Endometrial Cancer Diagnosed at an Early Stage during Lynch Syndrome Surveillance: A Case Report.

Lynch syndrome is an autosomal dominant inherited disorder caused by a germline pathogenic variant in DNA mismatch repair genes, resulting in multi-organ cancer. Annual transvaginal ultrasonography and endometrial biopsy are recommended for endometrial cancer surveillance in patients with Lynch syndrome in several guidelines; however, evidence is limited. Here, we present the case of a 51-year-old woman with endometrial cancer who underwent robot-assisted laparoscopic simple hysterectomy at an early stage detected by Lynch syndrome surveillance. The patient was a 51-year-old gravida zero woman without any medical history or symptoms. Her sister suffered from bladder, breast, rectal, and endometrial cancer and was diagnosed with Lynch syndrome using a hereditary cancer panel test (VistaSeq®). During gynecologic surveillance, the patient's endometrial cytology was classified as Papanicolaou class III. Therefore, she underwent endometrial curettage with hysteroscopy and was diagnosed with atypical endometrial hyperplasia. Robot-assisted hysterectomy was performed with a final pathological diagnosis of endometrial cancer (endometrioid carcinoma, Grade 1), stage 1A. She has remained disease-free for more than 12 months. Owing to advances in genetic medicine, prophylactic and therapeutic surgeries for hereditary cancers are increasing. To achieve an early diagnosis and treatment of Lynch syndrome-associated cancers, the importance of Lynch syndrome surveillance should be more widely recognized.

A case of a pregnant woman with locally advanced cervical esophageal cancer treated with definitive chemoradiotherapy.

The information of definitive radiotherapy for a pregnant woman with malignancy was limited; however, it was reported to be potentially feasible with minimal risks. We performed definitive chemoradiotherapy for a pregnant woman with locally advanced cervical esophageal cancer. Feasibility of radiotherapy and safety of fetus were confirmed by the phantom study estimating fetal dose, and monitoring it in each radiotherapy session. The planned chemoradiotherapy completely eradicated esophageal cancer while preserving her laryngopharyngeal function. A female infant was delivered by cesarian section after planned chemoradiotherapy, and she grew without any apparent disorders 2 years after chemoradiotherapy. Chemoradiotherapy might be one of the treatment options for a pregnant woman with cervical esophageal cancer especially wishing the preservation of laryngopharyngeal function.

Risk Factors for Septic Shock After Irinotecan-Containing Chemotherapy: An Exploratory Case-Control Study.

BACKGROUND AND OBJECTIVES: Irinotecan sometimes causes lethal septic shock but the risk factors remain unclear. This retrospective case-control study explored the potential risk factors for septic shock following irinotecan treatment. METHODS: All women who received irinotecan-containing chemotherapy for gynecologic malignancies at Shizuoka General Hospital from October 2014 to September 2020 were investigated. The clinical backgrounds and blood test results of those who developed septic shock after irinotecan-containing chemotherapy were compared with those who did not. Odds ratios (ORs) for developing septic shock after receiving irinotecan were calculated with 95% confidence intervals (CIs), using univariable logistic regression analysis. RESULTS: During the study period, 147 women received irinotecan-containing chemotherapy. Three women developed septic shock due to neutropenic enterocolitis after irinotecan treatment, and 144 did not. The three patients with septic shock had recurrent cervical cancer, heterozygous variants in the uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) gene (two patients had *1/*6, one had *1/*28 variants), a history of concurrent chemoradiation therapy, 50-60 Gy of pelvic irradiation, and platinum-combined chemotherapy. A history of pelvic irradiation was identified as a possible risk factor for developing septic shock after irinotecan-containing chemotherapy (OR 63.0, 95% CI 5.71-8635; p < 0.001). The OR of UGT1A1 polymorphism for septic shock was 9.09 (95% CI 0.86-1233; p = 0.070) in the complete case analysis. CONCLUSION: Medical personnel involved in cancer therapy should consider the possible risk of septic shock developing due to neutropenic enterocolitis when administering irinotecan-containing chemotherapy in patients with a history of pelvic irradiation.

Validity of Weekly Administration of Carboplatin after Carboplatin-Induced SIADH: Two Case Reports and Literature Review.

Chemotherapy-induced severe hyponatremia is a life-threatening condition. Platinum-based agents play a key role in ovarian cancer treatment but are more likely to cause hyponatremia than other anticancer agents. The optimal strategy for treating ovarian cancer in cases of severe platinum agent-induced hyponatremia remains unclear. We encountered 2 patients with ovarian cancer who developed syndrome of inappropriate antidiuretic hormone secretion (SIADH) after chemotherapy with involved carboplatin. Case 1 was a recurrent ovarian clear-cell carcinoma with peritoneal dissemination, and the patient developed severe hyponatremia due to SIADH on day 5 after receiving triweekly docetaxel and carboplatin (DC) therapy. The chemotherapy regimen was changed to weekly DC therapy, and she completed six cycles of regimen without electrolyte disturbance or tumor recurrence. Case 2 was a newly diagnosed advanced high-grade serous ovarian carcinoma, stage IIIC, with a BRCA1 mutation. She developed SIADH on day 8 after receiving triweekly paclitaxel and carboplatin (TC) therapy as adjuvant therapy after primary debulking surgery. The regimen was changed to weekly TC therapy, and she completed the schedule of chemotherapy without electrolyte disturbance and transitioned to maintenance therapy with a PARP inhibitor. In conclusion, weekly carboplatin administration might be a promising alternative to triweekly carboplatin administration after the development of carboplatin-induced SIADH.

Figla promotes secondary follicle growth in mature mice.

The in vitro growth (IVG) of human follicles is a potential fertility option for women for whom cryopreserved ovarian tissues cannot be transplanted due to the risk of cancer cell reintroduction; however, there is currently no established method. Furthermore, optimal IVG conditions may differ between the follicles of adult and pre-pubertal females due to molecular differences suggested by basic research. To systematically identify differences between the secondary follicles of adult and pre-pubertal females, a comparative transcriptomic study using mice was conducted herein. Among differentially expressed genes (DEGs), Figla was up-regulated in mature mice. We successfully down-regulated Figla expression in secondary follicle oocytes by a Figla siRNA microinjection, and the subsequent IVG of follicles showed that the diameter of these follicles was smaller than those of controls in mature mice, whereas no significant difference was observed in premature mice. The canonical pathways of DEGs between control and Figla-reduced secondary follicles suggest that Figla up-regulates VDR/RXR activation and down-regulates stem cell pluripotency as well as estrogen signaling. We demonstrated for the first time that folliculogenesis of the secondary follicles of premature and mature mice may be regulated by different factors, such as Figla with its possible target genes, providing insights into optimal IVG conditions for adult and pre-pubertal females, respectively.

Oncofertility care in young women and the outcomes of pregnancy over the last 5 years.

AIM: To ascertain the actual outcomes of oncofertility care in young women to provide more appropriate care. MATERIALS & METHODS: We analyzed the data of 67 female patients under 43 years of age who underwent oncofertility care between January 2015 and September 2019. RESULTS: There were 28 patients with breast cancer, 19 patients with hematologic cancer and 20 patients with other cancer diagnoses. Breast cancer patients tended to take longer than hematologic cancer patients to initiate oncofertility treatment. Despite undergoing oncofertility care, seven of nine pregnant patients did not choose assisted reproductive technology (ART). CONCLUSION: As spontaneous pregnancies were more common than ART pregnancies in our study, pregnancy by not only ART but also non-ART method is a viable option for young cancer survivors.

Placenta Accreta in a Woman with Childhood Uterine Irradiation: A Case Report and Literature Review.

The pregnancies of childhood cancer survivors who have received uterine irradiation are associated with a high risk of several obstetrical complications, including placenta accreta. The present case was a 26-year-old pregnant woman with a history of myelodysplastic syndrome treated with umbilical cord blood transplantation following chemotherapy and total body irradiation at the age of 10. Despite every possible measure to prevent preterm labor, uterine contractions became uncontrollable and a female infant weighing 892 g was vaginally delivered at 27+4 weeks of gestation. Under the postpartum ultrasonographic diagnosis of placenta accreta, we selected to leave the placenta in situ. Although emergency bilateral uterine artery embolization was required, complete resorption of the residual placenta was accomplished on the 115th day postpartum. Our experience highlighted the following points. (1) The expectant management of placenta accreta arising in an irradiated uterus may not only fulfill fertility preservation, but may also reduce possible risks associated with cesarean hysterectomy. (2) Due to extreme thinning of and a poor blood supply to the myometrium, reaching an antepartum diagnosis of placenta accreta in an irradiated uterus is difficult. (3) The recurrence of placenta accreta in subsequent pregnancies needs to be considered after successful preservation of the uterus.

Endovascular trophoblast expresses CD59 to evade complement-dependent cytotoxicity.

In the human placenta, extravillous trophoblasts (EVTs) invade maternal decidual tissues (interstitial trophoblasts) and maternal spiral arteries (endovascular trophoblasts). Although endovascular trophoblasts are directly exposed to maternal blood containing complement components, they are not eliminated by complement-dependent cytotoxicity (CDC). In this study, we investigated the expression and possible function of CD59, one of the membrane-bound complement regulators, in EVTs. Immunohistochemistry of early embryo implantation sites revealed that CD59 was hardly expressed on interstitial trophoblasts, whereas it was intensely expressed on endovascular trophoblasts. Using the human EVT-like cell line Swan71, we established CD59-silencing Swan71 cells (Sw_CD59sh) and non-silencing control Swan71 cells (Sw_CTRsh). In vitro cell apoptosis assay showed that Sw_CD59sh cells were significantly more susceptible to CDC as compared to Sw_CTRsh. Our results suggest that CD59 confers some protection against maternal complement attack to the endovascular trophoblasts.

Versican V1 in human endometrial epithelial cells promotes BeWo spheroid adhesion in vitro.

The endometrium extracellular matrix (ECM) is essential for embryo implantation. Versican, a large chondroitin sulfate proteoglycan that binds hyaluronan and forms large ECM aggregates, can influence fundamental physiological phenomena, such as cell proliferation, adhesion and migration. The present study investigated the possible role of versican in human embryo implantation. Versican V1 expression and secretion in human endometrial epithelial cells (EECs) was most prominent in the mid-secretory phase. Versican expression in EECs significantly increased after treatment with estrogen and progesterone, but not by estrogen alone. We also established versican V1-overexpressing Ishikawa (endometrial cancer cell line) cells (ISKW-V1), versican V3-overexpressing (ISKW-V3) and control GFP-overexpressing (ISKW-GFP) Ishikawa cells. By the in vitro implantation model, the attachment ratio of BeWo (choriocarcinoma cell line) spheroids to the monolayer of ISKW-V1, but not of ISKW-V3, was found significantly enhanced compared with attachment to the ISKW-GFP monolayer. The conditioned medium derived from ISKW-V1 (V1-CM) also promoted the attachment of BeWo spheroids to the ISKW monolayer. However, this attachment-promoting effect was abolished when V1-CM was pretreated with chondroitinase ABC, which degrades chondroitin sulfate. Therefore, out of the ECM components, versican V1 may facilitate human embryo implantation.

Platelet-derived microparticles and soluble factors differentially regulate human endometrial epithelial cell movement.

PROBLEM: We previously proposed that platelets promote re-epithelialization during menstruation. As cell movement is one of the important cell behaviors in the process of tissue remodeling, we examined the effects of platelets on endometrial epithelial cell invasion. METHOD OF STUDY: The platelets were isolated from healthy women. Using a human endometrial epithelial cell-derived immortalized cell line, EM-E6/E7/hTERT cells, we examined the effects of platelets and platelet-derived condition media with or without microparticles on the morphological and invasive properties of EM-E6/E7/hTERT cells. RESULTS: Platelets and microparticle-containing conditioned media inhibited Matrigel invasion by EM-E6/E7/hTERT cells along with an increase in cortical ring formation, whereas microparticle-depleted conditioned media promoted their invasion without any significant changes of cortical ring formation. CONCLUSION: These results support our previous proposal and newly suggest the dual roles of platelets: platelet-derived soluble factors that promote cell movement in the distant area, and microparticles that induce re-epithelialization by endometrial epithelial cells in the proximal area.

CD9 suppresses human extravillous trophoblast invasion.

During human placentation, the extravillous trophoblast (EVT) invades the maternal decidua and reconstructs maternal spiral arteries. However, the precise mechanisms that control EVT behavior have not yet been elucidated in detail. CD9 has been reported to be a cell-motility-related molecule. Since we previously observed that CD9 was expressed on human EVT, we examined the possible involvement of CD9 in the invasion process of EVT. Placental and umbilical samples were obtained from patients who underwent legal abortions, normal delivery, or hysterectomy. The expression of CD9 at the implantation site and on isolated EVT from a villous explant culture, an EVT-derived immortalized cell line, Swan71, and HUVEC was examined by immunocytochemical staining, flow cytometry, and RT-PCR. The effects of anti-CD9 functional antibody (ALB6) on EVT and Swan71 cell invasion were further examined by matrigel invasion assay along with shRNAmir gene knockdown treatment. CD9 was highly expressed on EVT at the boundary region of EVT invasion and intravascular EVT. EVT and Swan71 cell invasions were promoted by ALB6 or shRNAmir treatment. CD9 expression on Swan71 cells was reduced under hypo-oxygenic conditions, while its expression was increased by the co-culture with HUVEC. These findings suggest that CD9 could attenuate EVT invasion under the influence of an oxygen environment and maternal endothelial cells, proposing that CD9 is a potential regulator of human placental formation.

Rupture of a degenerated uterine fibroid as a cause of acute abdomen: a case report.

BACKGROUND: Uterine fibroid is one of the most common pelvic neoplasms. It is rare for this condition to manifest as acute symptoms necessitating emergency surgical intervention. CASE: A 46-year-old, Japanese woman was referred to our emergency room for sudden epigastric discomfort. A pelvic mass was felt, and computed tomography demonstrated a 13-cm hypodense multilocular cystic mass adjacent to the uterus. The anterior wall of the cyst was thinned and discontinued, suggesting rupture of the cyst. There was also massive ascites. Peritoneal irritation caused by rupture of an ovarian cyst was suspected, and an emergency exploratory laparotomy was performed. The patient was found to have a distended cystic mass protruding from the posterior surface of the uterus with 3,200 mL of blood-stained ascites. Closer examination revealed a 1-cm tear on the tumor surface, and both solid and cystic parts to the mass. Microscopically the tumor showed a proliferation of myometrial cells without atypia and hyaline degeneration. These findings were interpreted as a rupture of uterine fibroid after cystic degeneration. CONCLUSION: Rupture of degenerated cystic fibroid is rare, but it should be included in the differential diagnosis when encountering patients with a cystic tumor and massive ascites.

Eph-ephrin A system regulates human choriocarcinoma-derived JEG-3 cell invasion.

OBJECTIVES: The Eph-ephrin system is a unique system that can induce multiple cellular responses such as cell migration, regulation of angiogenesis, and axonal guidance. Previously, the Eph-ephrin system was reported to regulate human extravillous trophoblast invasion. In this study, we examined the possible involvement of the Eph-ephrin system in the invasion of malignant gestational trophoblastic diseases using a human choriocarcinoma-derived cell line, JEG-3. METHODS: The mRNA expression of class A Ephs and ephrins on JEG-3 cells was examined by reverse transcription-polymerase chain reaction. The effects of recombinant human Eph A1 (r-Eph A1) and r-ephrin A4 on the proliferation and invasion of JEG-3 cells were investigated by cell proliferation and Matrigel invasion assays. The alterations of integrin expression on JEG-3 cells in the presence of r-Eph A1 and r-ephrin A4 were investigated by flow cytometry. The induction of phosphorylation of focal adhesion kinase in JEG-3 cells by r-ephrin A4 was examined by Western blot analysis. RESULTS: By reverse transcription-polymerase chain reaction, mRNAs of Eph A1, A2, and A4 and ephrin A1, A4, and A5 were detected on JEG-3 cells. In Matrigel invasion assay, both r-Eph A1 and r-ephrin A4 promoted the invasion of JEG-3 cells without affecting cell proliferation. During 24-hour culture with r-Eph A1 and r-ephrin A4, the increase in integrin α 5 expression on JEG-3 cells was observed by flow cytometry. Western blotting analysis showed that r-ephrin A4 induced dephosphorylation of focal adhesion kinase in JEG-3 cells. CONCLUSIONS: These findings suggest that Eph-ephrin interaction plays some role in the regulation of choriocarcinoma invasion in cooperation with integrins.

Successful infertility treatment following fertility-sparing surgery and chemotherapy for ovarian immature teratoma: a case report and a literature review.

INTRODUCTION: Malignant ovarian germ cell tumors (MOGCTs) are highly chemosensitive tumors most commonly found in adolescent girls and young women. However, patients with advanced disease can now be successfully cured with fertility-sparing surgery and adjuvant chemotherapy, resulting in childbearing. CASE: A 24-year-old nulliparous Japanese woman was diagnosed as having a stage IIIc immature teratoma. After fertility-sparing surgery, she received four cycles of chemotherapy consisting of cisplatin, etoposide, and pepleomycin. She married at the age of 34, but did not conceive due to sexual dysfunction of her husband. At the age of 38, intrauterine insemination was performed following ovulation induction with clomid and human menopausal gonadotrophin, which resulted in a singleton pregnancy. A healthy female infant was delivered at 38 weeks' gestation. CONCLUSION: Treatment might sometimes be needed for infertile women with a history of MOGCTs, but further studies are needed to determine whether infertility treatment, including ovulation induction, is appropriate.