宮村 浩徳

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)

症例は65歳女性、ネフローゼ症候群の精査加療目的のため当院腎臓内科に入院管理となった。腎生検で膜性腎症と診断されたが、ステロイド治療に抵抗性であったため、二次性膜性腎症が疑われた。原因検索として行ったCT検査で子宮頸部に腫瘤性病変を認めたため、当科に紹介となった。子宮頸部腫瘍の病理診断は扁平上皮癌であり、MRI検査で長径96mmの腫瘍を認め、腟および膀胱への浸潤と坐骨転移を認めた。以上より、二次性膜性腎症を合併した子宮頸癌FIGO stage IV B期(TNM;T4N1M1)と診断し、シスプラチンを用いた同時化学放射線療法(concurrent chemoradiotherapy;以下CCRT)を行った。CCRT施行後、子宮頸部腫瘤は消失し病理学的完全奏効となり、同時に膜性腎症も改善した。現在治療開始後30ヵ月が経過し、再発なく経過観察中である。悪性腫瘍に起因した二次性膜性腎症においては、腎機能を含めた全身状態を考慮した上で積極的な抗腫瘍治療が重要と考えられた。(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)

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.

Atrial natriuretic peptide is biologically activated by the atrial natriuretic peptide-converting enzyme, corin, and has an important role in regulating blood pressure. We detected elevated serum corin levels in women with pre-eclampsia. Interestingly, the serum corin levels were also found to be elevated in pregnancies with a related disorder, unexplained fetal growth restriction (FGR) without hypertension, suggesting that this phenomenon is not simply a response to maternal hypertension. CORIN mRNA levels were not elevated in placentas from pre-eclampsia or unexplained FGR cases. Likewise, similar signal intensities were found for corin in placental syncytiotrophoblast cells by immunostaining. In contrast, corin signals were higher in maternal decidua cells from pre-eclampsia and unexplained FGR cases. These data suggest that corin may be upregulated in maternal decidua in response to an etiologic pathway that is common to pre-eclampsia and FGR.

Although embryo screening by preimplantation genetic diagnosis (PGD) has become the standard technique for the treatment of recurrent pregnancy loss in couples with a balanced gross chromosomal rearrangement, the implantation and pregnancy rates of PGD using conventional fluorescence in situ hybridization (FISH) remain suboptimal. Comprehensive molecular testing, such as array comparative genomic hybridization and next-generation sequencing, can improve these rates, but amplification bias in the whole genome amplification method remains an obstacle to accurate diagnosis. Recent advances in amplification procedures combined with improvements in the microarray platform and analytical method have overcome the amplification bias, and the data accuracy of the comprehensive PGD method has reached the level of clinical laboratory testing. Currently, comprehensive PGD is also applied to recurrent pregnancy loss due to recurrent fetal aneuploidy or infertility with recurrent implantation failure, known as preimplantation genetic screening. However, there are still numerous problems to be solved, including misdiagnosis due to somatic mosaicism, cell cycle-related background noise, and difficulty in diagnosis of polyploidy. The technology for comprehensive PGD also requires further improvement.

OBJECTIVE: A common haplotype M2 consisting of minor SNP alleles located in the ANXA5 gene promoter region has been described as a risk factor for various obstetric complications such as recurrent pregnancy loss, pre-eclampsia and pregnancy-related thrombophilic disorder. However, the question of whether it is the maternal or fetal genotype that contributes to the onset of these disorders remains to be resolved. METHODS: We analyzed ANXA5 gene variants in the blood and placental tissues from pre-eclampsia patients and normotensive controls. ANXA5 expression was examined by qRT-PCR, Western blotting and immunostaining. Results were compared between M2 and non-M2 carriers. RESULTS: The M2 haplotype was found to be significantly frequent in placentas from pre-eclamptic patients relative to the controls (25.5% versus 10%, P = 0.044), In contrast, no significant differences were observed in maternal blood (13.0% versus 11.3%, P = 0.597). The placental expression of ANXA5 mRNA was found to be lower in M2 carriers. When examined by Western blot and immunostaining, the ANXA5 protein levels were found to be affected more by the placental than the maternal genotype. Histological examination of the placentas from the pre-eclamptic patients demonstrated that a placental M2 haplotype correlated more closely than maternal M2 with the severity of perivillous fibrin deposition. CONCLUSIONS: Although preliminary, these results suggest that hypomorphic M2 alleles in the in placental ANXA5 promoter, whether transmitted maternally or paternally, might be an essential determinant of an increased risk of pre-eclampsia via local thrombophilia at the feto-maternal interface.

OBJECTIVE: It is well documented that anti-angiogenic factors are likely to play essential roles in the etiology of pre-eclampsia. Apelin is a small peptide that may potentially act as an angiogenic factor. The expression of apelin was examined at the RNA and protein levels in this study. METHODS: We compared the expression of apelin, examined using quantitative reverse-transcription polymerase chain reaction, western blotting, enzyme-linked immunosorbent assay and immunostaining, between pre-eclamptic patients and normotensive controls. RESULTS: Apelin messenger RNA is significantly decreased in pre-eclamptic placentas compared with normotensive pregnancies (p<0.05). Apelin protein levels are also lower in pre-eclamptic placentas than the controls but higher in the maternal circulation in pre-eclampsia patients. Immunohistochemical signals for apelin and its receptor APJ were detected mainly in the cytoplasm of syncytiotrophoblasts in chorionic villi and trophoblast-lineage cells in the decidua of term placentas. In early gestation, stronger APJ signals were observed at the cellular membrane. CONCLUSIONS: A functional role of the apelin--APJ system is likely in early gestation, and this raises the possibility that a dysfunctional apelin--APJ system contributes to the onset of pre-eclampsia via decreased angiogenic activity in placental implantation.

We encountered a 46-year-old woman with synchronous quintuple primary cancers. She did not present with any symptoms, and her tumors were discovered at a gynecological screening. She had clear cell adenocarcinoma of the right ovary, moderately differentiated endometrioid adenocarcinoma of the endometrium, moderately differentiated adenocarcinoma of the ascending colon, well-differentiated adenocarcinoma of the rectum, and poorly differentiated papillary adenocarcinoma of the left lung. A fluorodeoxyglucose-positron emission tomography and other imaging techniques were extremely useful for the diagnosis of multiple primary cancers. Moreover, MSH2 protein expression was absent in the tumors of the ovary, endometrium, ascending colon, and rectum, while the rectal cancer also lacked MLH1 protein. These findings suggested that an abnormality of DNA mismatch repair genes was responsible for carcinogenesis.

Recent findings have raised the possibility that polymorphisms within the annexin A5 gene (ANXA5) promoter contribute to the etiology of recurrent pregnancy loss (RPL). In our present study, 243 Japanese women who had suffered more than three fetal losses and a group of 119 fertile controls were genotyped for four ANXA5 gene promoter single-nucleotide polymorphisms (SNPs; SNP1-4: g.-467G >A, g.-448A>C, g.-422T>C, g.-373G>A) previously reported to be associated with this disorder. An additional two SNPs located within the 5'-untranslated region of the ANXA5 (SNP5 and 6: g.-302T>G, g.-1C>T) were also evaluated. Our case--control study revealed that the minor allele was significantly more frequent in the RPL group than controls for all six of these SNPs, among which SNP5 showed the highest significance (P= 0.002). As with the M2 haplotype for SNP1-4 (A-C-C-A) for a western population in previous reports, a haplotype comprising all of the minor alleles for SNP1-6 (A-C-C-A-G-T), the third major haplotype in the Japanese population, showed a significantly higher frequency in our current RPL subjects than in controls (P= 0.025). In addition, the second major haplotype (G-A-T-G-G-C) was found to confer a significant risk of RPL (P= 0.036), implicating SNP5 as a major risk determinant for this disease. Our present findings support the hypothesis that genomic variations within the ANXA5 gene upstream region impact upon the disease susceptibility to RPL. Our data indicate that SNP5 is a novel risk factor for this disease in the Japanese population.