Search

Mixed gestational trophoblastic tumors are exceptionally rare and have variable clinicopathological presentations. We report 3 such tumors with different combinations of choriocarcinoma (CC), placental site trophoblastic tumor (PSTT), and epithelioid trophoblastic tumor (ETT). The patients' age ranged from 38 to 44 years. Mixed trophoblastic tumor was not considered at the initial diagnosis and all 3 tumors were proven of gestational origin by DNA genotyping. Patient #1 presented with serum human chorionic gonadotropin (hCG) of 97 mIU/mL and a 5.6-cm cervical mass that was initially interpreted as PSTT on biopsy. Hysterectomy revealed a mixed PSTT (60%) and ETT (40%) with extrauterine metastases of only the ETT component. The tumor recurred 15 months after a multiagent chemotherapy and was tested positive for programmed death-ligand 1. The patient received immune checkpoint inhibitor therapy and remained disease-free after 24 months. Patient #2 presented with vaginal bleeding and serum hCG of 46,458 mIU/mL. An endometrial biopsy was interpreted as CC. Recurrence developed in the uterus and lung after methotrexate-based chemotherapy. A mixed CC and ETT were eventually diagnosed upon consultation review. Patient #3 presented with a complete hydatidiform mole and serum hCG of 744,828 mIU/mL. Three months after methotrexate, followed by actinomycin D therapy, a uterine mass was found. Hysterectomy revealed a mixed CC and PSTT. In conclusion, the rarity, elusive presentation, and wide range of histology make the diagnosis of mixed trophoblastic tumors highly challenging. The clinical management and prognosis are dictated by each component of the tumor. CC component must be considered when the patient presents with a high serum hCG level., Competing Interests: The authors declare no conflict of interest., (Copyright © 2024 by the International Society of Gynecological Pathologists.)

Choriocarcinoma is characterized as the most aggressive malignant alternation of gestational trophoblastic neoplasm; however, this illness is a curable malignancy. Although a rarity, this disease affects a female patient's life and causes a fatal condition. Choriocarcinoma is a life-threatening disease since it is initially insidious and can rapidly lead to masive hemorrhage, even death. Choriocarcinoma should be suspected in childbearing-age women with the high-risk scores according to FIGO. The study aims to report a severe case of widespread metastatic choriocarcinoma to optimize the treatment with multiagent chemotherapy and a multidisciplinary cooperation at our center. A G1P0 20-year-old woman was referred to the hospital for suspicion of metastatic choriocarcinoma after self-stopping chemotherapy because of the COVID-19 pandemic. During hospitalization, the tumor metastasized and presented profuse intraabdominal hemorrhage. The patient underwent immediate surgical intervention to control bleeding, and a definitive diagnosis was accurately established by the histopathological examination. After surgery, the EMA/CO regimen was administered as the first line of treatment, despite the patient being in a coma and requiring a ventilator machine. After 6 cycles of the EMA/CO regimen, her serum β-hCG level decreased to 8 mUI/mL, however, her β-hCG concentration was not down to a negative value. Thus, the patient received paclitaxel/cisplatin alternating with paclitaxel/etoposide (TP/TE regimen) for complete remission following 2 cycles. The delays in choriocarcinoma treatment are prognostic factors for worse outcomes, whereas chemotherapy may be considered a suitable treatment even in a patient's coma, thus improving a prognosis substantially.

Background: Choriocarcinoma is a highly malignant pregnancy-related trophoblastic neoplasm, characterized by early metastasis to the lungs. Therefore, patients may manifest nongynecological symptoms owing to distant metastases. The incidence of choriocarcinoma after a term pregnancy is really rare (1/160,000 pregnancies)., Case Presentation: We report a case of a 20-year-old Iranian woman, gravida 2 para 1 live 1 abortion 1, who was referred to our gynecology department with sudden onset dyspnea and pain in the left hemithorax the day after her labor. The index pregnancy was without any complications. After the initial workup, the elevation of β-human chorionic gonadotropin (HCG) levels (> 1,000,000) along with the identification of clinical (vaginal lesions) and radiological evidence of distant metastases (bilateral pulmonary nodes) directed us toward pulmonary metastatic choriocarcinoma diagnosis. After the oncology consult, the etoposide, methotrexate, actinomycin D, cyclophosphamide, and vincristine chemotherapy regimen was started for the patient. She responded well to the treatment and is currently continuing her chemotherapy process., Conclusion: The prognosis of choriocarcinoma is very good if the treatment is started on time. We suggest that clinicians should consider gestational trophoblastic neoplasia in their differential diagnosis of the post-natal period complications, especially after a term and nonmolar pregnancy., (© 2024. The Author(s).)

Background: Choriocarcinoma is a rare and highly malignant form of gestational trophoblastic disease that may develop following pregnancy, abortion, or a hydatiform mole. Renal metastatic involvement by post molar choriocarcinoma is even rarer. In this case report, we describe a unique case of post molar choriocarcinoma with a solitary renal metastasis in the absence of a primary uterine tumor and metastases in other sites, which presented with urological symptoms and spontaneous renal hemorrhage., Case Presentation: A 41-year-old Persian woman with history of complete hydatiform mole presented with severe flank pain, nausea, vomiting, gross hematuria, and vaginal bleeding. Laboratory tests demonstrated a serum beta human chorionic gonadotropin hormone level of 60,000 mIU/mL. Imaging studies showed a lesion at the lower pole of the left kidney with active bleeding surrounded by hematoma, as well as an empty uterine cavity. Additionally, bilateral pleural effusion was detected without any lesion within the lungs. Subsequently, the patient underwent laparotomy, partial nephrectomy, and left para-ovarian cystectomy. Endometrial curettage was also carried out. The histopathology report revealed choriocarcinoma renal metastasis with high expression of beta human chorionic gonadotropin, cytokeratin 7, and Ki 67. Moreover, there were no malignant cells in the endometrial curettage specimens, and a corpus luteum cyst was found within the para-ovarian cyst. Further investigations revealed that the pleural effusion was free of malignant cells, and there was no evidence of metastatic lesions in the brain. As a result, the patient was referred to the oncology department to receive chemotherapy, and the beta human chorionic gonadotropin levels dropped to 5 mIU/mL after receiving courses of a standard regimen of etoposide, methotrexate, actinomycin D, cyclophosphamide, and vincristine/oncovin over 3 weeks. Finally, monthly measurements of beta human chorionic gonadotropin levels for 6 months indicated that levels have constantly remained within normal ranges, showing no evidence of recurrence or new metastasis., Conclusions: Urological symptoms such as hematuria or spontaneous renal hemorrhage might be the only presentation of post molar choriocarcinoma with renal involvement. Thus, it can be beneficial to measure serum beta human chorionic gonadotropin levels among females of childbearing age who present with unexplained urological symptoms, especially if there is a history of prior hydatiform mole., (© 2024. The Author(s).)

Background: Delayed postpartum hemorrhage is rare, with an incidence of 0.5% to 2.0% in all pregnancies. The most important causes are placental remnants, infections, and placental bed subinvolution. Postpartum choriocarcinoma, a highly malignant complication of pregnancy, is a rare condition that can be easily misdiagnosed as other common causes, such as gestational remnants, and delays the diagnosis., Methods: Four patients visited our clinic complaining of delayed postpartum hemorrhage, combined with respiratory and neurological symptoms in 2 cases. Two cases were confirmed by histopathological examination and in addition, medical history, elevated human chorionic gonadotropin (hCG) level, and imaging findings help confirm the diagnosis of delayed postpartum hemorrhage caused by postpartum choriocarcinoma in other cases. Individualized combination chemotherapies were prescribed. In the light of massive cerebral metastasis in case 2, intrathecal methotrexate injection combined with whole-brain radiotherapy was prescribed., Results: Due to the absence of routine monitoring of β-hCG following full-term delivery, there was widespread metastasis at the time of diagnosis. Three patients got complete remission and there is no sign of recurrence. One patient had relapse and widespread metastasis and died at home 6 months after the last chemotherapy., Conclusion: It is important to be aware of the possibility of choriocarcinoma in patients with delayed postpartum hemorrhage. Clinicians should improve the recognition of choriocarcinoma following full-term delivery, emphasize the monitoring of β-hCG, comprehensively analyze the general condition of patients, and conduct standardized and individualized chemotherapy protocols., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

Background: The standard treatment for gestational choriocarcinoma is chemotherapy., Objective: To describe the risk of recurrence with expectant management of gestational choriocarcinoma that has reached a normal human chorionic gonadotropin level after tumor removal without adjuvant chemotherapy., Methods: A retrospective multicenter international cohort study was conducted from 1981 to 2017 involving 11 gestational trophoblastic disease reference centers with patient's follow-up extended until 2023. Clinical and biological data of included patients were extracted from each center's database. The inclusion criteria were i) histological diagnosis of gestational choriocarcinoma in any kind of placental tissue retrieved, ii) spontaneous normalization of human chorionic gonadotropin level following choriocarcinoma retrieval, iii) patient did not receive any oncological treatment for the choriocarcinoma, iv) and at least 6 months of follow-up after the first human chorionic gonadotropin level normalization., Results: Among 80 patients with retrieved gestational choriocarcinoma and whose human chorionic gonadotropin level normalized without any other oncological therapy, none had a recurrence of choriocarcinoma after a median follow-up of 50 months. The median interval between choriocarcinoma excision and human chorionic gonadotropin level normalization was 48 days. The International Federation of Gynecology and Obstetrics/World Health Organization risk score was ≤6 in 93.7% of the cases., Conclusions: This multicenter international study reports that selected patients with gestational choriocarcinoma managed in gestational trophoblastic disease reference centers did not experience any relapse when the initial tumor evacuation is followed by human chorionic gonadotropin level normalization without any additional treatment. Expectant management may be a safe approach for highly selected patients., (© 2024 Published by Elsevier Ltd.)

Background: Gestational choriocarcinoma occurs very rare in conjunction with pregnancy and it is camouflage for diagnosis., Methods: We present a rare case of asymptomatic choriocarcinoma in a viable pregnancy that was successfully diagnosed by ultrasonography and had timely treatment., Results: According to the ultrasonography, early diagnosis and treatment monitoring of choriocarcinoma during a viable pregnancy was administered and the newborn was discharged., Conclusion: Choriocarcinoma in pregnancy is camouflaged, and its clinical presentation varies widely. Despite an asymptomatic status, metastasis can occur, and ultrasonography is important for early diagnosis and treatment monitoring., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

Rationale: The global prevalence of leprosy has decreased substantially, and cases of leprosy infection are extremely rare in China. In this report, we present a case of recurrent choriocarcinoma complicated by leprosy infection during chemotherapy., Patient Concerns: A 24-year-old Chinese woman (gravida 3, para 2) presented to a local hospital with vaginal bleeding. Her medical history included a previous diagnosis of hydatidiform mole., Diagnoses, Interventions and Outcomes: The patient was diagnosed with choriocarcinoma and received chemotherapy in 6 cycles. Shortly after the initial treatment was completed, the disease recurred twice with resistance to multiple chemotherapeutic agents. In her second recurrence of choriocarcinoma, she was diagnosed with leprosy with many cutaneous nodules throughout her entire body. The patient was administered chemical treatment for leprosy with the multidrug therapy regimen after being diagnosed. To prevent exacerbating the infection, no immunotherapy was utilized to treat cancer, and the infection was well-controlled at the conclusion of anticancer therapy., Lessons: Because of immunological reduction, cancer patients are susceptible to a variety of infections. For patients with cancer, prevention and early detection of rare infectious diseases should receive special attention. Immunotherapy must be used with caution when treating patients with cancer and infections., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2023 the Author(s). Published by Wolters Kluwer Health, Inc.)

Competing Interests: Competing interests: None declared.

Rationale: Choriocarcinoma is a highly invasive gestational trophoblastic neoplasm, usually metastasis to lung and brain, but occurrence of choriocarcinoma following spontaneous abortion presenting as a vertebral tumor is extremely rare, to the best of our knowledge. Because of the poor diagnosis and high malignancy, the low progression-free survival follows up., Patient Concerns: We here are reporting a case of choriocarcinoma that presented with vertebral tumor induced paralysis of limbs and incontinence of urine., Diagnosis: Combined with the childbearing history, high β-human chorionic gonadotrophinin levels, and imaging examination, a clinical diagnosis was made exactly. Till the pathological results after the operation of lumbar spinal canal tumorectomy, the diagnosis was exactly clear., Interventions: After performing the laminectomy, the fierce bleeding follows up, just did the temporary limited decompression. Because of the vertebral artery embolization, lumbar spinal canal tumorectomy, spinal canal and root canal decompression, subdural decompression and hematoma removal were performed., Outcomes: After performing the operation and chemotherapy timely and positively, the patient lost consciousness and died due to the pulmonary embolism at last., Lessons: This is the first case report describing choriocarcinoma with metastases to the spine amongst Chinese population as well. Early metastasis is one of the marked tendencies of choriocarcinoma, but spine metastasis and the related spinal oppressional symptoms were found instead of vaginal bleeding in this case, which is indeed rare., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2023 the Author(s). Published by Wolters Kluwer Health, Inc.)

Choriocarcinoma is one of the most aggressive gestational trophoblastic neoplasias (GTN). Methotrexate (MTX) resistance is the main cause of treatment failure in choriocarcinoma. However, the mechanism of MTX resistance in choriocarcinoma is poorly known. This study aims to explore the function of Lectin galactoside-binding soluble 3 binding protein (LGALS3BP) in MTX-resistance in choriocarcinoma cells. Gradual dose escalation of MTX was used to establish MTX-resistant choriocarcinoma cells (JAR-MTX and JEG3-MTX cell lines). RNA-sequencing was used to explore the differentially expressed genes. Plasmids or SiRNA transfection was used to regulate the expression of LGALS3BP. ELISA was used to detect the concentrations of LGALS3BP in the serum of MTX-sensitive and MTX-resistant patients. qRT-PCR, Western blot, and CCK-8 assay were used to determine the effects of LGALS3BP on MTX-resistance in JAR and JEG3 cells. The results showed the relative resistance index (RI) of MTX is 791.50 and 1040.04 in JAR-MTX and JEG3-MTX, respectively. LGALS3BP was up-regulated in MTX-resistant cells compared to original cells in both RNA and protein level. The concentrations of LGALS3BP were higher in the sera of MTX-resistant patients than in MTX-sensitive patients. Knocking down LGALS3BP can reverse the MTX-resistance in JAR-MTX and JEG3-MTX cells. In summary, we preliminarily established two MTX-resistant cells, and performed RNA-sequencing, and found LGALS3BP may play important role in MTX-resistance. Our work not only provides a research tool (MTX-resistant cells) for other researchers, but gives some hint on how MTX resistance is regulated.

Background: Metastatic choriocarcinoma in the third trimester of pregnancy is extremely rare., Case Presentation: A 25-year-old Chinese woman (gravida 3, para 0) who was 28 weeks pregnant was admitted for sudden convulsion, aconuresis, and unconsciousness. The decision was made to perform an emergency cesarean delivery and craniotomy, hematoma clearance, and decompression. Pathological examination confirmed choriocarcinoma with brain metastasis. The patient underwent chemotherapy with the etoposide, cisplatin (EP) and etoposide, methotrexate and dactinomycin alternating with cyclophosphamide and vincristine (EMACO) regimens. A satisfactory result was achieved., Conclusions: When encountering intracranial mass or bilateral pulmonary nodules in a pregnant woman, especially one in the third trimester, metastatic choriocarcinoma should be considered., (© 2021. The Author(s).)

Choriocarcinoma syndrome is an uncommon, potentially fatal complication of germ cell tumors (GCTs) in adults, but it is not well documented in children. Pediatric central nervous system (CNS) GCTs comprise a rare group of malignancies not usually associated with extra-CNS metastatic disease. Here, we report the case of a pediatric patient with a suprasellar mixed GCT and pulmonary metastases who presented with intratumoral hemorrhage and stroke. Choriocarcinoma syndrome developed soon after initiating chemotherapy. The primary tumor and pulmonary metastases were successfully treated using a multidisciplinary approach, including neurovascular intervention, chemotherapy, and craniospinal irradiation., (© 2021 Wiley Periodicals LLC.)

Choriocarcinoma is an aggressive malignant trophoblastic neoplasm. The rapid growth of neoplastic tissue and myometrial invasion can cause uterine perforation. It is important to quickly diagnose the disease and plan treatment because these tumors are nearly always curable, and fertility can be preserved in most cases with proper management. The outbreak of novel coronavirus disease has affected the whole world since January 2019 and caused delays in treatment and follow-up of patients all over the world. In this study, we report a case of choriocarcinoma who postponed her admission to the hospital after diagnosis because she was afraid of the pandemic and lost her fertility due to uterine rupture and massive intra-abdominal hemorrhage.

Rationale: Choriocarcinoma is a highly aggressive tumor. It occurs infrequently during pregnancy. The management of choriocarcinoma during pregnancy poses several challenges., Patient Concerns: At 34 weeks of gestation, a 21-year-old primigravida was transferred to the emergency room for cephalgia, reduced fetal movements, and left intra-atrial intracavitary thrombus., Diagnosis: Choriocarcinoma in the third trimester with lung and brain metastases, pulmonary vein thrombosis (PVT), and systemic thrombosis., Intervention: An emergency cesarean section was performed. Subsequently, low-molecular-weight heparin anticoagulation combined with multiagent chemotherapy was administered., Outcome: A 1.59 kg live female was born. Multiagent chemotherapy combined with anticoagulation led to complete regression of the cerebral and pulmonary lesions and the dissolution of pulmonary vein thrombus. At the 11-month follow-up, the patient remained in complete remission without complications, and her child was disease-free., Lessons: This is the first case of gestational choriocarcinoma with PVT. Our case suggests that conservative therapy can be the first choice for small, asymptomatic PVT secondary to choriocarcinoma., Competing Interests: The authors have no funding and conflicts of interests to disclose., (Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.)

α-Solanine, a bioactive compound mainly found in potato, exhibits anti-cancer activity towards multiple cancer cells. However, its effects on human choriocarcinoma have not been evaluated. In the present study, we investigated the effect of α-solanine on cell proliferation and apoptosis in human choriocarcinoma in vitro and in vivo. The results showed that α-solanine, at concentrations of 30 μM or below, did not affect the cell viability of the choriocarcinoma cell line JEG-3. However, colony formation was significantly decreased and cell apoptosis was increased in response to 30 μM α-solanine. In addition, α-solanine (30 μM) reduced the migration and invasion abilities of JEG-3 cells, which was associated with a downregulation of matrix metalloproteinases (MMP)-2/9. The in vivo findings provided further evidence of the inhibition of α-solanine on choriocarcinoma tumor growth. α-Solanine suppressed the xenograft tumor growth of JEG-3 cells, resulting in smaller tumor volumes and lower tumor weights. Apoptosis was promoted in xenograft tumors of α-solanine-treated mice. Moreover, α-solanine downregulated proliferative cellular nuclear antigen (PCNA) and Bcl-2 levels and promoted the expression of Bax. Collectively, α-solanine inhibits the growth, migration, and invasion of human JEG-3 choriocarcinoma cells, which may be associated with the induction of apoptosis.

Placental choriocarcinoma is a malignant trophoblastic tumor associated with placentation. During placentation, complicated molecular networks are mediated by endocrine and paracrine signals. Serotonin neurotransmitters have been identified in the transmembrane region of human placental choriocarcinoma (HPC) cells as tumor promoters; therefore, their antagonists have anti-cancer properties. Although methiothepin, a serotonin receptor antagonist and FDA-approved psychotropic agent, has shown multi-pharmacological functions in various disease models, its anti-tumorigenic activity and mechanisms underlying its action against HPC are unknown. Therefore, we identified the anti-cancer effects of methiothepin in JEG3 and JAR HPC cells. Methiothepin attenuated mitochondrial function and induced endoplasmic reticular stress, reducing oxidative phosphorylation and causing metabolic shifting in HPC cells. Furthermore, methiothepin showed synergistic pharmacological effects with paclitaxel in HPC cells. Our results highlight the robust tumor-suppressive function of methiothepin in HPC. Our findings provide new insights into the repositioning of methiothepin from a psychotropic agent to novel anti-cancer agents, especially against HPC.

Objective: Using a transcriptional approach on tissue samples, we sought to identify predictive biomarkers of post molar malignant transformation, and of choriocarcinoma chemosensitivity to mono- (methotrexate or actinomycin D) or polychemotherapy [EMA(Etoposide, Methotrexate, Actinomycin D)-CO(Cyclophosphamide, Vincristine) and EMA-EP(Etoposide, Cisplatine)] regimens., Methods: We studied the expression of a 760-gene panel (PanCancer Pathway) related to oncogenesis and immune tolerance in tissue samples of complete hydatidiform moles and gestational choriocarcinoma., Results: We did not identify any differentially expressed gene between moles with post molar malignant transformation in choriocarcinoma (n = 14) and moles with remission (n = 20). In monochemoresistant choriocarcinoma (n = 34), four genes (HLA-G, COL27A1, IL1R2 and GLI3) had a significantly reduced expression and one (THEM4) had an increased expression [FDR (false discovery rate) adjusted p-value ≤ 0.05] when compared to monochemosensitive choriocarcinoma (n = 9). The proportion of trophoblast cells and the intensity of immunohistochemical HLA-G expression were reduced in monochemoresistant choriocarcinoma (p < 0.05). In polychemoresistant choriocarcinoma (n = 20) we did not identify differentially expressed genes with an FDR adjusted p-value ≤ 0.05 when compared to polychemosensitive choriocarcinoma (n = 15). Gene pathway analysis revealed a predicted activation of IFN ᵞ in monochemoresistant choriocarcinoma and inhibited IL2 and TNF in polychemoresistant choriocarcinoma. The main biological functions predicted to be altered in chemoresistant choriocarcinoma were related to immunological homeostasis and leukopoiesis., Conclusion: HLA-G is a strong candidate gene to predict choriocarcinoma resistance to monochemotherapy and that further studies are required to implement its routine quantification in the decision process for the management of gestational choriocarcinoma., Competing Interests: Declaration of competing interest The authors report no conflict of interest., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Apomorphine is a derivative of morphine that is used for the treatment of Parkinson's disease because of its effects on the hypothalamus. Therapeutic effects of apomorphine have also been reported for various neurological diseases and cancers. However, the molecular mechanisms of the antitumor effects of apomorphine are not clear, especially with respect to choriocarcinoma. This is the first study to elucidate the anticancer effects of apomorphine on choriocarcinoma. We found that apomorphine suppressed the viability, proliferation, ATP production, and spheroid formation of JEG3 and JAR choriocarcinoma cells. Moreover, apomorphine activated the intrinsic apoptosis pathway by activating caspases and inhibited the production of anti-apoptotic proteins in choriocarcinoma cells. Further, apomorphine caused depolarization of mitochondria, calcium overload, energy deprivation, and endoplasmic reticulum stress in JEG3 and JAR cells. We confirmed synergistic effects of apomorphine with paclitaxel, a traditional chemotherapeutic agent, and propose that apomorphine could be a potential therapeutic agent in choriocarcinoma and an important candidate for drug repositioning that could help overcome resistance to conventional chemotherapy.

Proliferation, differentiation and apoptosis of trophoblast cells are required for normal placental development. Impairment of those processes may lead to pregnancy-related diseases. Disruption of endoplasmic reticulum (ER) homeostasis has been associated with several reproductive pathologies including recurrent pregnancy loss and preeclampsia. In the unfolded protein response (UPR), specific ER-stress signalling pathways are activated to restore ER homeostasis, but if the adaptive response fails, apoptosis is triggered. Protein kinase RNA-like endoplasmic reticulum kinase (PERK), inositol-requiring enzyme 1 (IRE1) and Activating transcription factor 6 (ATF6) are central players in UPR and in ER-stress-induced apoptosis, as well as downstream transcription factors, as C/EBP homologous protein (CHOP). Our previous studies have shown that the endocannabinoid 2-arachidonoylglycerol (2-AG) modulates trophoblast cell turnover. Nevertheless, the role of ER-stress on 2-AG induced apoptosis and cannabinoid signalling in trophoblast has never been addressed. In this work, we used BeWo cells and human primary cytotrophoblasts isolated from term-placenta. The expression of ER-stress markers was analysed by qRT-PCR and Western blotting. ROS generation was assessed by fluorometric methods, while apoptosis was detected by the evaluation of caspase -3/-7 activities and Poly (ADP-ribose) polymerase (PARP) cleavage. Our findings indicate that 2-AG is able to induce ER-stress and apoptosis. Moreover, the eukaryotic initiation factor 2 (eIF2α)/CHOP pathway involved in ER-stress-induced apoptosis is triggered through a mechanism dependent on cannabinoid receptor CB2 activation. The results bring novel insights on the importance of ER-stress and cannabinoid signalling on 2-AG mechanisms of action in placenta.

Persistent gestational trophoblastic disease can arise from any type of antecedent pregnancy, including molar and tubal pregnancies. While most cases of persistent gestational trophoblastic disease present within the first year following initial diagnosis, recurrence has rarely been reported many years after initial diagnosis. Distinguishing recurrence from a new independent lesion is clinically important. A 25-yr-old woman presented with a mass in the right uterine cornu that was discontiguous with the endometrial cavity and was associated with an elevated serum human chorionic gonadotropin level. She had a history of an invasive complete hydatidiform mole with lung involvement treated with chemotherapy 5 yr prior. Wedge resection of the right cornu was performed due to concern for a cornual ectopic pregnancy. Pathologic evaluation demonstrated a choriocarcinoma. Molecular genotyping confirmed the tumor as recurrent disease genetically related to the prior complete hydatidiform mole. She completed 4 cycles of EMA-CO therapy, and has been disease-free with undetectable serum human chorionic gonadotropin level for 2 yr.

Objective: Although methotrexate (MTX) is commonly used for the treatment of choriocarcinoma, chemoresistance to MTX may occur in a considerable fraction of patients. Further understanding on the mechanisms of MTX resistance would help to develop more effective therapy for choriocarcinoma., Methods: Quantitative proteomic approach involving TMT labeling and LC-MS/MS was used to identify MTX resistance-related proteomic profiles in choriocarcinoma cell models. Pathway and process enrichment analysis were conducted to identify MTX resistance-related biological processes/molecular pathways. CCK-8 viability assay, clonogenic survival assay, and BrdU incorporation analysis were used to examine the chemosensitivity to MTX in choriocarcinoma cells., Results: In total, 5704 protein groups were identified, among which 4997 proteins were quantified. Bioinformatic analysis revealed that multiple biological processes/molecular pathways might be associated with MTX resistance in JEG3/JEG3/MTX cell systems. DPP4 and METTL7A were selected for further investigation. Increased expression of DPP4 or METTL7A was observed in MTX-resistant cancer cell lines and choriocarcinoma tissues. Knockdown of DPP4 or METTL7A significantly decreased cell viability, impaired clonogenesis, and increased apoptosis after MTX treatment in JEG3/MTX and JAR/MTX cells; while over-expression of DPP4 or METTL7A promoted cell viability and reduced apoptosis following exposure to MTX in JEG3, JAR and BEWO cells. Further, DPP4 and METTL7A differentially activated prosurvival signaling pathways including PI3K/AKT, ERK1/2 and STAT3, and attenuated the accumulation of reactive oxygen species (ROS) in choriocarcinoma cell lines., Conclusions: DPP4 and METTL7A might promote MTX resistance through activating pro-survival signaling pathways and attenuating the accumulation of ROS in choriocarcinoma cells. Targeting DPP4 and METTL7A might be useful to sensitize choriocarcinoma cells to MTX-based chemotherapy., Competing Interests: Declaration of competing interest The authors declare that they have no competing interests., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Schisandrin A (SchA) has been reported as a multidrug resistance-reversing agent; however, its antitumor effects have been rarely reported. Consequently, we attempted to explore whether SchA per se possesses an antitumor property in choriocarcinoma JEG-3 and BeWo cells and its potential mechanisms. JEG-3, BeWo, and HTR-8/SVneo cells were stimulated with SchA at different concentrations (10-100 μM), and cellular viability was evaluated with Cell Counting Kit-8. After stimulation with SchA, proliferation, apoptosis, migration, and invasion were detected by bromodeoxyuridine assay, Annexin V-fluorescein isothiocyanate/propidium iodide (Annexin V-FITC/PI) method, and a Transwell system, in JEG-3 cells transfected with short hairpin-RNA for maternally expressed 3. Western blot was performed to quantify protein. MEG3 was examined by a quantitative reverse transcription-polymerase chain reaction. MEG3 was downregulated in choriocarcinoma tissues. SchA diminished cellular viability, decreased proliferative activity, inhibited migratory and invasive behaviors, and repressed phosphorylation of regulators of phosphatidylinositol 3 kinase/protein kinase B/nuclear factor κB (PI3K/AKT/NF-κB) signaling cascade in gestational choriocarcinoma cells. MEG3 was upregulated by SchA in JEG-3 and BeWo cells. SchA exhibited little suppressive effects in JEG-3 cells lacking MEG3. Besides, the phosphorylation of transducers was evoked in MEG3-silenced JEG-3 cells despite stimulation with SchA. SchA administration repressed the growth of JEG-3 and BeWo cells by upregulating MEG3. Besides, SchA blocked PI3K/AKT/NF-κB signal cascade by elevating MEG3., (© 2020 Wiley Periodicals, Inc.)

5,6,7,8,3,4'-Hexamethoxyflavone, also called nobiletin (NOB), widely found in the citrus peel, is one of the main byproducts in citrus processing. NOB is considered safe, but its safety for women during pregnancy is unknown. Therefore, the effect of NOB on apoptosis in human choriocarcinoma trophoblast cells (BeWo cells) was evaluated. Cells were divided into four groups and cultured with different concentrations of NOB (0, 10, 33, and 100 μM) for 12, 24, 36, and 48 h respectively. Cell viability was detected by CCK-8 assay, cell morphology was detected by a Cell Imaging Multi-Mode Reader, and cell cycle and apoptosis were detected by flow cytometry. Cleaved PARP level, the expressions of B cell lymphoma 2 (BCL2) family proteins, and p53 pathway proteins were detected by Western blot. The results showed that after 48 h of cell culture, the cell viability was decreased significantly, but apoptosis was significantly increased. Compared to the cells without NOB treatment, the cells treated with NOB at 10 or 33 μΜ showed no significant differences in the number of suspended cells or late apoptosis rate, except the increase of cell viability. Treatment of NOB at the concentration of 100 μM improved cell viability, attenuated apoptosis, decreased suspended cells, and did not alter the G1 phase arrest, compared with the non-NOB-treated group after 48 h of culturing. The 100 μΜ NOB treatment increased the levels of BCL2 and BCLX L , and decreased p53 accumulation in BeWo cells at 48 h, but had no effect on the expression of BAX, BAK, BAD, p21, and G1 phase arrest. These findings provide evidence that NOB (10, 33, and 100 μΜ) was safe for BeWo cells. NOB at the concentration of 100 μΜ could attenuate apoptosis in BeWo cells, which might be helpful to prevent pregnancy-related diseases caused by apoptosis.

Objective: This study aimed to evaluate the efficacy and toxicity of 4-day chemotherapy with methotrexate, etoposide, and actinomycin D (MEA) for patients who were diagnosed with choriocarcinoma and high-risk gestational trophoblastic neoplasia (GTN)., Methods: Between January 1999 and December 2015, 29 patients were treated with 4-day MEA after being diagnosed with choriocarcinoma or high-risk GTN. Complete remission to 4-day MEA and adverse effects were retrospectively evaluated., Results: The complete remission rates were 79.3% (23/29) and 87.5% (21/24) in all patients and in those who received 4-day MEA as first-line therapy, respectively. Of six patients who developed drug resistance to 4-day MEA, three patients showed complete remission by other treatments, while the other three patients died of the disease. The major adverse effects were leukocytopenia, anemia, and nausea. Of 23 patients who were cured with 4-day MEA, treatment was changed to the etoposide and actinomycin D (EA) regimen in 14 patients, because of leukocytopenia, hepatotoxicity, and stomatitis. Among 20 patients who required hormonal therapy, 15 patients showed normal menstrual cycles after therapy. Five patients had nine conceptions (seven term live births and two spontaneous abortions). No babies were premature or had low birth weight nor did they have congenital anomalies., Conclusion: The results suggest that the efficacy and the adverse effects of 4-day MEA for choriocarcinoma and high-risk GTN may be the same level as EMA/CO. However, further study will be needed for determining the criteria of changing the treatment regimen from 4-day MEA to the EA regimen.

Introduction: Choriocarcinoma is malignant cancer originating from placental trophoblast. The incidence of this cancer is estimated at 0.57-1.1 per 1000 births in the United States of America, Australia, Europe, and New Zealand. The rate is much higher in South East Asia and Japan with two occurrences per a thousand births. Telomerase activity is an important part of the apoptotic process. Increased telomerase activity will result in cellular immortality and poor prognosis in cancer. Vitamin A possess an essential role in cell proliferation and differentiation. One of the active metabolites of vitamin A is All-Trans Retinoic Acid (ATRA)., Methods: In this study, we examined the role of ATRA against telomerase activity in choriocarcinoma cell. This cell was derived from BeWo cell line (ATCC CCL-98) and were given different doses of ATRA., Results: From this study, Choriocarcinoma cell that was given ATRA in dosage of 50μg/ml inhibit telomerase activity by extending the cycle time of 39.51±0.09, compared to the control group with a cycle time of 37.62±0.43. Cycle length change consistently with higher dose of ATRA., Conclusion: This study has proven that ATRA could inhibit telomerase activity by lengthening the cycle. Changes in the increase of ATRA doses in this experimental test need to be studied further on experimental animals, either administered as a single agent or as an addition to standard treatment of trophoblastic disease.

Background and Purpose: Choriocarcinoma (CCA) is a rare form of malignant trophoblastic disease. Systemic polychemotherapy with etoposide, methotrexate, actinomycin D, cyclophosphamide, and vincristine (EMA/CO) is the mainstay of treatment for metastatic disease. Due to the rarity of the condition, however, the evidence basis for this management is small and other chemotherapy regimens may also be effective. The reported case presents anecdotal evidence of an effective etoposide monotherapy treatment., Method: CASE PRESENTATION: We report the case of a patient with gestational choriocarcinoma and pulmonary metastases initially treated with methotrexate. Due to local disease progression, she underwent hysterectomy and continued treatment with methotrexate. After pulmonary progression, she was switched to oral etoposide., Results: After four cycles of etoposide monotherapy at a oral dosage of 100 mg d1-7, q28, the patient had no evidence of disease according to human chorionic gonadotropin serum levels and imaging studies. The treatment was well tolerated with World Health Organization (WHO) grade 2 alopecia and hot flushes as the most prominent side effects. The patient has achieved a sustained complete remission with a follow-up of 6 years., Conclusion: Oral etoposide may be an effective treatment alternative to EMA/CO in selected patients with oligometastatic CCA.

Objective: To evaluate the survival and functional outcome of patients with brain metastasis due to gestational trophoblastic neoplasia (GTN)., Methods: A 17-year retrospective study based on case review of women with brain metastasis from GTN identified by the electronic databases held in the French Reference Centre., Primary Outcome Measure: 5-year overall survival calculated with the Kaplan-Meier method., Secondary Outcome Measures: causes of death, prognostic factors and functional outcomes., Results: 21 patients had GTN brain metastasis and were treated with multidrug chemotherapy without concomitant whole-brain radiation therapy. Three patients died early (< 4 weeks) of cerebral hemorrhage, 3 died ≥ 1 months after treatment initiation and 15 were alive at the date of last contact. The overall survival rate at 5 years was 69.8% (95% CI 44.3-85.3). After excluding early deaths, the survival rate at 5 years was 81.5% (95% CI 52.3-93.7). No predictive factor of survival was identified. Although 11 of the 12 (92%) surviving patients contacted still reported sequelae, nine of them (75%) had resumed a normal life., Conclusions: After excluding early deaths, this study implies a high survival rate in patients with brain metastasis from GTN. These results were achieved in the total absence of whole-brain radiotherapy and almost completely without the need for intrathecal methotrexate.

Carvacrol is a monoterpenoid phenol present in the oils of various plants including Origanum vulgare (oregano) or Origanum majorana (marjoram). For a long time, it has been used as spice in foods because of its antimicrobial properties. Additionally, it appears to have anticancer effects against some cancer but this has not been well studied. Therefore, we conducted various assays to confirm the effects of carvacrol on choriocarcinoma cell lines (JAR and JEG3). Our results indicate that carvacrol has antiproliferative properties and induces apoptosis, resulting in increased expression of proapoptotic proteins. Additionally, carvacrol disrupted the mitochondrial membrane potential and induced calcium ion overload in the mitochondrial matrix in both JAR and JEG3 cells. Furthermore, carvacrol generated oxidative stress and lipid peroxidation in both JAR and JEG3 cells. Moreover, carvacrol-suppressed phosphoinositide 3-kinase-protein kinase B and extracellular signal-regulated kinase 1/2 mitogen-activated protein kinase (MAPK) signal transduction whereas expression of phosphor-P38 and c-Jun N-terminal kinase MAPK was increased. Together, our results indicate that carvacrol may be a possible new therapeutic agent or supplement for the control of human choriocarcinomas., (© 2018 Wiley Periodicals, Inc.)

Background: Gestational trophoblastic neoplasia rarely occurs in term pregnancies. Stage IV choriocarcinoma treated with conventional chemotherapy can result in death as a result of hemorrhagic sequelae at tumor sites., Case: A 30-year-old woman at 34 weeks of gestation presented with a persistent cough, worsening dyspnea, and vaginal bleeding. Chest radiograph demonstrated innumerable lung nodules, and quantitative β-hcg concentration exceeded 1.3 million milli-international units/mL. Cesarean delivery was performed for presumed abruption. Placental pathology demonstrated choriocarcinoma, and imaging confirmed stage IV disease with a World Health Organization score of 14. Remission was achieved after two courses of low-dose induction chemotherapy followed by 10 cycles of combination chemotherapy., Conclusion: Gestational trophoblastic neoplasia should be considered in a pregnant or postpartum woman presenting with atypical vaginal bleeding. Coexistent pulmonary or neurologic findings may suggest advanced disease.

Gestational trophoblastic neoplasia (GTN) can result from the over-proliferation of trophoblasts. Treatment of choriocarcinoma, the most aggressive GTN, currently requires high doses of systemic chemotherapeutic agents, which result in indiscriminate drug distribution and severe toxicity. To overcome these disadvantages and enhance the chemotherapeutic efficacy, chondroitin sulfate A (CSA)-binding nanoparticles were developed for the targeted delivery of doxorubicin (DOX) to choriocarcinoma cells using a synthetic CSA-binding peptide (CSA-BP), derived from malarial protein, which specifically binds to the CSA exclusively expressed in the placental trophoblast. CSA-BP-conjugated nanoparticles rapidly bonded to choriocarcinoma (JEG3) cells and were efficiently internalized into the lysosomes. Moreover, CSA-BP modification significantly increased the anti-cancer activity of the DOX-loaded nanoparticles in vitro. Intravenous injections of CSA-BP-conjugated nanoparticles loaded with indocyanine green (CSA-INPs) were rapidly localized to the tumor. The CSA-targeted nanoparticles loaded with DOX (CSA-DNPs) strongly inhibited primary tumor growth and, more importantly, significantly suppressed metastasis in vivo. Collectively, our results highlight the potential of the CSA-BP-decorated nanoparticles as an alternative targeted delivery system of chemotherapeutic agents for treating choriocarcinoma and for developing new GTN therapies based on drug targeting.

The trophoblast cells which form the placenta, have a high potential for invading other tissues. Owing to certain mechanisms, trophoblast cells may lose their ability to control cell proliferation, and develop into pregnancy-related tumors, known as choriocarcinomas. Choriocarcinomas mostly develop from the hydatidiform mole, which is frequently found in pregnant women. Owing to their ability to rapidly metastasize through the hematogenous route, choriocarcinomas are very hard to cure if not detected at the proper time. Although numerous studies are attempting to identify the major pathways in choriocarcinoma cells, the critical pathway responsible for the origin of choriocarcinomas is still unclear. In this study, we identified that chrysin has inhibitory effects on human choriocarcinoma cells. The study demonstrated that chrysin disrupts intracellular homeostasis by altering the mitochondrial membrane potential (MMP), cytosolic Ca 2+ levels, production of reactive oxygen species (ROS), and lipid peroxidation, leading to the death of choriocarcinoma cells (JAR and JEG3). Additionally, the effects of chrysin on choriocarcinoma cells were found to be mediated via the regulation of the AKT, ERK1/2, and JNK signaling pathways. Altogether, the anti-cancer effects of chrysin can aid the development of a novel therapeutic strategy against the progression of human choriocarcinomas., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Rationale: Near-term intraplacental choriocarcinoma (IC) coexisting with massive fetomaternal hemorrhage (FMH) is rare, and its clinical course is poorly understood. Here, we report a new case from our hospital, with detailed discussion and literature review., Patient Concerns: A 21-year-old Chinese female at 35 weeks gestation was admitted to our hospital due to reduced fetal movement. Near-term IC coexisting with massive FMH was diagnosed after delivery., Intervention: The mother and infant were followed 3 months after delivery. Beta-human chorionic gonadotropin (β-HCG), pathological examination of the placenta, and computed tomography scans were performed for the mother and β-HCG was performed for the infant., Outcomes: The mother's β-HCG serum level increased from 31,280 IU/L (6 days postdelivery) to 192,070 IU/L (49 days postdelivery), and then steadily fell to 42,468 IU/L (3 months postdelivery) without chemotherapy. The mother died from metastasis and cerebral hemorrhage. The infant survived and his β-HCG serum level fell to within the normal range without chemotherapy., Lessons: FMH associated with near-term IC is a rare disease. Measurement of maternal β-HCG may therefore represent a useful parameter when IC is a possible differential diagnosis. A pathological examination of the placenta should be performed in all cases of FMH to better identify cases of IC. Future research should aim to develop methods of identifying which patients with IC should receive chemotherapy, whether we should use single- or multiagent chemotherapies, and whether there is a positive correlation between chemotherapy regimen and β-HCG serum levels.

Somatic endometrial carcinomas with trophoblastic components have only rarely been described. To better characterize this distinctive combination of histotypes, we report herein 4 new cases, representing the largest cohort reported thus far, and review previously reported cases. The 4 new patients ranged in age from 61 to 77 yr (mean, 68 yr). The first patient had a grade 2 endometrioid carcinoma, surgical International Federation of Gynecology and Obstetrics stage IA, that recurred 5 months later at the vaginal apex with purely choriocarcinoma elements, suggestive of unsampled trophoblastic areas in the uterus. The 3 other patients were all International Federation of Gynecology and Obstetrics stage III, and included 2 cases of dedifferentiated endometrial carcinoma with 40% and 20% choriocarcinoma components, and 1 case of grade 1 endometrioid carcinoma with a 40% choriocarcinoma component. Postoperative serum β-human chorionic gonadotropin was elevated in all patients. All received adjuvant combination chemotherapy, but all were dead of disease with distant metastases at an average of 11.75 mo (range, 7-16 mo) after primary staging. Data from our cases were combined with those from 24 cases that had previously been reported in the literature between 1972 and 2016. Analysis of this combined data indicates that endometrial carcinoma with trophoblastic component is a rare neoplasm that occurs primarily in postmenopausal patients. The trophoblastic component is most commonly a choriocarcinoma and the somatic component is most commonly an endometrioid carcinoma or an adenocarcinoma/carcinoma reported without further specification; the somatic component may be a diverse array of histotypes or histotype admixtures. Serum and/or urine β-human chorionic gonadotropin is elevated in almost all patients, and fluctuations of β-human chorionic gonadotropin generally correlated with tumor relapses or recurrences. The stage distribution and patient outcomes in the current and previously reported patients suggests that trophoblastic differentiation usually, but not invariably denotes clinical aggressiveness.

Silibinin is a flavonolignan extracted from seeds of milk thistles. Traditionally, it has been used as a therapeutic agent for liver disorders, and now it is well-known for its anti-cancer effects. However, studies on anti-cancer effects of silibinin on choriocarcinoma are very limited. Therefore, we performed proliferation and apoptosis assays to determine effects of silibinin on the viability of human choriocarcinoma (JAR and JEG3) cells. Our results showed that silibinin significantly inhibited proliferation and induced apoptosis in both JAR and JEG3 cells, and significantly increased reactive oxygen species (ROS) and lipid peroxidation. Moreover, silibinin disrupted mitochondrial function by inducing permeabilization of mitochondrial membrane potential and calcium ion efflux in JAR and JEG3 cells. Furthermore, silibinin-induced apoptosis in choriocarcinoma cells via AKT, mitogen-activated protein kinases (MAPK) and unfolded protein response (UPR) signal transduction. Collectively, our results suggest that silibinin is a novel therapeutic agent or dietary supplement for management of human placental choriocarcinomas., (© 2017 Wiley Periodicals, Inc.)

Objective: To evaluate expectant management versus immediate chemotherapy following pathological diagnosis of gestational choriocarcinoma (GCC) in patients with nonmetastatic disease., Methods: Multicenter retrospective cohort that included patients with histological diagnosis of GCC with nonmetastatic disease followed at one of thirteen Brazilian referral centers for gestational trophoblastic disease from January 2000 to December 2016., Results: Among 3191 patients with gestational trophoblastic neoplasia, 199 patients with nonmetastatic GCC were identified. Chemotherapy was initiated immediately in 152 (76.4%) patients per FIGO 2000 guideline, while 47 (23.6%) were managed expectantly. Both groups presented with similar characteristics and outcomes. All patients (n=12) who had normal human chorionic gonadotropin (hCG) in the first 2-3weeks of expectant management achieved complete sustained remission with no chemotherapy. Only 44.7% (21 patients) of patients who were expectantly managed needed to receive chemotherapy due to plateauing or rising hCG level in the first 2-3weeks of follow up. The outcome of patients receiving chemotherapy after initial expectant management was similar to those who received chemotherapy immediately after the diagnosis in terms of need for multi-agent chemotherapy or number of cycles of chemotherapy. There was no case of relapse or death in either group. Logistic regression analysis showed that age≥40years and hCG≥92,428IU/L at GCC diagnosis were risk factors for needing chemotherapy after initial expectant management of nonmetastatic GCC., Conclusion: In order to avoid exposing patients unnecessarily to chemotherapy, close surveillance of women with pathological diagnosis of nonmetastatic GCC seems to be a safe practice, particularly for those who have a normal hCG at the time of diagnosis. If confirmed by other studies, the FIGO guidelines may need to be revised., (Copyright © 2017 Elsevier Inc. All rights reserved.)

A 36-year-old with metastatic and refractory choriocarcinoma following single- and multi-agent chemotherapy and surgical metastectomy experienced a durable remission after receiving therapy with an anti-endoglin monoclonal antibody and bevacizumab. Treatment options and scientific advances in this disease are highlighted., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Rationale: Choriocarcinoma accompanied with pulmonary embolism (PE) is rare and difficult to diagnose and treat. There are about 25 cases reported in literature, which presented variable clinical characteristics and prognosis., Patient Concerns: We reported a case of choriocarcinoma presenting PE as the first manifestation in a 26-year-old Chinese female., Diagnoses: Four months before her admission to our hospital, she presented to a local hospital with respiratory manifestations, and was first diagnosed as bronchitis and treated with antibiotics without improvement, and subsequently suspected of having pulmonary tuberculosis and receive anti-tuberculosis therapy, with no response. Upon admission to our hospital, spiral computed tomography-pulmonary angiography revealed complete occlusion of right pulmonary artery, leading to PE. She received thrombolysis and anticoagulant therapy, without improvement. Further interrogation of the patient revealed a history of irregular vaginal bleeding and multiple pregnancies and abortions. Following the laboratory report of a significantly elevated level of serum beta-human chorionic gonadotropin (β-HCG) combined with other clinical and laboratory findings, a diagnosis of choriocarcinoma accompanied with PE was established based on the criteria formulated by the International Federation of Gynecology and Obstetrics and guideline of European Society for Medical Oncology., Interventions: With 1 cycle of chemotherapy with etoposide-methotrexateactinomycin D-cyclophosphamide-vincristine (EMA-CO), her dyspnea and other symptoms improved, with a significant decrease in the serum β-HCG level and pulmonary artery pressure., Outcomes: Unfortunately, she showed bone marrow inhibition, could not continue further chemotherapy, and finally died after discharging. We reviewed 25 similar cases in the literature, and found that all 17 cases receiving chemotherapy showed complete recovery while 6 of 8 cases without chemotherapy died during hospitalization., Lessons: This case report illustrates the challenges in diagnosis of choriocarcinoma presenting with respiratory manifestations, and highlights the importance of early diagnosis and timely appropriate chemotherapy in management of this disease.

Cigarette smoke (CS) contains over 60 well established carcinogens. In this study, we examined the effects of benzo(a)pyrene (B(a)P), a main CS component, on the viability and apoptosis of JEG-3 and BeWo human choriocarcinoma cancer cell lines. An MTT assay confirmed that B(a)P decreased the cell viability of JEG-3 and BeWo cells in a dose-dependent manner. Additionally, Western blot (WB) assay revealed that protein expression of cyclin D and cyclin E decreased, while protein expression of p21 and p27 was increased in response to B(a)P treatment for 48 h. The changes in reactive oxygen species (ROS) levels in JEG-3 and BeWo cells exposed to B(a)P were also measured by a dichlorofluorescein diacetate (DCF-DA) assay, which revealed that ROS levels increased in response to B(a)P treatment for 48 h. WB assay also confirmed that each B(a)P treatment of JEG-3 and BeWo cells for 4 h promoted the expression of phosphorylated eukaryotic initiation factor 2 alpha protein (p-eIF2α) and C/EBP homologous protein (CHOP), which are known to be involved in ROS-mediated endoplasmic reticulum stress (ER-stress) related apoptosis. Overall, the protein expression of Bax (a pro-apoptosis marker) increased, while the expression of Bcl-xl (an anti-apoptotic marker) decreased and the number of apoptotic cells increased in response to B(a)P treatment for 48 h. Taken together, these results suggest that B(a)P has the potential to induce apoptosis of JEG-3 and BeWo human choriocarcinoma cancer cells by increasing the ROS level and simultaneously activating ER-stress., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Chemotherapy is typically used to treat choriocarcinoma. However, a small proportion of this malignancy develops resistance to common chemotherapeutic drugs such as methotrexate (MTX) and floxuridine (FUDR). This study aimed to investigate the role and potential mechanisms of chloride intracellular channel protein 1 (CLIC1) in the development of chemoresistance in choriocarcinoma JeG3 cells. Two chemoresistant sublines were induced from their parental cell line JeG3 through intermittent exposure to MTX (named JeG3/MTX) or FUDR (named JeG3/FUDR). It was found that expression of CLIC1 was significantly higher in the chemoresistant sublines JeG3/MTX and JeG3/FUDR than in their parental cell line JeG3. Knockdown of CLIC1 by specific siRNA significantly increased cell sensitivity to MTX and FUDR in vitro and in vivo. Moreover, the high expression of CLIC1 in chemoresistant sublines was associated with upregulation of multidrug resistance-associated protein 1 (MRP1). Knockdown of CLIC1 decreased the expression of MRP1 accordingly. While reexpression of CLIC1 in the parental cell JeG3 increased its resistance to MTX and FUDR, depletion of MRP1 significantly blunted CLIC1 reexpression-mediated acquirement of chemoresistance in JeG3 cells. In conclusion, our results suggest that CLIC1 may serve as a critical mediator of chemoresistance in human choriocarcinoma JeG3 cells. The CLIC1-mediated chemoresistance is achieved through positive regulation of MRP1. Depletion of either CLIC1 or its downstream MRP1 may be a promising therapeutic strategy concerning reversing the chemoresistance in human choriocarcinoma JeG3 cells.

Luteolin is a natural compound known for its anticancer effects on various human cancers by regulating signal transduction cascades. However, the effects of luteolin on human placental choriocarcinoma are not known. Results of the present study revealed that luteolin decreased viability of JAR and JEG-3 cells, which are valuable placental models, in a dose-dependent manner, and it induced apoptosis and loss of mitochondrial membrane potential in JAR and JEG-3 cells. The results also suggested that the PI3K/AKT pathway was inhibited by luteolin treatment of JAR and JEG-3 cells in a dose- and time-dependent manner. Next, we established effects of luteolin in the presence of pharmacological inhibitors of PI3K/AKT, ERK1/2 MAPK, and mTOR on proliferation of JAR and JEG-3 cells. In addition, these inhibitors were used to verify phosphorylation of AKT, GSK3beta, and ERK1/2 and to confirm mechanisms regulated by luteolin in JAR and JEG-3 cells. We also determined levels of SREBP1 and SREBP2 expression to investigate regulatory functions of luteolin in lipid metabolism in JAR and JEG-3 cells. Expression levels of both SREBP1 and SREBP2 mRNAs were significantly reduced, but only SREBP1 protein was influenced by luteolin. We compared viability of JAR and JEG-3 cells in response to luteolin alone or in combination with other chemotherapeutic drugs (etoposide, cisplatin, and paclitaxel) and found that luteolin has synergistic effects with the conventional chemotherapeutic drugs as an anticancer agent. Collectively, these results showed that luteolin plays an important role in the treatment of human choriocarcinoma cells by inhibiting the PI3K/AKT/mTOR/SREBP cascade and expression of lipogenic genes., (© 2016 by the Society for the Study of Reproduction, Inc.)

Background: The objective of our study was to investigate the clinical characteristics and prognosis of postterm choriocarcinoma patients at Peking Union Medical College Hospital within the past 30 years., Methods: The clinical characteristics and pertinent follow-up data of 272 patients with postterm choriocarcinoma diagnosed from December 1985 through December 2014 in our hospital were reviewed. The clinical characteristics of two cohorts cut off at 2006 were compared using χ (2) tests. Risk factors of prognosis were estimated by multivariate Cox proportional regression analysis., Results: The most common initial symptom was abnormal uterine bleeding. After individualized treatment 239 patients (87.9 %) achieved complete remission, including 140 patients received initial treatment of 5-fluorouracil-based multidrug chemotherapy. There were almost no statistically significant differences in the clinical characteristics and survival rates between the two cohorts. The results of the multivariate analysis showed that history of resistance to multidrug chemotherapy, liver metastasis and FIGO score greater than 12 were independent risk factors of prognosis., Conclusions: Postterm choriocarcinoma patients were usually accompanied by several high-risk factors that should received combined chemotherapy to prevent delay in adequate treatment. 5-fluorouracil-based multidrug chemotherapy, which has been applied at PUMCH for several decades, can be an effective initial treatment for postterm choriocarcinoma patients. More emphasis should be placed on those who have history of resistance to multidrug chemotherapy, liver metastasis or a FIGO score greater than 12.

Objective: Term pregnancy with choriocarcinoma is a rare condition that can be a serious health threat to both the mother and the fetus. We present a rare case of term pregnancy with choriocarcinoma presenting as severe fetal anemia and postpartum hemorrhage., Case Report: A 34-year-old woman, gravida 3 para 2, was admitted for profuse vaginal bleeding 2 weeks after cesarean delivery of a full-term anemic baby. Transvaginal sonography revealed a 4.7-cm×10.6-cm heterogenous lesion in the endometrial cavity. Dilatation and curettage was done and a pathologic report revealed choriocarcinoma. Metastatic workup showed lung metastasis. The patient achieved remission after eight cycles of chemotherapy in the form of etoposide, methotrexate, actinomycin D, cyclophosphamide, and vincristine. There was no evidence of recurrence in the subsequent 3 years of regular follow up., Conclusion: Although fetomaternal hemorrhage is a rare form of presentation of choriocarcinoma, its presence should alert the physician to investigate the cause further. This chemotherapy regimen was effective in our case and the patient needed to be followed up carefully., (Copyright © 2016. Published by Elsevier B.V.)

Gestational choriocarcinoma ended with a successful parturition is extremely rare, especially in cases where multiple metastases occurred.A 29-year-old Chinese primigravida was admitted with vaginal bleeding at 32 gestational week, and diagnosed with gestational choriocarcinoma with vaginal, pulmonary, and cerebral metastasis after pathological, and imaging examination. At 33 gestational week, a healthy infant was delivered by cesarean section. Although no evidence of choriocarcinoma or any other forms of gestational trophoblastic diseases was found in the placenta and uterine curettages, the patient was given 7 cycles of postpartum chemotherapy. Her serum beta-human chorionic gonadotropin level fell to the normal range, and the metastatic lesions reduced. The baby is still free from diseases, and the patient reports no clinical manifestation 4 years after the hospital discharge.Despite its rapid metastases and complications, gestational choriocarcinoma still can be successfully treated by postpartum chemotherapy with the least delay.