伊藤 真友子

OBJECTIVE: Uterine carcinosarcoma (UCS) is a rare and aggressive gynecological cancer with high recurrence rates and is associated with a poor prognosis. It is also characterized by a high frequency of copy number alterations (CNAs). This study aimed to determine which gene CNA contributes to progression-free survival (PFS) in patients with UCS to identify potential prognostic biomarkers and therapeutic targets. METHODS: DNA was extracted from formalin-fixed paraffin-embedded tissues of surgical specimens from 24 patients with UCS who were treated at Fujita Health University. Using the PleSSision-Rapid test, the mutation information of 145 cancer genes was analyzed. Oncoplot analysis was used to visualize gene mutation profiles. χ2 test, Kaplan-Meier analysis, and log-rank test were used for statistical analyses. RESULTS: The most frequently observed gene mutation was TP53 in the 24 UCS cases studied, while genes associated with the PI3K/AKT/mTOR signaling pathway, including PIK3CA, PTEN, PIK3R1, and PIK3R2 were commonly detected. In the χ2 test analysis, TP53 loss (p=0.029), PIK3CA amplification (p=0.034), and TSC2 loss (p=0.034) were significantly associated with recurrence. Kaplan-Meier survival analysis demonstrated a significant association between PIK3CA amplification and TSC2 loss with PFS, as determined by the log-rank test (p<0.05). CONCLUSION: In patients with UCS, TSC2 loss is linked to poorer PFS, highlighting its utility as a prognostic marker. The association between TSC2 loss and increased recurrence risk highlights the potential therapeutic advantage of targeting the mTOR pathway in TSC2-deficient tumors.

INTRODUCTION: Alternative RNA splicing adds diverse variations to gene function, and its abnormalities are occasionally associated with the etiology of disease. We examined this possibility in pre-eclampsia. METHODS: We performed transcriptome analysis of placentas from pre-eclamptic and normotensive pregnancies and screened for disease-specific aberrant splicing. RESULTS: We identified aberrant splicing at exon 14 in the ZC3H4 gene. This in-frame exon is generally skipped in placentas from normal pregnancies but often observed in those from pre-eclampsia patients. The level of exon inclusion did not correlate with disease severity, such as blood pressure or fetal weight, but showed an association with the decrease in placental weight. Significantly, placental blood flow resistance measured by Doppler ultrasound correlated with the level of ZC3H4 exon 14 inclusion, suggesting that this retention leads to the onset and/or symptoms of pre-eclampsia. ZC3H4 is known to act on transcriptional regulation via suppression of lncRNA expression. Moreover, the SOD1 gene, encoding superoxide dismutase that eliminates toxic free superoxide radicals, was identified in the downstream gene group for ZC3H4. Indeed, the expression of SOD1 was found in this current study to be decreased in the pre-eclamptic placenta in correlation with the levels of ZC3H4 exon 14 retention. DISCUSSION: Aberrant splicing of ZC3H4 gene may induce excessive oxidative stress in the placenta via the downregulation of downstream SOD1 expression thereby leading to the onset and development of pre-eclampsia.

INTRODUCTION: The da Vinci SP surgical system is a surgical platform capable of implementing robotic-assisted surgery through a single port and was first introduced in Japan at our hospital. In this paper, we describe our experience of the initial introduction of the da Vinci SP surgical system and its surgical outcomes. This is the first report on the surgical outcomes of using da Vinci SP, and its comparison with the conventional system in Japan. METHODS: After developing an application for a highly difficult new medical technology in-house, we compared the surgical outcomes (median values) of 15 patients who had undergone total hysterectomy at our hospital using the da Vinci SP (1-port) system (SP group) for uterine myoma after March 2023 and of 154 patients who underwent total hysterectomy using the conventional da Vinci Xi (four ports) system (Xi group) for uteri weighing <500 g. RESULTS: The results of the comparison of the characteristics between 15 patients in the SP group and 154 patients in the Xi group were as follows: uterus weight (g): 230 (90-500) versus 222 (55-496) (p = .35); surgical time (minutes): 199 (171-251) versus 198 (88-387) (p = .63); intraoperative blood loss (mL): 13 (5-82) versus 20 (2-384) (p = .17); and rate of surgical complication (%): 0.0 versus 1.3 (p = .66). The data indicated a comparable weight of the resected uterus, surgical time, intraoperative blood loss, and rate of surgical complications between the two groups. CONCLUSION: Robotic-assisted total hysterectomy using the da Vinci SP surgical system allowed clinicians to safely perform surgeries according to the conventional systems.

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.