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Objective: The treatment for high risk or recurrent gestational trophoblastic neoplasia (GTN) is a highly toxic multi-agent chemotherapy. For patients with progressive or recurrent GTN, checkpoint inhibitors have demonstrated anti-tumor activity; however, identification of novel therapies for GTN remain an unmet need. Therefore, we sought to characterize the molecular landscape of GTN to identify potential therapeutic targets., Methods: GTN samples were analyzed using a combination of molecular - next-generation sequencing (NGS) or whole exome sequencing (WES)- and protein- Immunohistochemistry (IHC) analyses. GTN samples encompassed complete moles, choriocarcinoma, epithelioid trophoblastic tumors (ETT), and placental site trophoblastic tumors (PSTT)., Results: We analyzed 30 cases of GTN including 15 choriocarcinoma, 7 ETT, 5 PSTT, 1 invasive mole and 2 mixed histologies. The median age was 41.5. GTN samples were found to be PD-L1 positive (92.3%), tumor mutational burden (TMB) low (92.8%), and microsatellite stable (MSS) (100%). Forty-six percent of choriocarcinoma specimens contained a genomic alteration including TP53 (33%) and homologous recombination repair (HRR) (13%) genes. Alterations in RTK-RAS pathway signaling was present in 40% of ETT cases., Conclusions: The high rate of PD-L1 positivity in this real-world database and reported in prior literature support continued clinical trial development evaluating immunotherapy for treatment of GTN. Other potential targeted treatments identified include Wee1, PARP and MEK inhibitors based on molecular alterations in TP53, HRR genes, and RTK-RAS pathways respectively., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Leah McNally: None. Sharon Wu: employee of Caris Life Sciences. Kurt Hodges: employee of Caris Life Sciences. Matt Oberley: employee of Caris Life Sciences. John J Wallbillich: None. Nathaniel L Jones: None. Thomas J Herzog: Scientific Advisory Boards &/or Honorarium: Aadi Bioscience, Astra Zeneca, Caris, Clovis, Eisai, Epsilogen, Genentech, GSK, J&J, Merck, Mersana, Novocure, Seattle Genetics. Premal H Thaker: Grants to institution from: Merck and GSK. Scientific Advisory Boards: AstraZeneca, GlaxoSmithKline, Immunon, Immunogen, SeaGen, Novocure, Mersana, Verastem, Zentalis. Angeles Alvarez Secord: Duke receives Clinical trial grant funding from AbbVie, Aravive, AstraZeneca, Clovis, Eisai, Ellipses Pharma, GSK, I-MAB Biopharma, Immunogen, Merck, Oncoquest, Roche/Genentech, Seagen, Inc., Theradex, VBL, Zentalis, and the National Cancer Trial Network. Advisory Boards (uncompensated) for AstraZeneca, Clovis, Gilead, GSK, Immunogen, Imvax, Merck, Mersana, Natera, Onconova, Oncoquest. Participation on Steering Committees (uncompensated): Aravive (AxXelerate); Roche/Genentech (AtTEND trial); VBL (OVAL trial); and Oncoquest (GOG-3035/FLORA-5). SGO Board of Directors, GOG Foundation Board of Directors, AAOGF Board of Trustees. Marilyn Huang: University of Miami received clinical grant funding fromMerck, Jansen; Scientific advisory board: Clovis, Seattle Genetics, Eisai, Immunogen, VB111, Tesaro/GSK, Voluntis/Aptar Digital Health., (Published by Elsevier Inc.)

Background: Malignant ovarian germ cell tumors are rare tumors, affecting young women with a generally favorable prognosis. The French reference network for Rare Malignant Gynecological Tumors (TMRG) aims to improve their management. The purpose of this study is to report clinicopathological features and long-term outcomes, to explore prognostic parameters and to help in considering adjuvant strategy for stage I patients., Patients and Methods: Data from patients with MOGCT registered among 13 of the largest centers of the TMRG network were analyzed. We report clinicopathological features, estimated 5-year event-free survival (5y-EFS) and 5-year overall survival (5y-OS) of MOGCT patients., Results: We collected data from 147 patients including 101 (68.7%) FIGO stage I patients. Histology identifies 40 dysgerminomas, 52 immature teratomas, 32 yolk sac tumors, 2 choriocarcinomas and 21 mixed tumors. Surgery was performed in 140 (95.2%) patients and 106 (72.1%) received first line chemotherapy. Twenty-two stage I patients did not receive chemotherapy. Relapse occurred in 24 patients: 13 were exclusively treated with upfront surgery and 11 received surgery and chemotherapy. 5y-EFS was 82% and 5y-OS was 92.4%. Stage I patients who underwent surgery alone had an estimated 5y-EFS of 54.6% and patients receiving adjuvant chemotherapy 94.4% (P < .001). However, no impact on estimated 5y-OS was observed: 96.3% versus 97.8% respectively (P = .62). FIGO stage, complete primary surgery and post-operative alpha fetoprotein level significantly correlated with survival., Conclusion: Adjuvant chemotherapy does not seem to improve survival in stage I patients. Active surveillance can be proposed for selected patients with a complete surgical staging., (Copyright © 2020 Elsevier Inc. All rights reserved.)

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.)

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.)

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.)

Objective: To evaluate the effect of a clinicopathologic diagnosis of choriocarcinoma (CCA) on clinical characteristics, extent of disease, and response to chemotherapy in low-risk gestational trophoblastic neoplasia (GTN)., Methods: We reviewed the records of 678 patients with low-risk GTN (FIGO stage I and stages IIIII, score<7) treated from 1962 to 2009. Patient and disease characteristics, treatment course, as well as clinical response and survival were analyzed retrospectively. Patients with a clinicopathologic diagnosis of CCA were compared to those with a clinical diagnosis of postmolar GTN., Results: Of 678 women with low-risk GTN, 129 (19.0%) had a clinicopathologic diagnosis of CCA. Patients with CCA had higher parity (median 1 vs. 0, p=0.003), more pretreatment human chorionic gonadotropin (hCG) levels at >100,000mIU/mL (12.7% vs. 5.9%, p=0.009), longer duration of disease (19.6 vs. 9.9weeks, p<0.001), and higher FIGO scores (median 2 vs. 1, p<0.001) compared with those with other histology; however, patients with CCA and postmolar GTN presented with similar stage of disease (stage I, 83.1% vs 88.2%, p=0.126). Although there was no difference in survival between groups, increased resistance to first-line methotrexate chemotherapy was significantly associated with a diagnosis of postmolar CCA (OR 2.67, p=0.007)), pretreatment hCG level at >10,000mIU/mL (OR 2.62, p=0.002), and higher FIGO score (3-4: OR 2.02, p=0.027; 5-6: OR 5.56, p<0.001) on multivariate analysis., Conclusions: Clinicopathologic diagnosis of postmolar CCA in patients with low-risk GTN is associated with higher pretreatment hCG levels, higher FIGO scores, and increased resistance to first-line single-agent methotrexate chemotherapy., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Objective: To determine whether single agent chemotherapy with intramuscular methotrexate 50mg administered on days 1, 3, 5, and 7 and oral folinic acid 15mg administered on days 2, 4, 6, and 8 in 2 weekly cycles (IM MTX/FA) is an effective treatment regimen for patients with low risk gestational choriocarcinoma., Method: Electronic databases were searched to identify patients with gestational choriocarcinoma at the Sheffield and Charing Cross supra-regional trophoblastic disease centres from January 2000 to December 2011. Clinical notes of low risk patients with FIGO score 0-6 were retrospectively reviewed to assess treatment outcomes and subsequent relapse., Results: 65 patients were identified with low risk choriocarcinoma. Serum hCG levels normalised in 24 patients without the requirement of chemotherapy (19 with histological confirmation, 4 highly suspicious histology and 1 clinical diagnosis). Of 23 patients with histologically confirmed choriocarcinoma, 8 (35%) had a sustained complete response to IM MTX/FA and did not relapse. Both patients with FIGO score 6, and 1 patient with FIGO stage III metastatic disease developed resistance to IM MTX/FA and required further treatment. Despite the development of drug resistance or relapse all patients were successfully salvaged by subsequent treatments., Conclusions: Not all patients with low risk choriocarcinoma that have had primary intervention prior to staging, such as surgical resection or uterine evacuation will require chemotherapy, providing hCG levels continue to decline to normal. Low risk (FIGO 0-5) patients should initially receive IM MTX/FA due to its low toxicity, outpatient administration and reasonable efficacy. Patients with FIGO score 6 or FIGO stage III disease should make an informed choice between IM MTX/FA and combination chemotherapy., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Background: Choriocarcinomas unrelated to pregnancy, teratomas, or germ cell tumors have been found in the stomach, lungs, colon, esophagus, bladder, breast, renal pelvis and other sites., Case: We present a case of a 58-year-old woman with endometrial carcinoma with choriocarcinomatous differentiation. She received surgery and chemotherapy for endometrial adenocarcinoma. However, a metastatic tumor of choriocarcinomatous element appeared at the vaginal cuff 9 months after surgery. Additional chemotherapy for choriocarcinoma resulted in a decrease in the serum hCG and the tumor regressed. Fifty months following surgery, she is alive without disease., Conclusion: Treatment and follow-up must be performed not only for the adenocarcinoma element but also for the choriocarcinoma element in patients presenting with endometrial carcinoma with choriocarcinomatous differentiation.

Purpose/objective: To investigate whether exogenous PUMA expression suppresses the growth of drug-resistant choriocarcinoma cells and sensitizes them to chemotherapeutic agents., Methods: An adenovirus expressing PUMA (Ad-PUMA), alone or in combination with chemotherapeutic agents (5-FU, vp16, MTX), was used to treat drug-resistant choriocarcinoma cells jeg-3/vp16 and parental jeg-3. The growth inhibitory and proapoptotic effects of Ad-PUMA both in vitro and in vivo were examined. The mechanisms of PUMA-mediated growth suppression and apoptosis were investigated by an analysis of caspase 3 activation and the change of mitochondrial membrane potential. The levels of PUMA, p53 and caspase 3 were detected by Western blotting., Result: PUMA was expressed lower in jeg-3/vp16 than in jeg-3. jeg-3/vp16 responded much less sensitively to 5-FU and vp16 treatment than jeg-3, though PUMA was up-regulated in both cells. Exogenous PUMA expression resulted in potent growth suppression of jeg-3/vp16 and jeg-3 through induction of apoptosis. Ad-PUMA sensitized jeg-3 and jeg-3/vp16 to chemotherapeutic agents. When Ad-PUMA 10MOI and 5-FU, vp16 or MTX were combined respectively, IC50 of drugs decreased by 8.66-, 18.66- and 13.06-fold compared with those treated by anticancer drugs alone in jeg-3/vp16, while in jeg-3, IC50 decreased only by 1.80-, 1.78- and 2.76-fold. Ad-PUMA restored the sensitivity of choriocarcinoma cells to chemotherapeutic agents by enhancing apoptosis induced by anticancer drugs. Similar results could be observed in vivo. Xenograft tumors were inhibited by Ad-PUMA or vp16. In the drug-resistant group, the inhibitory rate increased from 14.57% to 78.93% in vp16 and vp16 combined with Ad-PUMA subgroups. While in the parental group, the inhibitory rate increased but slightly, from 66.39% to 71.56%., Conclusion: PUMA is an important player in the therapeutic responses to chemotherapeutic agents of choriocarcinoma cells. In addition to its role in inhibiting tumor growth, low dose of Ad-PUMA significantly restored the sensitivity of choriocarcinoma cells to chemotherapeutic agents in vitro and in vivo. Exogenous PUMA is potentially useful as a sensitizer in treating drug-resistant choriocarcinoma.

Background: Although most patients at high risk of Gestational Trophoblastic Neoplasia (GTN) respond to standard treatments, there is a group of patients that will die because of it. The use of new single or combination drugs in this population has become a priority., Case Report: We present the case of a relapsed high risk choriocarcinoma patient who did not respond to several chemotherapy treatments nor to PET guided salvage surgery. Because of treatment toxicity, the patient was started on Capecitabine, with which she achieved total remission, still present after 15 months of starting treatment., Conclusions: The use of Capecitabine and the multidisciplinary management of this population should be taken into account for patients at high risk of relapsing to EP/EMA because of its efficacy and little toxicity.

Objective: Hydatidiform mole can be classified by histopathologic characteristics and by genetic constitutions and most complete moles are diploid, whereas most partial moles are triploid. We investigated the concordance between these two classifications, characterized moles with conflicting classifications, and compared the ability of the two classifications to discriminate between patients with and without a substantial risk of persistent trophoblastic disease., Methods: 294 cases of consecutively collected hydropic placentas clinically suspected of hydatidiform mole made the basis of this retrospective study. We determined the ploidy and reviewed the original histopathologic material in all cases. Data on possible chemotherapy were collected for each patient., Results: 270 of the conceptuses were histopathologically classified as hydatidiform mole. Among the 24 conceptuses classified as non-molar miscarriage, 20 were triploids, 2 were diploid androgenetic and 2 were diploid biparental. In 23% of the conceptuses, the histopathologic and genetic classifications were conflicting. 5% of the patients with hydropic placentas classified as partial mole encountered persistent trophoblastic disease; however, the genome was diploid in all these moles. None of 131 patients with a triploid hydropic gestation encountered persistent trophoblastic disease., Conclusion: As full concordance between the histopathologic and the genetic classifications was not found, we believe that features beyond the genetic constitution influence the development of morphologic features in hydatidiform moles. We recommend that gestations suspected of hydatidiform mole are subjected to histopathologic examination. If hydatidiform change and trophoblastic hyperplasia are identified, the ploidy should be used to identify patients with a high risk of persistent trophoblastic disease.

Background: Intraplacental choriocarcinoma is rare, and usually results in maternal metastasis at the time of diagnosis. Intraplacental choriocarcinoma involves both mother and infant is extremely rare. There was only one case report of intraplacental choriocarcinoma with confirmed metastases involving both the mother and the infant., Case: We describe a second case of intraplacental choriocarcinoma in a term placenta with both maternal and infantile metastases. Grossly, the primary lesion of the placenta resembled an old infarct. Microscopically, clusters of malignant trophoblasts arose from residual normal chorionic villi and infiltrated into the intervillous spaces. Both the mother and the infant received chemotherapy and were alive without disease after one year's follow-up., Conclusion: The optimal treatment for intraplacental choriocarcinoma is controversial. However, aggressive chemotherapy is suggested for patients with metastatic disease.

Introduction: Antecedent term pregnancy is an adverse prognostic factor in Gestational Trophoblastic Disease (GTD). In The Netherlands, patients with post term choriocarcinoma are considered high-risk independent of WHO score. In the present study, we assessed whether post term choriocarcinoma always has to be considered high-risk, requiring first line treatment with combination chemotherapy, or whether a subgroup of patients is distinguishable in which single-agent Methotrexate is a safe alternative., Patients and Methods: The study is a retrospective multicenter cohort study. Patients registered by the Dutch Working Party on Trophoblastic Disease between 1986 and 2004 with choriocarcinoma after a non-molar pregnancy were eligible. Hospital and outpatient records of the patients were reviewed., Results: In total, 68 patients with non-molar choriocarcinoma were registered of whom 44 had an antecedent term pregnancy. Most post term patients (77%) were high-risk according to the WHO staging system. The majority of patients presented with metrorraghia and high hCG levels. Lung and liver metastases were common (respectively 64% and 28%), probably caused by a delay in diagnosis (median interval 16 weeks). Patients were often Methotrexate-resistant (75%). Overall survival was 86% in patients with a post term choriocarcinoma., Conclusions: Although term pregnancy is an adverse prognostic factor in GTD, current survival is comparable to the general survival in high-risk patients. A subgroup of patients in which monotherapy would be sufficient could not be identified. Immediate administration of combination chemotherapy seems justified, even in those few cases when scoring systems would suggest low- or medium-risk disease.

Background: Well-established first-line chemotherapy (such as EMA-CO) is extraordinary active for gestational choriocarcinoma. However, it causes very serious situation once drug-induced acute interstitial lung disease occurs during the treatment., Case: A 31-year-old Japanese woman with metastatic choriocarcinoma was treated with EMA-CO as an initial chemotherapy regimen for seven cycles. Her beta-hCG dropped from 13,087 ng/ml to 2.2 ng/ml. At 11 days after 7th cycle of EMA-CO treatment, however, she developed respiratory failure, and was diagnosed as having EMA-CO-induced interstitial lung disease with bilateral ground-glass opacity on CT scan, and the examination of the bronchoalveolar lavage fluid. After high-dose steroid therapy, symptoms and ground-glass opacity on CT scan were remarkably improved. She then commenced a regimen of carboplatin (AUC 5) and paclitaxel (180 mg/m2). After completing 8 cycles, her beta-hCG dropped to <0.2 ng/ml. Three additional cycles were administered and the patient remained clinically free of disease, with normal beta-hCG levels for 11 months., Conclusions: Paclitaxel and carboplatin combination is active and appears to be a viable alternative to EMA-CO combination chemotherapy in metastatic choriocarcinoma even after EMA-CO-induced interstitial lung disease.

Objective: Gestational trophoblastic diseases (GTD), a group of rare placenta disorders, have a varying potential for invasion, either local, or remote under the form of metastases, and are definitely cured by chemotherapy in 85 to 99% of cases. Single-agent methotrexate is the usual primary treatment for women with low-risk trophoblastic tumors (TT), yet various regimens are currently used worldwide. We reviewed these regimens and the available evidence for evaluating their respective efficacy and tolerance., Methods: We performed an exhaustive literature search and applied the French agency for evaluation in healthcare (HAS) methodology for critical appraisal and level of evidence. We summarised the protocols used in the selected studies and their respective results regarding efficacy and toxicity., Results: We selected 18 original studies on the efficacy and tolerance of methotrexate used alone or in association with folinic acid for the treatment of nonmetastatic or low-risk metastatic trophoblastic tumors. Among these 18 studies, 15 were retrospective series, 3 were prospective series without any control group, and none were controlled clinical trial. We identified four main chemotherapy regimens and two very different strategies for repeating the treatment courses. It was not possible to perform a meta-analysis due to the lack of controlled clinical trials. Because all studies were observational with no control group and methods were heterogeneous for scoring women, setting criteria for starting therapy, defining remission, and collecting information on adverse events, we found no objective element allowing recommending one protocol rather than another., Conclusion: Objective comparison should be addressed in the scope of comparative trials organised at the national or even international level. However their feasibility is highly problematic for rare diseases such as GTD. International collaborative works should be encouraged to reduce practice variations and allow a better comparability between strategies.

Background: Choriocarcinoma mostly metastasizes to lung parenchyma. Its pulmonary tumor embolism and cardiac metastasis are very rarely encountered, of which antemortem diagnosis is even more rare., Case: To our knowledge, we present the first case of intracavitary cardiac metastasis and pulmonary tumor emboli of choriocarcinoma diagnosed and treated without any surgical intervention. Multi-agent chemotherapy led to almost complete regression of cardiac and pulmonary lesions and normalization of beta-hCG levels., Conclusion: Cardiac metastasis of choriocarcinoma must be kept in mind for cases of cardiac mass in reproductive age women, especially when history and clinical presentation are suggestive for gestational trophoblastic disease. As the tumor is highly sensitive, chemotherapy together with biochemical and radiological monitoring constitutes an effective treatment modality if cardiopulmonary functions are not deteriorating.

Background: Choriocarcinoma of the fallopian tube is extremely rare as is choriocarcinoma with a viable pregnancy. We present an unusual case of prima gravida at 33 weeks gestation that was diagnosed as having tubal choriocarcinoma which was successfully treated by chemotherapy., Case: A 31-year-old prima gravida at 32(+3) weeks gestation was admitted complaining of dyspnea and blood tinged sputum. Suspecting a left adnexal malignant tumor with pulmonary metastasis, delivery of the baby for optimal treatment of the mother's tumor was planned. Cesarean delivery was performed because of induction failure. Tumorectomy with left salpingectomy and infracolic omentectomy was performed for a left tubal tumor. Microscopic findings revealed choriocarcinoma with extensive hemorrhage. Its FIGO stage was III and its WHO prognostic score 12, representing high risk. After 4 cycles of chemotherapy, serum beta-hCG level fell to the normal range. The patient and her baby remain disease-free 16 months after disease diagnosis., Conclusion: This is the first reported case of tubal choriocarcinoma coexistent with a viable pregnancy, in which the baby survived and the mother was successfully treated by chemotherapy.

Background: Both preclinical data and case reports support the use of taxanes for high-risk metastatic choriocarcinoma., Case: We report the case of a 31-year-old with metastatic choriocarcinoma who required 3rd-line treatment with a paclitaxel-cisplatin-based regimen. She achieved a complete response and remains relapse-free 21 months after her last dose of chemotherapy., Conclusion: The literature suggests that paclitaxel contributes significantly to the treatment of choriocarcinoma and its use should be explored further. This is the first case report formally reporting its combination with cisplatin.

Objectives: The outcomes of patients with choriocarcinoma treated with fertility-preserving techniques and the children born to patients subjected to combined chemotherapy were examined retrospectively., Methods: We treated 191 patients with choriocarcinoma from 1965 through 2001. Of these, 62 were treated with fertility-preserving techniques (50 were cured and 12 died) and 129 with hysterectomy (88 were cured and 41 died)., Results: Between 1965 and 1972, survival in the hysterectomy group increased. Thereafter, no significant differences between the two groups were observed. Subsequently, the number of cases with uterus preservation increased and occupied about two thirds of all cases. There were no significant differences in patient survival between the two groups by FIGO stage, although the data tended to support uterus preservation. Of the 50 patients who underwent fertility-preserving treatment for choriocarcinoma, 23 conceived for a total of 43 pregnancies. Thirty-four children were born without congenital malformations. However, two babies were born with ventricular septal defect (VSD) and one with tetralogy of Fallot (TOF) (3/34; 8.8%). The three children were the second child born after combination chemotherapy. The total dose of Methotrexate (MTX) was higher in patients who delivered a child with a heart anomaly (P < 0.02)., Conclusions: Patients treated with fertility-preserving modalities had comparable survival rates to those undergoing hysterectomy at more recent time points. The incidence of congenital heart abnormalities was higher for patients undergoing combined chemotherapy than in the general population. The influence of anti-cancer agents on oocytes should be incorporated into any treatment plans for patients wishing to bear children.

Background: Choriocarcinoma arises in the ovary from gestational or nongestational origin. Nongestational choriocarcinoma of the ovary is extremely rare and the pure type is less frequent than the mixed type with other germ cell tumors. Diagnosis of pure nongestational choriocarcinoma is very difficult without genetic analysis., Case: We report a pure nongestational choriocarcinoma primarily arising in a 19-year-old woman's ovary. Following abdominal operative procedure, careful examination of the tumor revealed pure choriocarcinoma without combination of other germ cell tumors. We confirmed its nongestational origin by DNA polymorphism analysis. Multiple courses of chemotherapy with an EMA/CO regimen were effective for this case., Conclusion: Genetic analysis is useful tool in determining the origin of choriocarcinoma. We could distinguish the genetic origin of this tumor analyzing only two or three appropriate VNTR loci.

Dr. Roy Hertz is one of two scientists credited with discovering the first medical cure of a solid cancer. This paper presents a biographical history of Dr. Hertz and discusses his roles in the discovery of a cure for choriocarcinoma and as a pioneer for future research in cancer chemotherapy. This biography not only serves as a testament to the pioneering individuals in the field of chemotherapeutics but also represents the unique blend of medical, pharmacological, and physiological histories that led to the profound discovery. The timing and significance of the work of Drs. Hertz and Li cannot be overestimated. Their discovery was a spectacular success, demonstrating proof of the principle that chemotherapy can cure metastatic cancer and that an almost uniformly fatal cancer in young patients could be cured with a single chemotherapeutic agent, which stands as one of the greatest achievements in cancer research.

Background: Post-termchoriocarcinoma is a rare complication of pregnancy. The presence of epithelioid trophoblastic elements may lead to the persistence of locally invasive disease which is unresponsive to multiagent chemotherapy. Relapse is associated with an estimated mortality rate of 30%., Case: We present a case of Stage IC post-term choriocarcinoma and epithelioid trophoblastic tumor. While the metastatic sites in the lungs responded to multiagent chemotherapy, a hysterectomy was required to treat persistent disease in the uterus. The patient relapsed within 4 months of completion of chemotherapy. Relapse was treated with high-dose chemotherapy with peripheral stem cell support. The patient is alive with no evidence of disease 23 months posttransplant., Conclusions: The application of multimodality treatment and high-dose chemotherapy resulted in a successful outcome for this patient, indicating a potential role for high-dose therapy in patients who suffer a relapse of choriocarcinoma.

Objective: The aim of this study was to evaluate clinical manifestations, management options, and prognosis for women presenting with gestational trophoblastic tumors with vaginal metastasis., Method: Fifty-one patients with vaginal metastases were analyzed retrospectively between January 1985 and September 2000. Vaginal metastasis were documented by physical examination and tissue biopsy., Results: The incidence of vaginal metastasis in choriocarcinoma and invasive mole was 8.6 and 4.1%, respectively. The metastatic tumors were mostly located in the anterior wall of the lower part of vagina. Eighteen patients presented with hemorrhage and rupture. All patients were treated with 5-Fu combined chemotherapy. Vaginal packing was employed to stop bleeding in 16 patients. Three of them received selective angiographic embolization. Vaginal tumors disappeared after chemotherapy. Forty-four patients with complete remission were followed up periodically without evidence of recurrence., Conclusions: Large or multiple vaginal metastases place the patients at high risk for significant hemorrhage. 5-Fu combined chemotherapy is still a reliable method for treating vaginal metastases. Angiographic embolization is emerging as a successful procedure to control the severe hemorrhage of vaginal tumors.

Background: Gestational choriocarcinoma is a malignant tumor that frequently metastasizes to the highly vascularized organs such as the lung, brain, and liver via hematogenous spread. However, this tumor rarely metastasizes to the eye and only a few cases of metastasis to the choroid have been reported., Case: A 17-year-old woman presented with visual field defects, decreased vision, and increasing pain in her left eye. She had undergone evacuation of a complete hydatidiform mole 32 months prior to the presentation. Ophthalmologic evaluation revealed a metastatic choroidal tumor, and a CT scan showed a metastatic tumor in the left lung. The serum hCG level was elevated at 7780 mIU/ml. A clinical diagnosis of metastatic gestational choriocarcinoma involving the choroid and lung was made. The patient received 13 courses of combination chemotherapy, resulting in complete remission. Radiotherapy and surgical treatment were unnecessary., Conclusion: This is a very rare case of the successful treatment of gestational choriocarcinoma metastatic to the choroid using systemic chemotherapy alone., ((c)2001 Elsevier Science.)

Objective: The aim of this study was to explore the risk of pregnancy of patients who conceived within 1 year after successful chemotherapy for gestational trophoblastic tumor (GTT)., Methods: From 1966 to 1996, 22 patients who conceived within 1 year after chemotherapy were followed up and analyzed retrospectively., Results: Among 22 patients, 9 had term deliveries and 1 had a premature birth, 6 had induced abortion at the patient's request, and 6 had therapeutic abortion because of various indications such as repeated hydatidiform mole (1 case), intrauterine death (1 case), inevitable abortion (1 case), and threatened abortion (3 cases). The fetal loss rate was 27.1% (6/22). The incidence rate of gestational trophoblastic disease (GTD) was 9.1% (2/22). The incidence rate of GTT was 4.5% (1/22). The average interval between completion of chemotherapy and pregnancy was 10.25 months in the group of term pregnancies and 5.86 months in that of fetal loss (P < 0.05), indicating that the longer the interval, the lesser the risk of GTD., Conclusion: The results suggest that contraception for 1 year is necessary in patients with GTT after successful chemotherapy. However, in the case of a patient who conceives within 1 year, it is not necessary to terminate pregnancy, but the pregnancy must be carefully watched., (Copyright 2001 Academic Press.)

We report a patient who developed metastatic gestational choriocarcinoma following delivery of a normal, healthy child that, however, was anemic and required blood transfusion. The patient developed secondary postpartum hemorrhage over a period of several weeks and required curettage and myometrial contractants to control the bleeding. At the time of diagnosis the patient had extensive pulmonary metastases and ultrasound showed full penetration of the myometrium by tumor. Immediately following the second course of chemotherapy with etoposide, methotrexate, and actinomycin D, alternating with cyclophosphamide and vincristine, the patient developed sepsis associated with a uteroperitoneal fistula and required hysterectomy. The sepsis was associated with disseminated intravascular coagulopathy and adult respiratory distress syndrome. However, the patient's tumor was exquisitely sensitive to chemotherapy and with good intensive care unit support and chemotherapy the survived without residual scar except for the loss of reproductive function. There are two lessons to be learned from these events: (1) The syndrome of secondary postpartum hemorrhage with a fetus that is anemic spells a diagnosis of choriocarcinoma; and (2) color Doppler flow vaginal ultrasound performed at the time of presentation of trophoblastic tumors may be useful to show full penetration of the myometrium by tumor which may be a warning of possible scar rupture in a subsequent pregnancy.

Gestational choriocarcinoma metastasized to the nasal mucosa is extremely rare. An HIV-infected woman with choriocarcinoma presenting with a nasal mass is reported. The clinical findings are compared with a previous reported case. She responded to multiagent chemotherapy and has obtained complete remission. The role of HIV infection is also discussed.

Effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), 3,3',4,4',5-pentachlorobiphenyl (PCB126), a technical PCB mixture (Aroclor 1016), and a technical toxaphene mixture (Camphechlor) on aromatase (CYP19) activity were investigated in human choriocarcinoma JEG-3 cells. After 18 h incubation with TCDD, PCB126, Aroclor 1016 or toxaphene, ethoxyresorufin-O-deethylase (EROD), and aromatase activity were determined. To exclude serum effects, incubations were carried out with or without fetal calf serum in the medium. EROD activity was induced by both TCDD and PCB126 in the presence or absence of serum, which indicates that JEG-3 cells are responsive toward dioxin-like chemicals. Neither Aroclor 1016 nor toxaphene affected EROD activity in these cells. Calculated EC50 values for induction of EROD activity were 0.71 and 0.40 nM for TCDD, and 48 and 20 nM for PCB126 in presence or absence of serum, respectively. Incubation with TCDD or PCB126 with or without serum caused a concentration-dependent decrease in the aromatase activity of up to 4.9-fold. Calculated EC50 values for this effect were 52 pM and 13 nM for TCDD, and 75 and 48 nM for PCB126 in the presence and absence of serum, respectively. Aroclor 1016 and toxaphene had no effect on aromatase activity at concentrations up to 1.0 microM for Aroclor 1016 or 3.0 microM for toxaphene. These results show that aromatase activity can be decreased in a concentration dependent way within the same range where EROD activity is increased. In view of these results, possible effects of dioxin-like compounds on estrogen producing and androgen target cells should be studied in more detail.

A 41-year-old woman with pure ovarian choriocarcinoma and widespread liver metastases became refractory to standard cisplatin-based chemotherapy regimens. As metastatic disease was limited to the liver and operable, the patient underwent complete resection of three liver metastases. The serum human chorionic gonadotrophin level promptly returned to normal values. Pathologic studies demonstrated the presence of active residual disease composed of typical syncytiotrophoblastic and cytotrophoblastic cells and large mononucleated intermediate cells. The patient remained disease-free for more than 5 years after treatment. It is concluded that liver salvage surgery may cure patients with chemorefractory ovarian choriocarcinoma with metastases to the liver.

Two patients with resistant gestational choriocarcinoma were treated w with Taxol after extensive prior chemotherapy including EMACO and platinum-based salvage chemotherapy. Both patients showed significant responses to Taxol. One patient relapsed in the brain and liver after treatment and died. Taxol was combined with carboplatin in the other patient who achieved sustained clinical and hormonal remission after craniotomy and excision of resistant disease in the brain.

Gestational choriocarcinoma associated with a viable pregnancy is extremely rare, and such choriocarcinoma with metastases presenting during the pregnancy is even more exceptional. Metastases from this tumor may present in a variety of ways depending on the site of the metastatic lesion, and can be fatal before choriocarcinoma is even suspected. We describe a 32-year-old primigravida presenting at 31 weeks gestation with a grand mal seizure due to cerebral metastases secondary to gestational choriocarcinoma who was subsequently successfully treated with chemotherapy. To our knowledge this is the first reported case of choriocarcinoma presenting with signs due to cerebral metastases during pregnancy where both the mother and child survived. This paper emphasizes the need to consider metastatic choriocarcinoma in any gravid female who presents with unusual neurological signs because of the life-threatening nature of this potentially curable disease.

A 30-year-old white female was diagnosed with gestational trophoblastic disease in 1981. Despite an original World Health Organization score of 4 and initial aggressive combination chemotherapy, she was treated over a 9-year period with multiple chemotherapy agents and had undergone several operative procedures to remove metastatic lesions for persistent disease. Long-term remission has now been obtained after four courses of etoposide, ifosfamide, and cisplatin.

Twenty-six drug-resistant choriocarcinoma patients were treated with a PEBA regimen (cisplatin, etoposide, bleomycin, and adriamycin), supplemented by radiotherapy or surgery, from January 1988 to June 1992. A total of 80.8% of the patients had received at least four drugs, and 69.2% had received six or more cycles of combination chemotherapy. All of the patients were primarily treated with PEBA chemotherapy, 5 patients underwent hysterectomy, 9 patients received local lung and/or pelvis cobalt-60 irradiation, and 2 patients with brain metastases received whole brain irradiation. Twenty-five patients achieved a complete remission (CR 96.2%), but 7 patients relapsed. One patient with a relapse reentered sustained CR through surgery and further chemotherapy. Another patient who relapsed lives with tumor after local lung irradiation and chemotherapy. Nineteen patients (73.1%) were in sustained CR lasting at least 1 year. The side effects of the PEBA regimen were moderate and tolerable. We think that PEBA is an optimal regimen for the treatment of drug-resistant choriocarcinoma.

EMA/CO (etoposide-methotrexate-actinomycin D and Cytoxan-Oncovin) is an effective and well-tolerated chemotherapy regimen for the treatment of high-risk gestational trophoblastic disease. However, it is associated with significant neutropenia often requiring dose reductions and treatment delays. We describe the use of granulocyte colony-stimulating factor (G-CSF) in three patients in order to maintain the treatment schedule. A subcutaneous injection of 5 micrograms/kg/day was administered on Days 3-6 and 9-14 of each chemotherapy cycle. No patients had any adverse effects and all received full chemotherapy doses without any treatment delay. The addition of G-CSF to the EMA/CO regimen may benefit patients by achieving dose intensity in the treatment of high-risk gestational trophoblastic disease.

A 39-year-old woman with choriocarcinoma metastatic to the lungs and parametrium underwent total abdominal hysterectomy/bilateral salpingo-oophorectomy and follow-up chemotherapy with regression of the hCG assay, plateauing at 9 mIU/ml. Spinal fluid hCG assay was negative. An LH assay was performed which was 135 mIU/ml (2nd IRP-HMG). A quantitative hCG assay was performed on two sources of purified LH at varying concentrations to determine the contribution of LH cross-reactivity. When corrected for the LH contribution, the quantitative hCG was zero. Chemotherapy was discontinued. At 12-months follow-up the patient has remained in complete chemical remission and has an excellent performance status. Whenever a patient is oophorectomized, LH cross-reactivity should be ruled out as a cause for persistent low titers of hCG.

Choriocarcinoma of the nonmolar placenta is presumptively a rare entity and is usually associated with widespread maternal metastases at the time of diagnosis. Nonmetastatic disease goes unrecognized and undiagnosed because placental carcinoma can be limited to a few villi, and grossly evident disease is often misinterpreted as a placental infarct. The optimal treatment for patients with choriocarcinoma of the placenta is not known but aggressive combination chemotherapy is suggested for patients with metastatic disease. Historically, the prognosis for both mother and infant has been poor.

A case of severe Lactobacillus septicemia in a patient treated with chemotherapy because of metastatic choriocarcinoma is described. Although Lactobacillus is a ubiquitous commensal of the female genital tract, no earlier reference was found in the literature.

Although gestational choriocarcinoma is a rapidly invasive malignancy, metastatic invasion of this tumor to the heart is rare. We report an unusual case of coronary embolism, which was caused by malignant trophoblasts from choriocarcinoma in a 26-year-old woman. The woman presented with classic symptoms of ischemic heart disease after having successfully undergone chemotherapeutic treatment for choriocarcinoma several months earlier. Thus, she was thought to have coronary heart disease or to have developed cardiotoxicity from antineoplastic drugs. This is the first report of this type of metastatic localization and tumor involvement in the heart and underscores the need for suspecting isolated metastases in uncommon sites in patients with choriocarcinoma.

Treatment of choriocarcinoma is mostly successful but there is still appreciable mortality from early respiratory failure. A series of 135 patients with choriocarcinoma presenting with dyspnea between 1960 and 1988 was studied to find prognostic factors for early respiratory death and to identify how mortality may be further reduced. Mortality with respect to early respiratory death (ERD) was 11% and was significantly associated with WHO prognostic score, chest X-ray appearance, central cyanosis, tachycardia, anemia, and clinical evidence of pulmonary hypertension. Indicators on chest X ray of high risk of ERD were the presence of more than 10 opacities, extensive opacification of lung fields, size of metastases, and hazy background obscuring the vascular pattern. Intensity of initial treatment was not correlated with this outcome. A set of criteria has been derived which will predict ERD with 100% sensitivity and 38% positive predictive value. These are opacification of lung fields on chest X ray of more than 50%, OR initial plasma hCG level greater than 10(5) when there is anemia and a history of chest pain. Patients presenting with choriocarcinoma and dyspnea who fulfill these criteria should be considered for extracorporeal perfusion techniques. As respiratory failure in this condition is characterized by hypoxemia and right-to-left shunting, extracorporeal perfusion should be effective. Ventilation should be avoided as no patient survived mechanical ventilation.

The value of the 6-day subrenal capsule assay (SRCA) in predicting the effectiveness of chemotherapy was tested using three human choriocarcinomas. The SRCA method proved to be a valuable chemopredictive test for choriocarcinoma. The results of experimental chemotherapy in nude mice and the results of the SRCA in two types of choriocarcinoma correlated well. Two of three choriocarcinomas showed sensitivity to MAC combination chemotherapy [methotrexate, actinomycin D, cyclophosphamide), and all three showed greater sensitivity to VP-16. The administration of VP-16 for treatment of all three types of choriocarcinoma significantly reduced tumor size in a dose-dependent fashion. From these observations, we speculate that the SRCA may be applied to assess the effectiveness of chemotherapy against human choriocarcinoma.

Human choriocarcinoma (JEG-3) cells were transplanted into the cheek pouch of hamsters and treated with photodynamic therapy. Twenty-four hours after intraperitoneal injection of the photosensitizer dihematoporphyrin ether (DHE), 20 tumors were illuminated with 100 J/cm2 of 630-nm light from an argon pumped dye laser. Contralateral tumors served as controls. Dihematoporphyrin ether alone had no effect on tumor growth, while laser light in the absence of DHE resulted in complete regression in 3 tumors (17%), and partial regression in 4 of 18 tumors (22%), possibly due to hyperthermia, P greater than 0.10. Using the combination of DHE plus light (photodynamic therapy) complete tumor regression was noted after a single treatment in 11 of 20 tumors (55%, mean tumor volume 279 mm3) and in 7 of 7 tumors (100%) after a second treatment. Two of 20 tumors were not retreated. Therefore, 18 of 20 tumors (90%) were grossly destroyed by one or two photodynamic treatments. Contralateral control tumors continued to grow to a median volume of 990 mm3 (chi 2 = 26.30, P less than 0.0001). Choriocarcinoma transplanted into the hamster cheek pouch is highly responsive to photodynamic therapy.

The current study reviews post-term choriocarcinoma at the New England Trophoblastic Disease Center (NETDC) in order to expand knowledge of its clinical features. Between June 1965 and June 1981, 366 patients with persistent gestational trophoblastic disease were managed at the NETDC and 15 (4.1%) of these patients had choriocarcinoma following term pregnancy. Post-term choriocarcinoma has a propensity for early metastasis with frequent involvement of the liver and brain. Metastases were detected in 13 (86.7%) patients with post-term choriocarcinoma at the time of diagnosis. Seven patients (53.8%) with metastatic post-term choriocarcinoma had hepatic and/or cerebral involvement. Complete remission was achieved in both patients with nonmetastatic disease and in 8 (61.5%) patients with metastatic disease. When the time interval from the antecedent term delivery to diagnosis was less than 4 months, 7 (87.5%) of 8 patients achieved complete remission. The 5 patients who died from post-term choriocarcinoma all had hepatic and/or cerebral involvement. Patients with post-term choriocarcinoma should undergo a meticulous metastatic evaluation and if metastases are detected these patients should be treated with primary combination chemotherapy and with the selective use of irradiation and surgical therapy.

Photodynamic therapy (PDT) uses light-activated compounds, such as hematoporphyrins, to produce cytotoxic effects after illumination. Human choriocarcinoma cells were transplanted into the hamster cheek pouch to study PDT. The transplanted choriocarcinoma secretes human chorionic gonadotropin (hCG) in proportion to tumor volume. Red light (630 nm) from an argon-pumped dye laser (100-200 J/cm2) was used to illuminate tumors sensitized with dihematoporphyrin ether (DHE). Previous work has demonstrated complete regression (CR) of 90% of tumors (18/20) after one or two PDT sessions, while contralateral cheek pouch tumors continued to grow despite intraperitoneal DHE. Neither DHE nor laser light alone resulted in significant CRs. In this study we evaluated intratumoral injection of DHE followed in 2 hr by laser treatment. In all tumors, localization of DHE was demonstrated by induced fluorescence with ultraviolet light or He:Cd laser. After a single treatment, 14 of 38 tumors (37%) completely regressed (hCG less than mIU/ml); 4 tumors regressed grossly with low-level hCG [partial regression (PR)]. After repeat treatment there were 10 additional CRs in 19 rapidly enlarging tumors. After a third treatment 3 CRs and 3 PRs were achieved in 6 tumors. Because of large volumes, 2 of 3 progressing tumors failed to fluoresce uniformly after intratumoral DHE and were treated after intraperitoneal DHE injection; both completely responded. Overall, 29 of 38 tumors (76%) completely responded to PDT, and 7 partially responded (18%) with no gross tumor remaining in 5 of the 7. Only 5% of tumors (2/38) were non-responders. Photodynamic therapy results in gross elimination of 90% of tumors (52/58) in this model after intraperitoneal or intratumoral DHE sensitization (P less than 0.0001). DHE in chorio-carcinomas is easily detected and may enable detection of occult foci of malignancy. Choriocarcinoma transplanted into the hamster cheek pouch is highly responsive to photodynamic therapy. Clinical trials of PDT in gynecologic cancers are warranted to confirm the high response rates observed in refractory nongynecologic cancers.

Thirty-four patients with cerebral metastases from choriocarcinoma were treated between 1964 and 1978 by the Department of Gynecology of the Tumor Hospital Chung Shan Medical College, Kwongchow, People's Republic of China. Disease in 20.5% (7 of 34 patients) is currently in remission (12 to 120 months). Treatment was primarily by chemotherapy and Chinese herbs, with adjunctive craniotomy in selected patients. Myelosuppression was the main side effect.