Can Pretreatment Serum Beta-hCG be Used for Predicting Thyrotoxicosis in Gestational Trophoblastic Disease?

BACKGROUND: Gestational trophoblastic disease (GTD) comprises a diverse spectrum of entities of abnormal cellular proliferations originating in placental trophoblasts. The specific marker of GTD is beta-hCG which has a similar structure to the TSH molecule, interfering level of thyroid hormones. How and when to check for thyroid function test during this period remain challenging. OBJECTIVE: To assess values of pretreatment beta-hCG and its benefit for predicting thyrotoxicosis among patients with diagnoses of GTD. METHODS: Retrospective analytical study included all women diagnosed with GTD at Lampang Hospital from January 2010 to May 2020. The patients' pretreatment beta-hCG and thyroid function were collected. Sensitivity and specificity for detecting laboratory hyperthyroidism were reported and classified by pretreatment beta-hCG levels. RESULTS: Forty-four women with diagnoses of GTD were recruited. The range of pretreatment beta-hCG levels were classified  into 4 groups: beta-hCG > 50,000 IU/ml (group 1), beta-hCG > 100,000 IU/ml (group 2), beta-hCG > 150,000 IU/ml (group 3), beta-hCG > 200,000 IU/ml (group 4). The sensitivity for prediction of high fT4 were 100%, 94.1%, 94.1% and 88.2% in group 1,2,3 and 4, respectively, while the specificity were 12%, 20%, 32% and 44% in group 1,2,3 and 4, respectively. CONCLUSION: Pretreatment beta-hCG > 100,000 uIU/ml has the high sensitivity and acceptable specificity for predicting hyperthyroidism. So we don't need to check or wait for thyroid function test in patients who had beta-hCG < 100,000 IU/ml.

Early prediction of post-molar gestational trophoblastic neoplasia and resistance to methotrexate, based on a single serum human chorionic gonadotropin measurement.

BACKGROUND: Clinicians are unable to provide individualized counseling regarding risk of progression for patients with a complete hydatidiform mole (CHM). We developed nomograms enabling early prediction of post-molar gestational trophoblastic neoplasia (GTN) and resistance to methotrexate (MTX) based on a single serum human chorion gonadotropin (hCG) measurement. METHODS: We generated two nomograms with logistic regression: to predict post-molar GTN, and MTX resistance. For patients with high probability to progress to post-molar GTN or MTX resistance, we determined hCG cut-offs at 97.5% specificity to select patients for additional- or adjustments in current treatment. RESULTS: The nomograms had a good to excellent ability to distinguish either between patients with uneventful hCG regression versus progression to post molar GTN, or between patients cured by MTX versus patients in whom resistance would occur. At 97.5% specificity, we identified 66% (95%CI 56-75) of the 149 patients who would progress to post-molar GTN, four weeks after initial curettage. For patients treated with MTX, we identified 55% (95%CI 23-83) of the 43 patients who would become resistant, preceding their third course at 97.5% specificity. CONCLUSION: The nomograms and cut-off levels can be used to assist in counseling for patients diagnosed with CHM.

Placental site trophoblastic tumour: the rarest subtype of gestational trophoblastic disease.

Placental site trophoblastic tumour (PSTT) is a very rare form of gestational trophoblastic disease that grows slowly, secretes low levels of beta-subunit of human chorionic gonadotropin (ß-hCG), presents late-onset metastatic potential and is resistant to several chemotherapy regimens. Here, we report a case of PSTT in a 36-year-old woman who presented with amenorrhea and persistently elevated serum level of ß-hCG after a miscarriage. Transvaginal ultrasound revealed a hypovascular ill-defined solid lesion of the uterine fundus and MRI showed a tumour infiltrating the external myometrium with discrete early enhancement and signal restriction on diffusion-weighted imaging. PSTT was suspected, and after endometrial biopsy by hysteroscopy and posterior hysterectomy, microscopic examination allowed the final diagnosis. The level of ß-hCG dropped significantly in about a month after surgical treatment. Due to the rarity of PSTT, reporting new cases is crucial to improve the diagnosis and managing of these patients.

Avelumab in Patients With Gestational Trophoblastic Tumors With Resistance to Single-Agent Chemotherapy: Cohort A of the TROPHIMMUN Phase II Trial.

PURPOSE: Women with gestational trophoblastic tumors (GTT) resistant to single-agent chemotherapy receive alternative chemotherapy regimens, which, although effective, cause considerable toxicity. All GTT subtypes express programmed death-ligand 1 (PD-L1), and natural killer (NK) cells are involved in trophoblast immunosurveillance. Avelumab (anti-PD-L1) induces NK cell-mediated cytotoxicity. The TROPHIMMUN trial assessed avelumab in women with chemotherapy-resistant GTT. METHODS: In this phase II multicenter trial (ClinicalTrials.gov identifier: NCT03135769), women with GTT who experienced disease progression after single-agent chemotherapy received avelumab 10 mg/kg intravenously every 2 weeks until human chorionic gonadotropin (hCG) normalization, followed by 3 consolidation cycles. Rate of hCG normalization was the primary endpoint (2-step Simon design). RESULTS: Between December 2016 and September 2018, 15 patients were treated. Median age was 34 years; disease stage was I or III in 53.3% and 46.7% of women, respectively; and International Federation of Gynecology and Obstetrics (FIGO) score was 0-4 in 33.3%, 5-6 in 46.7%, and ≥ 7 in 20% of patients. Prior treatment included methotrexate (100%) and actinomycin D (7%). Median follow-up was 25 months, and median number of avelumab cycles was 8 (range, 2-11). Grade 1-2 treatment-related adverse events occurred in 93% of patients, most commonly (≥ 25%) fatigue (33.3%), nausea/vomiting (33.3%), and infusion-related reaction (26.7%). One patient had grade 3 uterine bleeding (treatment unrelated). Eight patients (53.3%) had hCG normalization after a median of 9 avelumab cycles; none subsequently relapsed. Probability of normalization was not associated with disease stage, FIGO score, or baseline hCG. One patient subsequently had a healthy pregnancy. In avelumab-resistant patients (46.7%), hCG was normalized with actinomycin D (42.3%) or combination chemotherapy/surgery (57.1%). CONCLUSION: In patients with single-agent chemotherapy-resistant GTT, avelumab had a favorable safety profile and cured approximately 50% of patients. Avelumab could be a new therapeutic option, particularly in patients who would otherwise receive combination chemotherapy.

Single or two drug combination therapy as initial treatment for low risk, gestational trophoblastic neoplasia. A Canadian analysis.

INTRODUCTION: Low risk gestational trophoblastic neoplasia, WHO prognostic score of 0 to 6, is highly curable. There is no consensus on the optimal chemotherapy. Common regimens are q2wk actinomycin-D (ACT-D), weekly intramuscular methotrexate (MTX) or multi-day MTX. Combination MTX/ACT-D is rarely used. METHODS: A four centre, retrospective cohort study was carried out comparing commonly used regimens: weekly MTX, q2weekly ACT-D and q2 weekly MTX and ACT-D. RESULTS: 412 patients - 196 MTX/ACT-D, 107 MTX, 109 ACT-D - were treated between October 1994 and January 2019. Initial regimen failure (secondary to resistance or toxicity) occurred in 37% (MTX), 21% (ACT-D) and 5% (MTX/ACT-D). Relapse after completion of primary therapy (initial plus switch to another therapy if needed) was rare (0-5%). All eventually were cured. Mean number of cycles required to achieve remission were 10.1 (MTX), 7 (ACT-D) and 5.6 (MTX/ACT-D) with corresponding mean treatment durations of 3.12, 2.9 and 2.26 months. Dosage reductions occurred in 3% (MTX), 0% (ACT-D) and 29% (MTX/ACT-D). Higher failure rates occurred with WHO prognostic scores of 5 to 6 and HCG levels ≥10,000. SUMMARY: Initial regimen failure ie the need to switch to an alternative treatment was more common with MTX. ACT-D and MTX/ACT-D were similar within prognostic score 0-4 or HCG < 10,000. ACT-D then appears the better initial choice with its superior convenience. Above these levels primary failure rates are less with MTX/ACT-D, making it a better choice.

Risk factors for second-line dactinomycin failure after methotrexate treatment for low-risk gestational trophoblastic neoplasia: a retrospective study.

OBJECTIVE: To find risk factors for second-line dactinomycin failure in patients with low-risk gestational trophoblastic neoplasia (GTN). DESIGN: Retrospective multicentre study. SETTING: Tertiary reference centre. POPULATION: Patients with low-risk GTN, treated with dactinomycin after methotrexate (MTX) failure. METHODS: Retrospective analysis of 45 patients with low-risk GTN treated with dactinomycin after MTX failure, registered between 2006 and 2018. MAIN OUTCOME MEASURES: Treatment outcome and risk factors for second-line dactinomycin failure. RESULTS: Thirty patients (66.7%) were cured and 15 patients (33.3%) required third-line therapy. Type of antecedent pregnancy and hCG levels pre-dactinomycin were risk factors for failure in univariate analysis (odds ratio [OR] 19.30, 95% CI 2.04-182.60, P = 0.01 and OR 2.77, 95% CI 1.18-6.50, P = 0.02, respectively). Level of hCG pre-dactinomycin remained a significant risk factor in multivariate analysis (OR 2.93, 95% CI 1.02-8.40, P = 0.045). Complete remission (CR) was achieved in 83.3% of patients with pre-dactinomycin hCG levels <10 ng/ml, in 75% with hCG levels between 10 and 20 ng/ml, in 66.7% with hCG levels between 20 and 30 ng/ml, and in 50% with hCG levels between 30 and 40 ng/ml. No patients with hCG levels >40 ng/ml achieved CR. Patients with dactinomycin failure were treated surgically and/or with multi-chemotherapy; all except one achieved CR. CONCLUSIONS: Treatment with dactinomycin after MTX failure in patients with low-risk GTN resulted in CR in 66.7%. Chance of curative treatment with dactinomycin is strongly related to the hCG level. TWEETABLE ABSTRACT: Chance of curative treatment with dactinomycin after MTX failure in GTN patients is strongly related to the level of hCG pre-dactinomycin.

Insights into the hyperglycosylation of human chorionic gonadotropin revealed by glycomics analysis.

Human chorionic gonadotropin (hCG) is a glycoprotein hormone that is essential for the maintenance of pregnancy. Glycosylation of hCG is known to be essential for its biological activity. "Hyperglycosylated" variants secreted during early pregnancy have been proposed to be involved in initial implantation of the embryo and as a potential diagnostic marker for gestational diseases. However, what constitutes "hyperglycosylation" is not yet fully understood. In this study, we perform comparative N-glycomic analysis of hCG expressed in the same individuals during early and late pregnancy to help provide new insights into hCG function, reveal new targets for diagnostics and clarify the identity of hyperglycosylated hCG. hCG was isolated in urine collected from women at 7 weeks and 20 weeks' gestation. hCG was also isolated in urine from women diagnosed with gestational trophoblastic disease (GTD). We used glycomics methodologies including matrix assisted laser desorption/ionisation-time of flight (MALDI-TOF) mass spectrometry (MS) and MS/MS methods to characterise the N-glycans associated with hCG purified from the individual samples. The structures identified on the early pregnancy (EP-hCG) and late pregnancy (LP-hCG) samples corresponded to mono-, bi-, tri-, and tetra-antennary N-glycans. A novel finding was the presence of substantial amounts of bisected type N-glycans in pregnancy hCG samples, which were present at much lower levels in GTD samples. A second novel observation was the presence of abundant LewisX antigens on the bisected N-glycans. GTD-hCG had fewer glycoforms which constituted a subset of those found in normal pregnancy. When compared to EP-hCG, GTD-hCG samples had decreased signals for tri- and tetra-antennary N-glycans. In terms of terminal epitopes, GTD-hCG had increased signals for sialylated structures, while LewisX antigens were of very minor abundance. hCG carries the same N-glycans throughout pregnancy but in different proportions. The N-glycan repertoire is more diverse than previously reported. Bisected and LewisX structures are potential targets for diagnostics. hCG isolated from pregnancy urine inhibits NK cell cytotoxicity in vitro at nanomolar levels and bisected type glycans have previously been implicated in the suppression of NK cell cytotoxicity, suggesting that hCG-related bisected type N-glycans may directly suppress NK cell cytotoxicity.

Next-Generation Sequencing Panel Analysis of Clinically Relevant Mutations in Circulating Cell-Free DNA from Patients with Gestational Trophoblastic Neoplasia: A Pilot Study.

Gestational trophoblastic neoplasia (GTN) originates from placental tissue and exhibits the potential for invasion and metastasis. Gene alterations in GTN have not been extensively studied because of a lack of qualified tumor specimens after chemotherapy. GTN has a rapid growth rate and is highly metastatic, which makes circulating tumor DNA (ctDNA) sequencing a promising modality for gene profiling. Accordingly, in this study, we performed targeted next-generation sequencing (NGS) of 559 tumor-associated genes using circulating cell-free DNA (cfDNA) collected prior to chemotherapy from 11 patients with GTN. All sequenced genes were associated with oncogenesis, progression, and targeted therapy. The average cfDNA level was 0.43 ± 0.22 ng/µL. Significant correlations were found between cfDNA concentration and maximum lesion diameter (r = 0.625, p=0.040) and time for human chorionic gonadotropin beta subunit (ß-HCG) recovering to normal level (r = 0.609, p=0.047). There were no significant correlations between cfDNA concentrations and ß-HCG expression level or lung metastasis. ctDNA mutations were detected in all patients, and 73 mutant genes were detected in 11 patients. BMPR1A (27.3%), LRP1B (27.3%), ERCC4 (18.2%), FGF14 (18.2%), HSP90AA1 (18.2%), KAT6A (18.2%), KMT2D (18.2%), MAP3K1 (18.2%), RANBP2 (18.2%), and ZNF217 (18.2%) mutations were detected as overlapping mutations. The mRNA and protein levels of bone morphogenetic protein receptor type 1A were significantly downregulated in human JAR and JEG-3 choriocarcinoma cells (p < 0.0001), whereas mRNA and protein levels of mitogen-activated protein kinase kinase kinase 1 were upregulated in these two cell lines (p=0.0128, p=0.0012, respectively). These genes may play important roles in GTN initiation and progression and may be candidate targets for GTN treatment. These findings suggested that cfDNA levels could provide potential assessment value in disease severity of GTN and that ctDNA sequencing was a promising approach for identifying gene mutations in GTN.

The impact of previous cesarean section (C/S) on the risk for post-molar gestational trophoblastic neoplasia (GTN).

OBJECTIVE: To investigate the relationship between previous cesarean section (C/S) and risk for post-molar gestational trophoblastic neoplasia (GTN). METHODS: Data from patients who were treated for hydatidiform moles between 1995 and 2016 were retrospectively reviewed. Patient age, gravidity, parity, abortion history, gestational age, pretreatment beta-human chorionic gonadotropin (HCG), previous molar pregnancy, clinical symptoms, enlarged uterus, theca lutein cyst, type of GTN, World Health Organization risk score, chemotherapy, and mode of delivery were recorded. Hazard ratios (HR) and 95% confidence intervals (CI) for variables associated with the occurrence of post-molar GTN and invasive mole were estimated by univariate and multivariate Cox proportional hazards models. RESULTS: From 1995 to 2016, 182 patients were diagnosed with molar pregnancy and underwent treatment. Patients with previous C/S (C/S group) had higher age (37.0 vs 32.8. p = 0.004), gravidity (3.1 vs 2.0, p < 0.001), and parity (1.6 vs 0.9, p < 0.001) than patients without previous C/S (non-C/S group). Post-molar GTN (43.5 vs 26.5%, p < 0.001), invasive mole (21.7 vs 3.7%, p < 0.001), hysterectomy (28.3 vs 6.6%, p < 0.001), and chemotherapy (45.7 vs 28.7%, p = 0.03) were more frequent in the C/S group. In multivariate analysis, independent risk factors for post-molar GTN were previous C/S (HR 5.1, 95% CI 2.1-12.7), abortion history (HR 6.3, 95% CI 2.5-15.6), and pretreatment ß-hCG (HR 1.3, 95% CI 1.1-1.6). CONCLUSIONS: In this study, C/S was a strong risk factor for occurrence of post-molar GTN and invasive mole. Aggressive treatment, such as multi-agent chemotherapy or hysterectomy, can be considered for hydatidiform moles in patients with a C/S history.

Incidence and outcome of gestational trophoblastic disease in lower Egypt.

BACKGROUND: Gestational trophoblastic disease (GTD) defines a spectrum of proliferative disorders of trophoblastic epithelium of the placenta. Incidence, risk factors, and outcome may differ from one country to another. OBJECTIVE: To describe incidence, patient characteristics, treatment modalities, and outcome of GTD at Mansoura University which is a referral center of Lower Egypt. METHODS: An observational prospective study was conducted at the GTD Clinic of Mansoura University. The patients were recruited for 12 months from September 2015 to August 2016. The patients' characteristics, management, and outcome were reported. RESULTS: We reported 71 clinically diagnosed GTD cases, 62 of them were histologically confirmed, 58 molar (33 CM and 25 PM) in addition to 4 initially presented GTN cases. Mean age of the studied cases was 26.22 years ± 9.30SD. Mean pre-evacuation hCG was 136170 m.i.u/ml ±175880 SD. Most of the cases diagnosed accidentally after abnormal sonographic findings (53.2%). Rate of progression of CM and PM to GTN was 24.2% and 8%, respectively. CONCLUSION: The incidence of molar pregnancy and GTN in our locality was estimated to be 13.1 and 3.2 per 1000 live births respectively. We found no significance between CM and PM regarding hCG level, time to hCG normalization, and progression rate to GTN.

When to stop human chorionic gonadotrophin (hCG) surveillance after treatment with chemotherapy for gestational trophoblastic neoplasia (GTN): A national analysis on over 4,000 patients.

OBJECTIVE: To determine the optimal duration of human chorionic gonadotrophin (hCG) surveillance following treatment for low and high risk gestational trophoblastic neoplasia (GTN) and establish whether the current surveillance protocol that recommends life-long hCG monitoring requires revision. METHODS: A population-based cohort study was undertaken using a national registry, comprising patients from both tertiary trophoblastic disease treatment units in the UK (London and Sheffield). All patients who received chemotherapy for low or high risk GTN in the UK between 1958 and 2014 in London and 1973 and 2015 in Sheffield (n = 4201) were included in the study. Patients with placental site trophoblastic tumours and epithelioid trophoblastic tumours were excluded due to their distinct clinical behavior, treatment and follow-up requirements. The risk of recurrence with time following completion of chemotherapy for low or high risk GTN was measured. RESULTS: The overall risk of relapse in this national cohort of 4201 patients was 4.7% (198/4201) with a median time to recurrence of 117.5 days (range 9 days to 6.54 years). The greatest risk of recurrence occurred in the first year after completing treatment for either low or high risk GTN measuring 72.7% (n = 112) or 86.4% (n = 38), respectively. The subsequent recurrence risk reduced over time with none observed beyond 7 years. CONCLUSIONS: The absence of any recurrences beyond seven years following completion of chemotherapy for GTN indicates that the UK policy of life-long hCG surveillance is unnecessary. Our revised conservative protocol recommends stopping after 10 years.

Persistent free-floating pelvic trophoblastic cysts following an interstitial ectopic pregnancy.

Persistent trophoblast after ectopic pregnancy has been demonstrated at the surgical site or as peritoneal implants. A 37-year-old woman (G5P2) experienced persistently low levels of beta-human chorionic gonadotropin (hCG) after surgical treatment for an interstitial pregnancy. Evaluation for persistent trophoblast, gestational trophoblastic neoplasm and heterophilic antibodies was negative. After 15 months without resolution, she elected for hysterectomy. We found four smooth, freely floating avascular cysts intraoperatively; pathological evaluation identified the cysts as trophoblastic tissue. Serum beta-hCG resolved postoperatively and remained negative at 1 year. Our case demonstrates the novel finding of trophoblastic tissue existing as free-floating cysts in the peritoneal cavity. With appropriate suspicion, these cysts can be identified on radiologic investigation and removed laparoscopically.

Kisspeptin as a potential biomarker throughout pregnancy.

Kisspeptins are a family of neuropeptides that are critical for the puberty initiation and female fertility. Plasma or serum kisspeptin is mainly derived from the placenta during pregnancy and plasma kisspeptin levels significantly increase across pregnancy. Plasma kisspeptin levels could be used as a potential biomarker for the detection of miscarriage, pre-eclampsia, gestational trophoblastic neoplasia (GTN), and fetal development. Kisspeptin may also be involved in the process of parturition by stimulating oxytocin secretion during term pregnancy. This review discussed the potential use of kisspeptin as a marker across pregnancy and highlighted the unresolved problems in this area. Tweetable abstract: Plasma kisspeptin levels could be used as a potential biomarker across pregnancy.

The value of an initial drop in human Chorionic gonadotropin levels in predicting a response to methotrexate in women with low-risk gestational trophoblastic neoplasia.

OBJECTIVES: The early identification of patients who are being treated for low-risk gestational trophoblastic neoplasia (LRGTN) with single-agent chemotherapy, who are at high risk of developing chemoresistance, is of crucial importance. The aim of our research was to evaluate the pretreatment beta subunit of human chorionic gonadotropin (ßhCG) concentration and its decrease after the administration of the first course of methotrexate (MTX) in predicting later chemo-resistance to single-agent chemotherapy. MATERIAL AND METHODS: A total of 46 patients diagnosed with LRGTN treated with a 5-day methotrexate (MTX) regimen were retrospectively studied. 24 of the patients were successfully cured with only MTX therapy (MTX group). The disease was considered resistant in the remaining 22 patients who, after MTX therapy, required further chemotherapy with an EMA/CO regimen (EMA/CO group). To compare changes in the ßhCG concentrations between the two courses of treatment (and the two groups), we calculated the percentage of decline. We determined the specificity and sensitivity of the initial ßhCG level and its percentage decline, as a potential predictor of the need for a future EMA/CO regimen. For diagnostic purposes, ßhCG levels were measured before the first and second administrations of MTX with a commercial ELISA kit. RESULTS: In the EMA/CO group, we found the initial ßhCG level before the first MTX dose was higher (median = 6275 mIU/mL, range: 21.53-192.610.0 mIU/mL) than in the MTX group (median = 532 mIU/mL, range: 56.5 mIU/mL-360.397.0 mIU/mL) (p = 0.034, Mann-Whitney test). The percentage decreases in the ßhCG values relative to the initial concentrations were higher in the MTX group (median decrease = 82.7%, range: from 13.3% to 99.9%) than in the EMA/CO group (median de- crease = 71.1%, range: from an increase of 56.1% to a decrease of 97.1%) (p = 0.0079, Mann-Whitney test). An analysis of the ROC curves implied optimal cutoff values for the initial ßHCG (6054 IU, sensitivity = 55%, specificity = 86%) and the percentage change in ßhCG levels (decrease by 76.5%, sensitivity = 72%, specificity = 71%). CONCLUSIONS: Women with initially higher ßhCG levels have a greater risk of developing MTX chemo resistance. It would be advantageous to consider administering an EMA/CO regimen in women with LRGTN when their initial ßhCG levels are greater than 6000.

False diagnosis of and needless therapy for presumed gestational trophoblastic disease in women with an unusual site of residual pregnancy.

OBJECTIVE: This study aimed to determine the diagnostic value of magnetic resonance imaging (MRI), hysteroscopy, and laparoscopy to avoid unnecessary treatment when patients present with clinical manifestations that are close to those of gestational trophoblastic neoplasia (GTN). METHODS: Three patients who were falsely diagnosed with presumed GTN and received needless chemotherapy in our hospital from July 2011 to March 2012 were studied. We also reviewed data of patients with similar clinical features who were diagnosed as having residual pregnancy in recent years. Clinical manifestations were evaluated. RESULTS: All three patients had persistently high serum ß-human chorionic gonadotrophin levels and a mass with abundant blood supply in the uterus after termination of pregnancy. The patients were diagnosed with GTN and underwent chemotherapy. They responded poorly to chemotherapy and underwent surgery. The pathological diagnosis in all patients was residual pregnancy. In recent years, no patients were misdiagnosed because pelvic MRI, hysteroscopy, or laparoscopy was used when residual pregnancy could not be excluded. CONCLUSION: Gynecologists should diagnose carefully when patients present with clinical manifestations that are close to those of GTN to avoid unnecessary treatment. MRI, hysteroscopy, and laparoscopy could be important examinations for excluding residual pregnancy.

Update on the diagnosis and management of gestational trophoblastic disease.

Gestational trophoblastic disease (GTD) arises from abnormal placenta and is composed of a spectrum of premalignant to malignant disorders. Changes in epidemiology of GTD have been noted in various countries. In addition to histology, molecular genetic studies can help in the diagnostic pathway. Earlier detection of molar pregnancy by ultrasound has resulted in changes in clinical presentation and decreased morbidity from uterine evacuation. Follow-up with human chorionic gonadotropin (hCG) is essential for early diagnosis of gestational trophoblastic neoplasia (GTN). The duration of hCG monitoring varies depending on histology type and regression rate. Low-risk GTN (FIGO Stages I-III: score <7) is treated with single-agent chemotherapy but may require additional agents; although scores 5-6 are associated with more drug resistance, overall survival approaches 100%. High-risk GTN (FIGO Stages II-III: score >7 and Stage IV) is treated with multiple agent chemotherapy, with or without adjuvant surgery for excision of resistant foci of disease or radiotherapy for brain metastases, achieving a survival rate of approximately 90%. Gentle induction chemotherapy helps reduce early deaths in patients with extensive tumor burden, but late mortality still occurs from recurrent resistant tumors.

Gestational Trophoblastic Neoplasia From Genetically Confirmed Hydatidiform Moles: Prospective Observational Cohort Study.

OBJECTIVE: The aim of this study was to evaluate the incidence and risk factors of gestational trophoblastic neoplasia (GTN) from hydatidiform moles (HMs) cytogenetically diagnosed in a prospective cohort setting. METHODS: The prospective observational cohort study included cases of cytogenetically defined molar pregnancies, which were diagnosed by a multiplex short tandem repeat polymorphism analysis. Cases were classified as androgenetic complete HMs (CHMs), diandric monogynic triploid partial HMs (PHMs), or biparental abortion. Gestational trophoblastic neoplasia was diagnosed according to the International Federation of Gynecology and Obstetrics 2000 criteria. Incidences for each category, that is, CHM, PHMs, and biparental abortion, were calculated. Clinical variables (age, partner age, gravidity, parity, height, weight, BMI, and gestational age) and laboratory data (serum human chorionic gonadotropin [hCG], white blood cell count, hemoglobin, and platelet count) were compared between spontaneous remission cases and GTN cases in androgenetic CHMs. RESULTS: Among 401 cases, 380 were classified as follows: 232 androgenetic CHMs, 60 diandric monogynic PHMs, and 88 biparental abortions. A total of 35 cases (15.1%) of CHMs, but only 1 case of PHM (1.7%) and no biparental abortions, exhibited progression to GTN. The hCG value before evacuation was significantly higher in GTN cases than in spontaneous remission cases (P = 0.001, Kruskal-Wallis test). Patient age was also significantly higher in GTN cases than in spontaneous remission cases (P = 0.002, Student t test). CONCLUSIONS: Under the cohort cytogenetic diagnosis setting, the traditional risk factors for GTN after molar pregnancy, hCG value before evacuation and age, were confirmed in androgenetic CHMs. The risk of GTN was lower for PHMs than for CHMs. However, 1 patient with cytogenetic PHMs developed into GTN.

Serum angiogenesis profile in gestational trophoblastic neoplasm using multiplex immunoassay.

AIMS: Gestational trophoblastic neoplasms (GTN) exemplify a rare, mostly curable but highly aggressive disease. It is often associated with a rapid formation of distant metastases and most likely with an intense neoangiogenesis processes. The aim of the study was to analyze markers in serum of patients with GTN before chemotherapy compared to healthy pregnant women. MAIN METHODS: In this study sixteen protein angiogenesis markers were evaluated in serum of 21 patients with GTN before chemotherapy and compared with healthy pregnant women. Markers were measured using BioPlex Pro Human Cancer Biomarker Panel 1 immunoassay. t-Tests and receiver operating characteristic curves were used for statistical analysis. KEY FINDINGS: Receiver operator curve analysis identified six proteins (sTIE-2, osteopontin, sIL-6α, sVEGFR-2, sEGFR, PECAM-1) which had sufficient sensitivity and specificity (AUC > 0,70) to distinguish GTN patients before the treatment from pregnant controls. The levels of three proteins (sTIE-2, osteopontin and sIL-6α) were altered in GTN patients before the treatment as compared to healthy controls (p = 0,0112; p = 0,0442; p = 0,0488, respectively) and thereby may serve as potential disease markers. SIGNIFICANCE: Serum concentration of proteins related to angiogenesis changes in the course of GTN and may appear useful in the diagnostic process of this disease.

Does a human chorionic gonadotropin level of over 20,000 IU/L four weeks after uterine evacuation for complete hydatidiform mole constitute an indication for chemotherapy for gestational trophoblastic neoplasia?

OBJECTIVE: To evaluate whether a human chorionic gonadotropin (hCG) level ≥20,000 IU/L four weeks after uterine evacuation for complete hydatidiform mole (CHM) is an appropriate indicator for initiating chemotherapy for the treatment of gestational trophoblastic neoplasia (GTN). STUDY DESIGN: Historical database review of 1228 women with CHM who received treatment and follow-up between January 2000 and June 2013 at four Brazilian trophoblastic disease centers. The primary outcome measure was the progression from CHM to GTN. The secondary outcomes were the occurrence of uterine perforation, staging of GTN, WHO/FIGO risk score, and treatment (use of single- or multiagent chemotherapy). RESULTS: An hCG level ≥20,000 IU/L four weeks after uterine evacuation for CHM, while occurring in only 6.1% of women, was the most important risk factor for the development of postmolar GTN (adjusted RR = 5.83; p < 0.01; CI: 3.47-9.79), with a sensitivity of 36.8%, a specificity of 98.6%, a positive predictive value of 80%, and a negative predictive value of 91.1%. On the other hand, there were no differences in postmolar GTN stage, prognostic score, or need for multiagent chemotherapy relative to hCG level ≥20,000 IU/L versus <20,000 IU/L. CONCLUSIONS: Although hCG level ≥20,000 IU/L four weeks after uterine evacuation for CHM was very predictive of development of post-molar GTN, delay in treatment until hCG plateau or increase did not affect outcomes, with no uterine perforations or treatment failures.

Human Chorionic Gonadotropin Regression Curves after Partial or Complete Molar Pregnancy in Flanders: Are They Different from Regression Curves from the Eighties?

BACKGROUND/AIMS: We updated human chorionic gonadotropin (hCG) regression curves created in the eighties after evacuation of complete and partial molar (CM and PM, respectively) pregnancies using modern hCG assays. We created similar curves for patients in need of chemotherapy (gestational trophoblastic neoplasia [GTN]). METHODS: A total of 126 patients who were diagnosed with gestational trophoblastic disease from 1990 to 2014 were included. We compared curves from 2 groups, CM and PM, with historical ones. The third group was a comparison of GTN patients receiving first-line chemotherapy and patients in need of a switch of chemotherapy. RESULTS: The regression curves were comparable to historical ones. According to the latter, mean time to normalization was 14-15 weeks after evacuation. We observed a normalization within 12 (CM) and 12.7 (PM) weeks. In addition, a remarkable but not statistically significant vertical shift (20 IU/L higher) was observed prior to day 60 compared with historical curves. The comparison in GTN patients showed a statistical significant difference, even at day 7. CONCLUSION: The presented hCG regression curves in the Flemish region were comparable with the ones of the eighties but with a vertical shift, hypothetically due to more sensitive assays. In addition, regression curves in GTN patients receiving chemotherapy can be used to evaluate response.