUSIONS: These data suggest that NGS-based sWGS, with the aid of QF-PCR, is a viable alternative karyotyping procedure that does not require cell culture. This method could also assist with genetic counseling for couples who undergoes embryo selection based on PGT-A data.

AIM: We aimed to evaluate the sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of noninvasive prenatal testing (NIPT) in high-risk pregnant women. METHODS: Pregnant women who underwent GeneTech NIPT, the most commonly used NIPT in Japan, between January 2015 and March 2019, at Japan NIPT Consortium medical sites were recruited for this study. The exclusion criteria were as follows: pregnant women with missing survey items, multiple pregnancy/vanishing twins, chromosomal abnormalities in the fetus other than the NIPT target disease, and nonreportable NIPT results. Sensitivity and specificity were calculated from the obtained data, and maternal age-specific PPV and NPV were estimated. RESULTS: Of the 45 504 cases, 44 263 cases fulfilling the study criteria were included. The mean maternal age and gestational weeks at the time of procedure were 38.5 years and 13.1 weeks, respectively. Sensitivities were 99.78% (95% confidence interval [95% CI]: 98.78-99.96), 99.12% (95% CI: 96.83-99.76), and 100% (95% CI: 88.30-100) for trisomies 21, 18, and 13, respectively. Specificities were more than 99.9% for trisomies 21, 18, and 13, respectively. Maternal age-specific PPVs were more than 93%, 77%, and 43% at the age of 35 years for trisomies 21, 18, and 13, respectively. CONCLUSION: The GeneTech NIPT data showed high sensitivity and specificity in the detection of fetal trisomies 21, 18, and 13 in high-risk pregnant women, and maternal age-specific PPVs were obtained. These results could provide more accurate and improved information regarding NIPT for genetic counseling in Japan.

OBJECTIVE: The proprotein convertase furin is known to be involved in the processing of pro-B-type natriuretic peptide (proBNP) and prorenin receptor (PRR), suggesting that it has a potential function in blood pressure regulation. We investigated the role of furin in the etiology of pre-eclampsia and its related disorder, unexplained fetal growth restriction (FGR) without hypertension. METHODS: We evaluated serum and placental furin levels in pre-eclampsia, FGR and uncomplicated pregnancy. Additionally, we investigated the correlation between the serum furin levels and products of furin enzymatic activity or clinical parameters. RESULTS: We demonstrated that the maternal circulation in cases of pre-eclampsia and FGR had lower levels of soluble furin than uncomplicated pregnancies. Both NT-proBNP and soluble PRR were elevated in pre-eclampsia, whereas only soluble PRR was at higher levels in unexplained FGR. Linear regression analysis revealed a negative correlation between the serum furin level and that of NT-proBNP or soluble PRR. While we observed that the serum furin or soluble PRR level correlated with blood pressure, a stronger correlation was observed with birth and placental weights. Further to this, the FURIN mRNA levels were significantly reduced in placental pre-eclamptic placentas as well as in FGR cases. CONCLUSION: These data suggest the possibility that reduced levels of furin may be the result of a negative feedback from the activation of the renin-angiotensin pathway that leads to feto-placental dysfunction with or without maternal hypertension. This may represent an etiologic pathway of pre-eclampsia and unexplained FGR.

poly(ADP-ribose)polymerase(PARP)阻害薬であるオラパリブは、プラチナ感受性再発卵巣癌に対して化学療法奏効後の維持療法として用いることで無増悪生存期間の有意な延長が示されている。本研究では、再発時にオラパリブ維持療法の適応となりうる卵巣癌患者の割合および背景を後方視的に検討した。2011年1月から2015年12月に藤田医科大学病院にて標準的な初回治療が施行された上皮性卵巣癌(卵管癌、原発性腹膜癌を含む)患者105例を対象とした。プラチナ感受性再発患者およびオラパリブ維持療法の適応となる患者の割合、背景、治療転帰につき後方視的に解析した。対象とした105例のうち再発を認めた患者は35例(33%)であり、プラチナ抵抗性再発は14例(13%)、プラチナ感受性再発は21例(20%)であった。プラチナ感受性再発患者21例に対する二次化学療法レジメンはパクリタキセル+カルボプラチン(TC)療法が最も多く、ベバシズマブ併用は6例(29%)であった。二次化学療法の奏効は、complete response(CR)が10例(48%)、Partial response(PR)が2例(10%)であった。再発治療でのオラパリブ維持療法の適応となりうる患者は上記の12例であり、再発患者の34%(12/35)、プラチナ感受性再発患者の57%(12/21)であった。プラチナ感受性再発に対する二次化学療法後のdisease-free interval(DFI)中央値は7ヵ月(3-18ヵ月)であった。プラチナ感受性再発患者の半数以上でオラパリブ維持療法の適応となることが示された。現行治療では再増悪時にプラチナ抵抗性となる可能性があり、オラパリブ維持療法によるDFIの延長が期待される。(著者抄録)

[目的]Retained products of conception(RPOC)とは、妊娠終了後に妊娠に関連する組織が子宮内に残存した状態で、産褥晩期出血の一因となるが、本邦では診断基準や管理方法が確立されていないのが現状である。そこで、本疾患の病態解明と管理指針の確立をめざして、当施設で経験したRPOCとその対応の現状について臨床的検討を行った。[方法]院内倫理審査委員会の承認の下、2012年から2019年の8年間に当院で経験したRPOCの臨床所見と治療について、診療録を用いて後方視的に検討を行った。[成績]対象期間中のRPOCは20例で、平均年齢は34歳(27-40)、先行妊娠の転帰は、流産(人工妊娠中絶含む)が7例、分娩が13例(正期産12例、早産1例)で、分娩様式は、経腟分娩10例、帝王切開分娩3例であった。治療法は、子宮収縮剤投与による保存的治療が4例で、これら全てが自然退縮し、外科的治療を行ったのは16例(子宮内容除去術5例、子宮鏡下経頸管的切除術10例、腹式単純子宮全摘出術1例)であった。超音波ドプラ検査で豊富な腫瘤内血流を認めたのは20例中18例で、このうち15例に外科的治療を行なった。大量出血により緊急対応を必要とした4例中3例に子宮動脈塞栓術(UAE)を実施したが、これら4例の腫瘤最大径は、それ以外の16例に比して有意に大きかった(62.5mm vs 27.2mm)(p<0.05)。[結論]RPOCの病態は多彩であり、保存的治療も選択肢となり得るが、腫瘤の大きさと経腟超音波ドプラ検査による腫瘤内血流所見が外科的治療を考慮するポイントとなる。(著者抄録)

BACKGROUND: Soluble fms-like tyrosine kinase 1 (sFlt-1) is believed to be a prominent component in the pathogenesis of pre-eclampsia, although the precise etiology has remained elusive. In this study, the etiological role of FLT1 variant was further validated in pre-eclampsia by examining this association in a Japanese sample population. METHODS: The genotypes of three variants (rs4769613, rs12050029 and rs149427560) were examined in the upstream region of the FLT1 gene in placentas from pre-eclamptic (n=47) or normotensive control (n=49) pregnancy samples. Additionally, FLT1 mRNA levels in placenta were determined by qRT-PCR. ELISA was further used to detect circulating sFlt-1 levels in maternal sera. The intergroup comparisons were made using the Mann-Whitney U test or one way analysis of variance and P values of less than 0.05 were considered statistically significant. RESULTS: First, the rs4769613 (C>T) and rs12050029 (G>A) genotypes were examined in placentas but no significant differences were found in the genotype or allele-type frequencies. Next, nearby short tandem repeat, rs149427560, was examined which manifested four size variants. In the genotypewise analysis, the frequency of the 474/476 heterozygote was significantly lower in pre-eclampsia (p<0.05). As expected, the FLT1 mRNA levels were significantly elevated in the pre-eclamptic placentas and sFlt-1 was higher in pre-eclamptic maternal sera. However, the genotype of these variants did not affect the FLT1 mRNA or serum sFlt-1 levels. CONCLUSION: Our findings did not support the hypothesis that genetic variations around the FLT1 gene affect the subtle expression changes underlying the etiologic pathway of pre-eclampsia. The hypothesis deserves further investigation through a larger sample size.

<title>Abstract</title> <sec> <title>Background</title> Human herpesvirus 6 (HHV-6) can be genetically transmitted from parent to child as inherited chromosomally integrated HHV-6 (iciHHV-6). HHV-6 reactivation occurs in pregnant women with iciHHV-6. We found no sex differences in the frequency of index cases with iciHHV-6 but inheritance from the father was more common. We evaluated the association between iciHHV-6 status and spontaneous abortion. </sec> <sec> <title>Methods</title> iciHHV-6 was confirmed by high viral DNA copy numbers in whole blood and somatic cells. The origin of integrated viral genome, paternal or maternal, was examined using the same method. The pregnancy history of 23 mothers in families with iciHHV-6 and 285 mothers in families without iciHHV-6 was abstracted. </sec> <sec> <title>Results</title> Of 23 iciHHV-6 index cases, 8 mothers and 15 fathers had iciHHV-6. Spontaneous abortion rates in mothers with and mothers without/fathers with iciHHV-6 and mothers in families without iciHHV-6 were 27.6%, 10.3%, and 14.8%, respectively (P = .012). Mothers with iciHHV-6 (odds ratio [OR], 6.41; 95% confidence interval [CI], 1.10–37.4) and maternal age at the most recent pregnancy ≥40 years (OR, 3.91; 95% CI, 1.30–11.8) were associated with 2 or more spontaneous abortions. </sec> <sec> <title>Conclusions</title> Mothers with iciHHV-6 is a risk factor for spontaneous abortion. </sec>

© 2020 The Author(s). Background: Women who receive negative results from non-invasive prenatal genetic testing (NIPT) may find that they later have mixed or ambivalent feelings, for example, feelings of accepting NIPT and regretting undergoing the test. This study aimed to investigate the factors generating ambivalent feelings among women who gave birth after having received negative results from NIPT. Methods: A questionnaire was sent to women who received a negative NIPT result, and a contents analysis was conducted focusing on ambivalent expressions for those 1562 women who responded the questionnaire. The qualitative data gathered from the questionnaire were analyzed using the N-Vivo software package. Results: Environmental factors, genetic counseling-related factors, and increased anticipatory anxiety, affected the feeling of ambivalence among pregnant women. Furthermore, pregnant women desired more information regarding the detailed prognosis for individuals with Down syndrome and living with them and/or termination, assuming the possibility that they were positive. Conclusions: Three major interrelated factors affected the feeling of ambivalence in women. Highlighting and discussing such factors during genetic counseling may resolve some of these ambivalences, thereby enhancing the quality of decisions made by pregnant women.

Examination of maternal plasma cell-free DNA (cfDNA) for noninvasive prenatal testing for fetal trisomy is a highly effective method for pregnant women at high risk. This can be also applied to fetal gender determination in female carriers of severe X-linked disease. Polymerase chain reaction (PCR) analysis is a relatively simpler and less expensive method of detecting Y chromosome-specific repeats (Y-specific PCR; YSP), but is limited by the risk of false-negative results. To address this, we have developed a combined strategy incorporating YSP and an estimation of the fetal DNA fraction. Multiplex PCR for 30 single nucleotide polymorphism (SNP) loci selected by high heterozygosity enables the robust detection of the fetal DNA fraction in cfDNA. The cfDNA sample is first subjected to YSP. When the YSP result is positive, the fetus is male and invasive testing for an X-linked mutation is then required. When the YSP result is negative, the cfDNA sample is analyzed using multiplex PCR. If fetal DNA is then found in the cfDNA, invasive testing is not then required. If the multiplex PCR analysis of cfDNA is negative for fetal DNA, the fetal gender cannot be determined and invasive testing is still required. Our technique provides a potentially effective procedure that can help to avoid unnecessary invasive prenatal testing in some female carriers of severe X-linked disease.

Recent findings have highlighted the possibility that polymorphisms within the annexin A5 gene (ANXA5) promoter contribute to the etiology of various obstetric complications. However, the underlying mechanisms are unknown. The M2 haplotype of the ANXA5 shows lower activity and less expression of ANXA5 mRNA. This gene promoter region has a motif that potentially forms a G-quadruplex structure. In vitro G-quadruplex propensity estimated by circular dichroism indicated that the M2 haplotype oligonucleotide manifested a decreased potential for G-quadruplex formation. In addition, in vivo G-quadruplex formation of the promoter region was evidenced by the presence of single-stranded DNA shown by sodium bisulfite treatment of placental genomic DNA. Comparative analysis indicated less potential in the M2 allele than the major allele. Promoter activity of the two haplotypes determined by luciferase reporter analysis correlated with the estimated G-quadruplex propensity. Our data lend support to the developing paradigm that genomic variation affects gene expression levels via DNA secondary structures leading to the disease susceptibility.

先天性肺気道奇形(Congenital pulmonary airway malformations:CPAM)は、胎児期に気管支系や肺胞の発達異常によって生じる先天性肺腫瘤で、近年では胎児超音波スクリーニングが普及し、出生前に診断される症例が増加している。本症の予後は一般に良好であるが、腫瘤の増大に伴い胎児水腫をきたす場合があり、胎児治療の手段として嚢胞羊水腔シャントや経母体ステロイド投与の有効性が報告されている。今回、出生前にCPAMと診断し、胎児腹水と羊水過多を合併した症例に経母体ステロイド投与を行い、胎児腹水の消失と腫瘍の縮小を認めた症例を経験した。症例は37歳、2妊1産。前医で妊娠20週の胎児超音波検査で左胸腔内に類円形の高輝度腫瘤を認め、本症を疑い経過観察が行われたが、妊娠23週より胎児腹水が出現し、妊娠25週で当院へ紹介となった。初診時の超音波検査で、左胸腔内に類円形の高輝度腫瘤像を認め、心臓が右側に偏位し、さらに胎児腹水と羊水過多(Amniotic fluid index:AFI 25.3cm)を認めた。また、腫瘤内への大血管からの血流はなく、実質性腫瘤像を呈することからCPAMのmicrocystic typeと診断した。胎児水腫の基準は満たさないが、腫瘤の増大に伴う圧迫による影響を考慮して、ステロイド治療の適応と判断した。インフォームド・コンセントを行った上で、妊娠26週0日に母体にbetamethazone 12mgを24時間おきに2回投与した。その後、3D超音波検査によるフォローアップで腫瘤は徐々に縮小し、妊娠32週には検出不能となり、胎児腹水は消失し羊水過多は改善し、妊娠39週1日に自然経腟分娩となった。児は3345gでApgar Score 9/9で出生し、出生時の胸部CTで左肺の過膨張と10mm大の嚢胞像を認めたが、呼吸障害を認めなかった為、待機的管理とした。その後、2歳時に肺炎を繰り返した為、胸腔鏡下左肺上葉切除術が施行されたが、術後経過は良好である。本症例のようなCPAMに対する3D超音波検査による診断は腫瘤の正確な評価を可能とし、経母体的ステロイド療法は、胎児予後の改善に寄与する可能性がある。(著者抄録)

遺伝性乳癌卵巣癌症候群(以下HBOC:hereditary breast and ovarian cancer syndrome)はBRCA遺伝子の変異があり、乳癌や卵巣癌などに罹患するリスクが高い遺伝性腫瘍症候群の一つである。当施設では、HBOC関連癌のうち卵巣癌、卵管癌および腹膜癌の診療にあたり、卵巣癌未発症のBRCA変異保持者に対してサーベイランスおよびリスク低減卵管卵巣摘出術(以下RRSO:risk-reducing salpingo-oophorectomy)を提供している。今回は、HBOCに対してRRSOを施行した一例について考察を加えて報告する。【症例】47歳。2妊2産。子宮筋腫の既往あり。乳癌に罹患した姉にBRCA2遺伝子に変異を認めたことから、BRCA遺伝学的検査目的にカウンセリング室を来談し、検査の結果HBOCと診断され、RRSO施行の是非について相談のため産婦人科に紹介受診となった。患者はRRSO施行推奨年齢に達していたため、RRSOのメリットとデメリットを説明し、RRSOを行う方針となった。手術は腹腔鏡下で両側付属器切除を行い、切除検体については詳細な病理学的検討を行って、STIC(Serous tubal intraepithelial carcinoma)や浸潤癌がないことを確認した。術後は腹膜癌発症の有無を経過観察中である。HBOCは通常の産婦人科患者のうち一定の割合を占める比較的頻度の高い遺伝性腫瘍である。産婦人科医師はBRCA1/2変異保持者に対しては卵巣癌サーベイランスの限界、リスク低減手術の予想される効果と副作用を説明できる知識をもち、RRSOを行うにあたっては、卵巣癌の易罹患者であることを念頭においた手術操作、術後管理が必要である。(著者抄録)

Thanatophoric dysplasia and achondroplasia are allelic disorders caused by a constitutively active mutation in the FGFR3 gene. Because thanatophoric dysplasia is a lethal disorder and achondroplasia is non-lethal, they need to be distinguished after ultrasound identification of fetal growth retardation with short limbs. Accordingly, we have developed a noninvasive prenatal test using cell-free fetal DNA in the maternal circulation to distinguish thanatophoric dysplasia and achondroplasia. A multiplex PCR system encompassing five mutation hotspots in the FGFR3 gene allowed us to efficiently identify the responsible mutation in cell-free DNA in all examined pregnancies with a suspected thanatophoric dysplasia or achondroplasia fetus. This system will be helpful in the differential diagnosis of thanatophoric dysplasia and achondroplasia in early gestation and in couples concerned about the recurrence of thanatophoric dysplasia due to germinal mosaicism.

OBJECTIVE: To evaluate the reasons for nonreportable cell-free DNA (cfDNA) results in noninvasive prenatal testing (NIPT), we retrospectively studied maternal characteristics and other details associated with the results. METHODS: A multicenter retrospective cohort study in pregnant women undergoing NIPT by massively parallel sequencing (MPS) with failed cfDNA tests was performed between April 2013 and March 2017. The women's data and MPS results were analyzed in terms of maternal characteristics, test performance, fetal fraction (FF), z scores, anticoagulation therapy, and other details of the nonreportable cases. RESULTS: Overall, 110 (0.32%) of 34 626 pregnant women had nonreportable cfDNA test results after an initial blood sampling; 22 (20.0%) cases had a low FF (<4%), and 18 (16.4%) cases including those with a maternal malignancy, were found to have altered genomic profile. Approximately half of the cases with nonreportable results had borderline z score. Among the women with nonreportable results because of altered genomic profile, the success rate of retesting using a second blood sampling was relatively low (25.0%-33.3%). Thirteen (11.8%) of the women with nonreportable results had required hypodermic heparin injection. CONCLUSIONS: The classification of nonreportable results using cfDNA analysis is important to provide women with precise information and to reduce anxiety during pregnancy.

現在、子宮筋腫などの良性腫瘍に対する手術療法としては腹腔鏡手術が広く普及し、そのうち根治的治療として腹腔鏡下子宮全摘出術が最も施行されている術式と思われる。当施設では、腹腔鏡手術を開始して以来、手術手技の習熟と術式の改良を重ねた結果、子宮体部切断後に頸部摘出を行うtwo steptotal laparoscopic hysterectomy(TTLH)を標準術式として実践している。一方、米国では2000年以降子宮亜全摘出術(laparoscopic subtotal hysterectomy;LSH)を施行する施設が増加し、近年は本邦でも一般的に実践されるようになってきている。しかしながら、両術式の優劣については一定の見解が得られていないため、2008年から2013年までに当施設で施行したTTLH群;32例およびLSH群;22例の手術成績や合併症、術後の機能回復などに与える影響について比較検討した。TTLH群とLSH群を比較した結果は、手術時間が258.5±9.6分、221.3±7.8分とLSH群で有意な短縮を認めるとともに(p&lt;0.01)、一方排尿機能は、有意差は認められないものの、8.0±9.1日、5.0±2.5日とLSH群で回復日数が早い傾向にあった(p=0.09)。また、術後合併症については、TTLH群で受診ないしは治療を要する腟断端部出血1例、腟断端部感染1例の計2例(6.3%)を認めたのに対し、LSH群では少量のcyclic bleedingを2例(9.1%)に認めた。子宮筋腫などの良性疾患に対する手術治療にあたっては、両術式における特有の合併症等を考慮し、各患者のニーズに応じた術式を選択することが重要と思われた。(著者抄録)

子宮筋腫、子宮腺筋症の術後早期に発症し、種々のホルモン治療に抵抗性を示し、かつ閉経後もなお増悪した深部子宮内膜症の1例を経験したので報告する。症例は46歳、G4P3、月経困難症のため当院を受診、子宮筋腫および子宮腺筋症の診断のもとに腹腔鏡下子宮亜全摘術、左付属器切除術を行った。術中所見では子宮後面に左側付属器が強固に癒着していたが、ダグラス窩には癒着を認めなかった(ASRM:8)。術後4ヵ月頃から背部痛、左足のしびれが出現し、尿管狭窄にともなう左水腎症を認めた。腟円蓋部5時方向に母子頭大の暗赤色の腫瘤発現を認め、直腸診では同腫瘤より左骨盤壁にかけて圧痛を伴う硬結を認めた。腟円蓋部腫瘤の生検にて子宮内膜症の所見を得た。そこで尿管ステントの留置の上GnRHアゴニスト製剤の投与を開始した。しかし、尿管狭窄に対する薬物治療の効果が不十分のため尿管新吻合術による尿路変更を行った。年齢が47歳であったため追い込み療法としてGnRHアゴニストに加え、ジエノゲスト、ダナゾール投与を繰り返したが左骨盤側壁の病変は薬物抵抗性を示し、また治療経過中に閉経となったが深部子宮内膜症の病勢は衰えなかった。以上の経過より薬物療法無効および癌化の可能性を考慮し、54歳時に根治を目的に腹腔鏡下深部子宮内膜症病巣切除術ならびに残存子宮頸部切除術、右付属器切除術を行い、その後の経過は良好であった。(著者抄録)

BACKGROUND: Nectins are cell adhesion molecules that play a pivotal role in adherens junctions and tight junctions. Our previous study using whole-genome oligonucleotide microarrays revealed that nectin-4 was upregulated in pre-eclamptic placentas. We investigated the role of nectin-4 in the etiology of pre-eclampsia. METHODS: We investigated the expression of nectin-4 using real-time RT-PCR, western blot and immunostaining. Additionally, we performed matrigel invasion assay and cytotoxicity assay using cells overexpressing the nectin-4. RESULTS: NECTIN4 transcripts were elevated in pre-eclamptic placentas relative to uncomplicated pregnancies. Nectin-4 protein levels in pre-eclamptic placentas were higher on a semi-quantitative western blot. Nectin-4 was localized at the apical cell membrane in syncytiotrophoblast cells and not at the adherens junctions. Nectin-4 was also detected in cytotrophoblasts and a subset of cells in the decidua. Nectin-4 overexpressing trophoblast cells migrated normally in the matrix. However, Natural killer (NK) cells showed a strong cytotoxic effect against nectin-4 overexpressing trophoblast cells. No causative genetic variation was evident in the NECTIN4 gene from a pre-eclamptic placenta. CONCLUSIONS: There are as yet unknown factors that induce nectin-4 overexpression in trophoblast cells that may contribute to abnormal placentation via an aberrant immune response and the onset of a pre-eclamptic 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.