Establishment and characterization of a non-gestational choriocarcinoma patient-derived xenograft model.

BACKGROUND: Non-gestational choriocarcinoma (NGC) is a rare subtype of malignant germ cell tumour and there is no consensus on its treatment. The lack of suitable preclinical models for NGC is a challenge in drug discovery research. Patient-derived xenograft (PDX) models recapitulate the tumour microenvironment of the original cancer tissue. Therefore, they have received considerable attention for studies on rare cancer. Here, we aimed to establish a PDX model from a patient with recurrent NGC. METHODS: Fresh NGC tumour tissue was immediately transplanted into a severely immune-deficient mouse (NOD.Cg-Prkdcscid1l2rgtm1Wjl/SzJ) and maintained for more than three in vivo passages. Subsequently, we evaluated the molecular characteristics of the PDX model using immunohistochemistry, polymerase chain reaction, and RNA sequencing. Moreover, the PDX tumours were transplanted into BALB/c nude mice, and we evaluated their sensitivity for cisplatin and methotrexate. RESULTS: The PDX tumour maintained the morphological features of NGC. Moreover, Immunohistochemistry revealed that the human chorionic gonadotropin, cytokeratin 7, and EpCAM expression levels were similar to those in the primary tumour. Furthermore, serum human chorionic gonadotropin levels were elevated in both the primary tumour and the PDX models. Additionally, using PCR analysis with species-specific primers, we confirmed that the PDX tumour contained human genes and was derived from human tissue. Moreover, the gene expression profile of the NGC was compared with that of epithelial ovarian cancer samples and cell lines, and 568 dysregulated genes in the NGC were extracted. The expression of the dysregulated genes in PDX was significantly correlated with that in the primary tumour (R2 = 0.873, P < 0.001). Finally, we demonstrated that the PDX tumour was sensitive to cisplatin and methotrexate; therefore, its clinical response to the agents was similar to that of the primary tumour. CONCLUSIONS: We successfully established a PDX model of NGC, to the best of our knowledge, for the first time. The established PDX retained the molecular and transcriptome characteristics of the primary tumour and can be used to predict drug effects. It may facilitate further research and the development of novel therapeutic agents for NGC.

A case of complete remission of intractable gestational choriocarcinoma with subsequent chemotherapy after pembrolizumab.

OBJECTIVE: Gestational choriocarcinoma is a gestational trophoblastic neoplasia (GTN) that originates from abnormal trophoblast proliferation. Although chemotherapy is effective for choriocarcinoma, personalized treatment becomes essential when patients develop chemoresistance. Here, we present the clinical course of a case of intractable choriocarcinoma that achieved complete remission with pembrolizumab following cytotoxic chemotherapy. CASE REPORT: A 38-year-old woman was initially diagnosed with low-risk GTN and treated with single- and multi-agent chemotherapy. She underwent a hysterectomy and was diagnosed with pathological choriocarcinoma with high-risk GTN. She was treated with multiple courses of several chemotherapy regimens. However, she did not achieve remission. Her choriocarcinoma showed high microsatellite instability; therefore, she took ten courses of pembrolizumab, but her hCG value increased. Subsequently, she underwent eight courses of paclitaxel and carboplatin alternating with paclitaxel and etoposide and achieved remission. CONCLUSION: This case suggests that pembrolizumab may improve the efficacy of subsequent chemotherapy.

The efficacy of therapeutic cervical cerclage in singleton pregnancies: a retrospective study.

OBJECTIVES: We compared the pregnancy prolongation effect attributable to cervical cerclage to that achieved by conservative management, and determined the cervical length for which cervical cerclage is effective. METHODS: We retrospectively examined medical records of 281 women admitted to our hospital between January 2013 and December 2017 for management of threatened preterm birth at 22-28 weeks of gestation. Obstetricians determined suitability for cervical cerclage, which was performed using the McDonald procedure in all cases. Of the 281 subjects, 71 underwent cervical cerclage (cerclage group); the other 210 received conservative therapy (non-cerclage group). We recorded maternal and neonatal characteristics of all patients. The two groups were compared in terms of length of extension of pregnancy and weeks of gestation at delivery. Multivariate analysis was performed to identify factors associated with extension of time to delivery. RESULTS: Our analyses revealed that the cerclage group was hospitalized earlier in pregnancy than the non-cerclage group (23.7 ± 1.5 weeks vs. 26.4 ± 1.9 weeks, p < .001) and had shorter cervixes (6.0 ± 9.4 mm vs. 16.9 ± 13.0 mm, p < .001). The two groups did not differ significantly in terms of gestational weeks at delivery. Multivariate analysis regarding extension of pregnancy revealed significant differences in extension of pregnancy related with cervical cerclage (26.65 days, 95% CI 17.0 - 36.3, p < .001) and cervical length <10 mm (-27.4 days, 95% CI -36.0--18.8, p < .001). While the time to delivery was extended by cervical cerclage in women with short cervixes (<25 mm), the two groups did not differ when cervical length was ≥15 mm. CONCLUSIONS: Cervical cerclage was a significant positive factor and short cervix was a significant negative factor for elongating pregnancy. In primigravida and multigravida women with no history of preterm birth, when the cervix is short (<10 mm), cervical cerclage should be recommended.

Cell surface membrane lysosome-associated membrane glycoprotein 2 promotes cell adhesion via abundant N-glycans in choriocarcinoma.

INTRODUCTION: Lysosome-associated membrane glycoprotein 2 (LAMP-2) is a target protein for glycosylation by N-acetylglucosaminyltransferase IV (GnT-IV), which catalyzes the formation of ß1,4GlcNAc branches on the mannose core of N-glycans in choriocarcinoma cells. However, the role of LAMP-2, especially when it is expressed in the cell surface membrane of choriocarcinoma cells, has not been well investigated in the progression of choriocarcinoma. This study aimed to elucidate the function of the cell surface membrane LAMP-2 in the malignancy of choriocarcinoma. METHODS: We evaluated the localization of LAMP-2 in some choriocarcinoma cell lines and clinical samples of choriocarcinoma, normal placenta, hydatidiform mole, and invasive mole by flow cytometry, immunocytochemistry, and immunohistochemistry. We performed functional experiments using the knockout or overexpression model of LAMP-2 in the presence or absence of galectins. RESULTS: LAMP-2 was observed in the cell surface membrane of some choriocarcinoma cell lines and tumor cells of choriocarcinoma tissue and trophoblasts of the placenta, hydatidiform mole, and invasive mole. Cell surface membrane LAMP-2 knockout decreased cell adhesion and invasion in choriocarcinoma cells. Conversely, cell surface membrane LAMP-2A overexpression increased cell adhesion and invasion. Experiments in the presence of galectins revealed that abundant N-glycans bound to the peptide core of the luminal side of the cell surface membrane LAMP-2 mediated cell adhesion of choriocarcinoma cells by interacting with galectins in the extracellular matrix (ECM). DISCUSSION: Cell surface membrane LAMP-2, which is glycosylated by GnT-IV, contributes to the malignancy of choriocarcinoma by promoting cell adhesion with the ECM via abundant N-glycans.

Evaluation of the risk of umbilical cord prolapse in the second twin during vaginal delivery: a retrospective cohort study.

OBJECTIVE: This study aimed to evaluate the success rate of vaginal delivery, the reasons for unplanned caesarean delivery, the rate of umbilical cord prolapse and the risk of umbilical cord prolapse in twin deliveries. DESIGN: Retrospective cohort study. SETTING: Single institution. PARTICIPANTS: This study included 455 women pregnant with twins (307 dichorionic and 148 monochorionic) who attempted vaginal delivery from January 2009 to August 2018. The following criteria were considered for vaginal delivery: diamniotic twins, cephalic presentation of the first twin, no history of uterine scar, no other indications for caesarean delivery, no major structural abnormality in either twin and no fetal aneuploidy. RESULTS: The rate of vaginal delivery of both twins was 89.5% (407 of 455), caesarean delivery of both twins was 7.7% (35 of 455) and caesarean delivery of only the second twin was 2.9% (13 of 455). The major reasons for unplanned caesarean delivery were arrest of labour and non-reassuring fetal heart rate pattern. The rate of umbilical cord prolapse in the second twin was 1.8% (8 of 455). Multivariate analysis revealed that abnormal umbilical cord insertion in the second twin (velamentous or marginal) was the only significant factor for umbilical cord prolapse in the second twin (OR, 5.05, 95% CI 1.139 to 22.472, p=0.033). CONCLUSIONS: Abnormal umbilical cord insertion in the second twin (velamentous or marginal) was a significant factor for umbilical cord prolapse during delivery. Antenatal assessment of the second twin's umbilical cord insertion using ultrasonography would be beneficial.

[PELVIC ORGAN PROLAPSE AND INGUINAL HERNIA AGGRAVATED BY OVARIAN FIBROTHECOMA WITH ASCITES].

We present a case of pelvic organ prolapse and inguinal hernia worsened by a benign ovarian tumor with ascites. A 61-year-old woman was referred to us complaining of feeling of something protruding from her vagina. She was diagnosed with Stage III cystocele. Behavioral therapy was administered as she had only slight subjective symptoms. She visited us eight months later due to a rapid aggravation of cystocele and voiding difficulty. She subsequently developed acute abdominal pain caused by incarcerated inguinal hernia. Abdominal ultrasound, MRI and CT showed a 10.6×9.0 cm pelvic mass with ascites. As an ovarian cancer with peritoneal dissemination was suspected, she immediately underwent total abdominal hysterectomy, bilateral salpingo-oophorectomy and colposuspension. Pathological diagnosis was fibrothecoma, a benign ovarian tumor. Postoperative course was uneventful, and ascites quickly disappeared in a manner similar to Meigs syndrome. Although no procedure was done to manage inguinal hernia, it was unproblematic for 18 months, after that it worsened, necessitating hernial repair. She had no recurrence of prolapse or ascites.Increased intra-abdominal pressure due to abdominal mass or ascites can worsen prolapse and hernial diseases such as inguinal, umbilical, and abdominal hernia. In this case, ovarian fibrothecoma with ascites seemed to be responsible for worsening of the prolapse and inguinal hernia. To conclude, it is important to consider background diseases when examining patients with prolapse and coexisting hernial diseases.