EMACO for treatment of gestational trophoblastic neoplasia: A multinational multicenter study.

OBJECTIVE: To investigate the efficacy and toxicity of etoposide, methotrexate, actinomycin D alternating with cyclophosphamide, and vincristine (EMACO) for treatment of gestational trophoblastic neoplasia, and for factors independently associated with EMACO resistance and disease-specific death in an international cohort. METHODS: Medical records of GTN patients who received EMACO during 1986-2019 from gestational trophoblastic disease centers from four countries including the USA, Thailand, Hungary, and Brazil, were retrospectively reviewed. Among 335 GTN patients, 266 patients who received EMACO as primary chemotherapy were included in the primary treatment group, and 69 patients who received EMACO after relapse/resistance to single-agent chemotherapy were included in the prior treatment group. RESULTS: Three-quarters (76.1%) of all patients achieved remission, and the survival rate was 89%. The prior treatment group had better outcomes than the primary treatment group relative to remission rate (87.0% vs. 73.3%, p = 0.014) and number of EMACO cycles to achieve remission (3 vs. 6 cycles, p < 0.001). Sustained remission increased to 87.2% in EMACO-resistant patients treated with later-line chemotherapy. Number of metastatic organs ≥2 (adjusted odds ratio [aOR]: 2.33, p = 0.049) was the only independent predictor of EMACO resistance among overall patients. Interval from index pregnancy ≥7 months (aOR: 4.34, p = 0.001), and pretreatment hCG >100,000 IU/L (aOR: 2.85, p = 0.028) were independent predictors of EMACO resistance in the high-risk subgroup. The only factor independently associated with disease-specific death was EMACO resistance (aOR: 176.04, p < 0.001). CONCLUSIONS: EMACO is an effective treatment for GTN. Number of metastatic organs and EMACO resistance were the independent predictors of EMACO resistance and disease-specific death, respectively.

The impact of the distance traveled between residence and gestational trophoblastic neoplasia reference center and clinical outcomes in Brazilian women.

OBJECTIVE: To relate the distance traveled from the patient's residence to the gestational trophoblastic neoplasia (GTN) reference center (RC) and the occurrence of unfavorable clinical outcomes, as well as to estimate the possible association between this distance and the risk of metastatic disease at presentation, the need for multiagent chemotherapy to achieve remission and loss to follow-up before remission. STUDY DESIGN: Retrospective historical cohort study of patients with GTN followed at 8 Brazilian GTN-RC, from January 1st, 2000 - December 31st, 2017. RESULTS: Evaluating 1055 cases of GTN, and using a receiver operating characteristic curve, we found a distance of 56 km (km) from the residence to the GTN-RC (sensitivity = 0.57, specificity = 0.61) best predicted the occurrence of at least one of the following outcomes: occurrence of metastatic disease, need for multiagent chemotherapy to achieve remission, or loss to follow-up during chemotherapy. Multivariate logistic regression adjusted by age, ethnicity, marital status and the reference center location showed that when the distance between residence and GTN-RC was ≥56 km, there was an increase in the occurrence of metastatic disease (relative risk - RR:3.27; 95%CI:2.20-4.85), need for multiagent chemotherapy (RR:1.36; 95%CI:1.05-1.76), loss to follow-up during chemotherapy (RR:4.52; 95CI:1.93-10.63), occurrence of chemoresistance (RR:4.61; 95%CI:3.07-6.93), relapse (RR:10.27; 95%CI:3.08-34.28) and death due to GTN (RR:3.62; 95%CI:1.51-8.67). CONCLUSIONS: The distance between the patient's residence and the GTN-RC is a risk factor for unfavorable outcomes, including death from this disease. It is crucial to guarantee these patients get prompt access to the GTN-RC and receive follow-up support.

Presentation, medical complications and development of gestational trophoblastic neoplasia of hydatidiform mole after intracytoplasmic sperm injection as compared to hydatidiform mole after spontaneous conception - a retrospective cohort study and literature review.

OBJECTIVE: To describe the natural history of hydatidiform mole (HM) after intracytoplasmic sperm injection (ICSI), emphasizing the clinical and oncological outcomes, as compared to patients who had HM after spontaneous conception (SC). STUDY DESIGN: Retrospective historical cohort study of patients with HM followed at the Rio de Janeiro Federal University, from January 1st 2000-December 31st 2020. RESULTS: Comparing singleton HM after SC to those following ICSI there were differences in terms of maternal age (24 vs 34 years, p < 0.01), gestational age at diagnosis (10 vs 7 weeks, p < 0.01), preevacuation human chorionic gonadotropin levels (200,000 vs 99,000 IU/L, p < 0.01), occurrence of genital bleeding (60.5 vs 26.9%, p < 0.01) and hyperemesis (23 vs 3.9%, p = 0.02) at presentation, and time to remission (12 vs 5 weeks, p < 0.01), respectively. There were no differences observed in the cases of twin mole, regardless of the form of fertilization that gave rise to HM, except molar histology with greater occurrence of partial hydatidiform mole (10.7 vs 40.0%, p = 0.01) following ICSI. Univariate logistic regression for occurrence of postmolar GTN after ICSI identified no predictor variable for this outcome. However, after adjusting for maternal age and complete hydatidiform mole histology, multivariable logistic regression showed the risk of GTN with HM after ICSI had an adjusted odds ratio of 0.22 (95%CI:0.05-0.93, p = 0.04), suggesting a possible protective effect when compared to HM after SC. CONCLUSIONS: Singleton HM after ICSI are diagnosed earlier in gestation, present with fewer medical complications, and may be less likely to develop GTN when compared with HM after SC.

Clinical characteristics and thyroid function in complete hydatidiform mole complicated by hyperthyroidism.

OBJECTIVES: To identify possible clinical factors associated with hyperthyroidism at presentation and to assess post-evacuation thyroid function in women with complete hydatidiform mole (CHM). METHODS: This observational study included women with CHM attending a specialized Brazilian center in 2002-2018. Clinical and laboratory data (serum hCG, TSH, fT4) were collected at presentation. Factors associated with hyperthyroidism were assessed by logistic regression. Receiver-operating characteristic curves were built to determine the hCG cutoff for predicting hyperthyroidism at CHM presentation. Post-molar evacuation follow-up included clinical assessment and close thyroid function monitoring. RESULTS: Of 137 CHM patients, 69 (50.3%) had hyperthyroidism of any type (43.5% subclinical, 56.5% overt) at presentation. Uterine fundal height > 16 cm or > gestational age (GA), and theca lutein cysts >6 cm were significantly associated with both subclinical and overt hyperthyroidism. The optimal hCG cutoff for predicting hyperthyroidism was 430,559 IU/L (sensitivity 85.5%, specificity 83.8%). Post-evacuation hyperthyroidism/transient hypothyroidism conversion was observed in 13% of the women with hyperthyroidism at presentation. Among the patients not showing conversion to hypothyroidism, median time for TSH normalization was 2 and 3 weeks for subclinical and overt hyperthyroidism, respectively. In the women with overt hyperthyroidism, fT4 was normalized at 2 weeks. CONCLUSIONS: Uterine fundal height > 16 cm, uterine fundal height > GA, theca lutein cysts >6 cm, and hCG >400,000 IU/L at presentation are associated with greater risk of hyperthyroidism and its complications. Close monitoring thyroid function during postmolar follow-up showed that, as thyroid hormones are normalized within 2-3 weeks post-evacuation, the use of beta-blockers or antithyroid drugs can be rapidly discontinued.

Distinct microRNA profiles for complete hydatidiform moles at risk of malignant progression.

BACKGROUND: MicroRNAs are small noncoding RNAs with important regulatory functions. Although well-studied in cancer, little is known about the role of microRNAs in premalignant disease. Complete hydatidiform moles are benign forms of gestational trophoblastic disease that progress to gestational trophoblastic neoplasia in up to 20% of cases; however, there is no well-established biomarker that can predict the development of gestational trophoblastic neoplasia. OBJECTIVE: This study aimed to investigate possible differences in microRNA expression between complete moles progressing to gestational trophoblastic neoplasia and those regressing after surgical evacuation. STUDY DESIGN: Total RNA was extracted from fresh frozen tissues from 39 complete moles collected at the time of uterine evacuation in Brazil. In the study, 39 cases achieved human chorionic gonadotropin normalization without further therapy, and 9 cases developed gestational trophoblastic neoplasia requiring chemotherapy. Total RNA was also extracted from 2 choriocarcinoma cell lines, JEG-3 and JAR, and an immortalized normal placenta cell line, 3A-subE. MicroRNA expression in all samples was quantified using microRNA sequencing. Hits from the sequencing data were validated using a quantitative probe-based assay. Significantly altered microRNAs were then subjected to target prediction and gene ontology analyses to search for alterations in key signaling pathways. Expression of potential microRNA targets was assessed by quantitative real-time polymerase chain reaction and western blot. Finally, potential prognostic protein biomarkers were validated in an independent set of formalin-fixed paraffin-embedded patient samples from the United States (15 complete moles progressing to gestational trophoblastic neoplasia and 12 that spontaneously regressed) using quantitative immunohistochemistry. RESULTS: In total, 462 microRNAs were identified in all samples at a threshold of <1 tag per million. MicroRNA sequencing revealed a distinct set of microRNAs associated with gestational trophoblastic neoplasia. Gene ontology analysis of the most altered transcripts showed that the leading pathway was related to response to ischemia (P<.001). Here, 2 of the top 3 most significantly altered microRNAs were mir-181b-5p (1.65-fold; adjusted P=.014) and mir-181d-5p (1.85-fold; adjusted P=.014), both of which have been shown to regulate expression of BCL2. By quantitative real-time polymerase chain reaction, BCL2 messenger RNA expression was significantly lower in the complete moles progressing to gestational trophoblastic neoplasia than the regressing complete moles (-4.69-fold; P=.018). Reduced expression of BCL2 was confirmed in tissue samples by western blot. Immunohistochemistry in the independent patient samples revealed significantly lower cytoplasmic expression of BCL2 in the villous trophoblasts from cases destined for progression to gestational trophoblastic neoplasia compared with those that regressed, both with respect to staining intensity (optic density 0.110±0.102 vs 0.212±0.036; P<.001) and to the percentage of positive cells (16%±28% vs 49.4%±28.05%; P=.003). CONCLUSION: Complete moles progressing to gestational trophoblastic neoplasia are associated with a distinct microRNA profile. miR-181 family members and BCL2 may be prognostic biomarkers for predicting gestational trophoblastic neoplasia risk.

Effectiveness and toxicity of second-line actinomycin D in patients with methotrexate-resistant postmolar low-risk gestational trophoblastic neoplasia.

OBJECTIVES: The purpose of this study was to evaluate both the outcomes and toxicity of second-line actinomycin D (ActD) chemotherapy in methotrexate (MTX) - resistant low-risk postmolar gestational trophoblastic neoplasia (GTN) with 5-day ActD versus pulsed ActD. METHODS: This retrospective cohort study included patients with MTX-resistant low-risk postmolar GTN from 1974 to 2016. Second-line chemotherapy consisted of 5-day ActD (10-12 µg/kg per day for 5 days every 14 days) or biweekly ActD (1.25 mg/m2 every 2 weeks). Data on patient characteristics, disease presentation, treatment outcome, and toxicity were collected. RESULTS: Sixty-eight MTX-resistant patients receiving ActD as second-line chemotherapy were identified (5-day ActD, 53 patients; pulsed ActD, 15 patients). No significant differences were observed in patient/disease characteristics and sustained remission (overall rate 72%) between second-line ActD regimens. Time to hCG remission was significantly faster (median 21 vs 47 days, p = .04) and required fewer treatment cycles (median 1 vs 2, p < .001) with 5-day ActD. Thrombocytopenia was only observed with 5-day ActD (64.6 vs 0%, p < .001). The frequency (60.4 vs 16.7%, p = .009) and severity (grade 3: 37.9 vs 0%, p = .045) of oral mucositis was significantly higher with 5-day ActD. Grade 2 alopecia was significantly more frequent (70.6 vs 16.7%, p = .02) with 5-day ActD. CONCLUSIONS: While 5-day ActD and pulsed ActD achieve comparable remission rates, due to its reduced toxicity, ease of administration, and patient convenience, pulsed ActD should be the treatment of choice for MTX-resistant postmolar low-risk GTN.

Gestational trophoblastic neoplasia lethality among Brazilian women: A retrospective national cohort study.

OBJECTIVE: To investigate GTN lethality among Brazilian women comparing cases of death by GTN with those who survived, thereby identifying factors associated with GTN lethality. METHODS: We retrospectively reviewed medical records of women with GTN treated at ten Brazilian GTN Reference Centers, from January 1960 to December 2017. We evaluated factors associated with death from GTN and used Cox proportional hazards regression models to identify independent variables with significant influence on the risk of death. RESULTS: From 2186 patients with GTN included in this study, 2092 (95.7%) survived and 89 (4%) died due to GTN. When analyzing the relative risk (RR), adjusted for WHO/FIGO score, patients with low risk disease had a significantly higher risk of death if they had choriocarcinoma (RR: 12.40), metastatic disease (RR: 12.57), chemoresistance (RR: 3.18) or initial treatment outside the Reference Center (RR: 12.22). In relation to patients with high-risk GTN, these factors were significantly associated with death due to GTN: the time between the end of antecedent pregnancy and the initiation of chemotherapy (RR: 4.10), metastatic disease (RR: 14.66), especially in brain (RR: 8.73) and liver (RR: 5.76); absence of chemotherapy or initial treatment with single agent chemotherapy (RR: 10.58 and RR: 1.81, respectively), chemoresistance (RR: 3.20) and the initial treatment outside the Reference Center (RR: 28.30). CONCLUSION: The risk of mortality from low and high-risk GTN can be reduced by referral of these patients to a Reference Center or, if not possible, to involve clinicians in a Reference Center with consultation regarding management.

Outcomes in the management of high-risk gestational trophoblastic neoplasia in trophoblastic disease centers in South America.

BACKGROUND: South America has a higher incidence of gestational trophoblastic disease than North America or Europe, but whether this impacts chemotherapy outcomes is unclear. The purpose of this study was to evaluate outcomes among women with high-risk gestational trophoblastic neoplasia (GTN) treated at trophoblastic disease centers in developing South American countries. METHODS: This retrospective cohort study included patients with high-risk GTN treated in three trophoblastic disease centers in South America (Botucatu and Rio de Janeiro, Brazil, and Buenos Aires, Argentina) from January 1990 to December 2014. Data evaluated included demographics, clinical presentation, FIGO stage, WHO prognostic risk score, and treatment-related information. The primary treatment outcome was complete sustained remission by 18 months following completion of therapy or death. RESULTS: Among 1264 patients with GTN, 191 (15.1%) patients had high-risk GTN and 147 were eligible for the study. Complete sustained remission was ultimately achieved in 87.1% of cases overall, including 68.4% of ultra high-risk GTN (score ≥12). Early death (within 4 weeks of initiating therapy) was significantly associated with ultra high-risk GTN, occurring in 13.8% of these patients (p=0.003). By Cox's proportional hazards regression, factors most strongly related to death were non-molar antecedent pregnancy (RR 4.35, 95% CI 1.71 to 11.05), presence of liver, brain, or kidney metastases (RR 4.99, 95% CI 1.96 to 12.71), FIGO stage (RR 3.14, 95% CI 1.52 to 6.53), and an ultra-high-risk prognostic risk score (RR 7.86, 95% CI 2.99 to 20.71). Median follow-up after completion of chemotherapy was 4 years. Among patients followed to that timepoint, the probability of survival was 90% for patients with high-risk GTN (score 7-11) and 60% for patients with ultra-high-risk GTN (score ≥12). CONCLUSION: Trophoblastic disease centers in developing South American countries have achieved high remission rates in high-risk GTN, but early deaths remain an important problem, particularly in ultra-high-risk GTN.

Effectiveness and toxicity of first-line methotrexate chemotherapy in low-risk postmolar gestational trophoblastic neoplasia: The New England Trophoblastic Disease Center experience.

OBJECTIVES: To assess the outcomes and toxicity of first-line methotrexate (MTX) chemotherapy in low-risk postmolar gestational trophoblastic neoplasia (GTN) patients receiving 8-day methotrexate or one-day methotrexate infusion regimens. METHODS: This retrospective cohort study was conducted at the New England Trophoblastic Disease Center (NETDC), between 1974 and 2014, and included 325 patients with FIGO-defined low-risk postmolar GTN receiving first-line 8-day MTX/folinic acid (FA) or one-day MTX infusion and FA. Demographics, disease presentation, initial treatment plan, treatment outcome, and treatment-related adverse events were assessed. RESULTS: Sustained remission (84% vs 62%, p<0.001) and need to switch to second-line therapy due to treatment-related adverse events (5.3% vs 0%, p=0.001) were higher for 8-day MTX/FA compared to one-day MTX infusion. MTX resistance, however, was more frequent with one-day MTX (34.5%) than with 8-day MTX/FA (7.3%, p<0.001). Relapse rates were similar with both regimens (3.0%). Compared to one-day MTX infusion, 8-day MTX/FA was associated with significantly higher gastrointestinal disorders (48% vs 24%), abnormal laboratory findings (48% vs 28%), eye disorders (37% vs 19%) and general disorders (22% vs 5%) (p<0.001). Only infection frequency did not differ between 8-day MTX/FA and one-day MTX infusion (20% vs 12%, p=0.083). CONCLUSIONS: This is one of the largest studies to comprehensively catalogue toxicities associated with 8-day MTX/FA and one-day MTX infusion. Although treatment-related adverse events were more frequent with 8-day MTX/FA, these were all self-limited and resolved with no long-term sequelae. Given this and its higher effectiveness, 8-day MTX/FA remains the treatment of choice at NETDC for patients with low-risk postmolar GTN.

Is chemotherapy always necessary for patients with nonmetastatic gestational trophoblastic neoplasia with histopathological diagnosis of choriocarcinoma?

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.

Does hormonal contraception during molar pregnancy follow-up influence the risk and clinical aggressiveness of gestational trophoblastic neoplasia after controlling for risk factors?

OBJECTIVE: To evaluate the influence of hormonal contraception (HC) on the development and clinical aggressiveness of gestational trophoblastic neoplasia (GTN) and the time for normalization of human chorionic gonadotropin (hCG) levels. METHODS: A retrospective cohort study was conducted with women diagnosed with molar pregnancy, followed at the Rio de Janeiro Trophoblastic Disease Center, between January 2005 and January 2015. The occurrence of postmolar GTN and the time for hCG normalization between users of HC or barrier methods (BM) during the postmolar follow-up or GTN treatment were evaluated. RESULTS: Among 2828 patients included in this study, 2680 (95%) used HC and 148 (5%) used BM. The use of HC did not significantly influence the occurrence of GTN (ORa: 0.66, 95% CI: 0.24-1.12, p=0.060), despite different formulations: progesterone-only (ORa: 0.54, 95% CI: 0.29-1.01, p=0.060) or combined oral contraception (COC) (ORa: 0.50, 95% CI: 0.27-1.01, p=0.60) or with different dosages of ethinyl estradiol: 15mcg (ORa, 1.33, 95% CI 0.79-2.24, p=0.288), 20mcg (ORa: 1.02, 95% CI: 0.64-1.65, p=0.901), 30mcg (ORa: 1.17, 95% CI: 0.78-1.75, p=0.437) or 35mcg (ORa: 0.77, 95% CI: 0.42-1.39, p=0.386). Time to hCG normalization ≥10weeks (ORa: 0.58, 95% CI: 0.43-1.08, p=0.071) or time to remission with chemotherapy≥14weeks (ORa: 0.60, 95% CI: 0.43-1.09, p=0.067) did not significantly differ among HC users when compared to patients using BM, when controlling for other risk factors using multivariate logistic regression. CONCLUSIONS: The use of HC during postmolar follow-up or GTN treatment does not seem to increase the risk of GTN or its severity and does not postpone the normalization of hCG levels.

Multiple pregnancies with complete mole and coexisting normal fetus in North and South America: A retrospective multicenter cohort and literature review.

OBJECTIVE: To determine the clinical characteristics of multiple gestation with complete mole and coexisting fetus (CHMCF) in North and South America. METHODS: Retrospective non-concurrent cohorts compromised of CHMCF from New England Trophoblastic Disease Center (NETDC) (1966-2015) and four Brazilian Trophoblastic Disease Centers (BTDC) (1990-2015). RESULTS: From a total of 12,455 cases of gestational trophoblastic disease seen, 72 CHMCF were identified. Clinical characteristics were similar between BTDC (n=46) and NETDC (n=13) from 1990 to 2015, apart from a much higher frequency of potentially life-threatening conditions in Brazil (p=0.046). There were no significant changes in the clinical presentation or outcomes over the past 5 decades in NETDC (13 cases in 1966-1989 vs 13 cases in 1990-2015). Ten pregnancies were electively terminated and 35 cases resulted in viable live births (60% of 60 continued pregnancies). The overall rate of gestational trophoblastic neoplasia (GTN) was 46%; the cases which progressed to GTN presented with higher chorionic gonadotropin levels (p=0.026) and higher frequency of termination of pregnancy due to medical complications (p=0.006) when compared to those with spontaneous remission. CONCLUSIONS: The main regional difference in CHMCF presentation is related to a higher rate of potentially life-threatening conditions in South America. Sixty percent of the expectantly managed CHMCF delivered a viable infant, and the overall rate of GTN in this study was 46%. Elective termination of pregnancy did not influence the risk for GTN; however the need for termination due to complications and higher hCG levels were associated with development of GTN in CHMCF.

Comparison of 2 Human Chorionic Gonadotropin Immunoassays Commercially Available for Monitoring Patients With Gestational Trophoblastic Disease.

OBJECTIVE: The aim of this study was to compare serum human chorionic gonadotropin (hCG) levels in patients with gestational trophoblastic disease (GTD) using 2 commercially available hCG immunoassays. METHODS: Serum samples were obtained from patients with GTD attending the Botucatu Medical School Trophoblastic Diseases Center of São Paulo State University (UNESP), from November 2014 to October 2015. Serum hCG levels were measured with both Architect i2000SR and Immulite 2000 XPi chemiluminescence assays. Serum hCG levels were compared against the null hypothesis. Agreement in clinical management decisions based on the hCG results was determined by comparing baseline hCG measurements and the hCG curves obtained with both assays. RESULTS: Seventy-three patients with GTD were included in the analysis. Of these, 45 had hydatidiform mole and spontaneous remission, whereas 28 had gestational trophoblastic neoplasia (GTN). There was a perfect (zero difference) agreement in mean hCG levels between Immulite 2000 XPi and Architect i2000 when hCG is less than 100 mIU/mL. For hCG values greater than 100 mIU/mL, there was a significant difference between assays (P < 0.05), with levels measured via Architect i2000SR being higher than those measured by Immulite 2000 XPi in patients with hydatidiform mole/spontaneous remission (R = 90%, P < 0.01) and GTN (R = 98%, P < 0.01). Baseline clinical management decisions showed agreement in 100% (73/37) of cases (κ = 1.0, P < 0.001), whereas decisions based on hCG curve agreed in 98% (71/72) of cases (κ = 0.93, P < 0.001). CONCLUSIONS: Immulite 2000 XPi is the most frequently recommended assay for diagnosing and monitoring patients with GTD. However, our results suggest that because Immulite 2000 XPi and Architect i2000 show very similar performance in measuring hCG levels and in determining clinical management, Architect may be used as an alternative.

Complete molar pregnancy in adolescents from North and South America: Clinical presentation and risk of gestational trophoblastic neoplasia.

OBJECTIVES: To compare complete hydatidiform mole (CHM) clinical presentation and risk factors associated with GTN development between North American and South American adolescents. METHODS: This non-concurrent cohort study was undertaken including adolescents with CHM referred to centers in North America (New England Trophoblastic Disease Center, Harvard University, USA), and South America (Botucatu Trophoblastic Disease Center-São Paulo State University, Brazil; Trophoblastic Unit of Central University of Venezuela and Maternidad Concepcion Palacios of Caracas, Venezuela) between 1990 and 2012. Data were obtained from medical records and pathology reports. Study participants were allocated into 2 groups: North America (NA) and South America (SA). RESULTS: In NA and SA, 13.1% and 30.9% of patients with hydatidiform mole were adolescents, respectively. Of these, 77.6% in NA and 86.1% in SA had pathologic diagnosis of CHM (p=0.121). Vaginal bleeding (SA=69% vs NA=51%; p=0.020), anemia (SA=48% vs NA=18%; p<0.001), and elevated serum hCG (SA=232,860mIU/mL vs NA=136,412mIU/mL; p=0.039) were more frequent in SA than in NA. Median gestational age at diagnosis (SA=12weeks, NA=11weeks; p=0.030) differed whereas GTN development rate (SA=20%, NA=27%; p=0.282) showed no significant difference between groups. Compared to NA, medical complications and clinical factors associated with post-molar GTN were more frequent among SA adolescents. CONCLUSIONS: Medical complications and clinical factors associated with GTN development were more frequent in SA than in NA adolescents with CHM, suggesting that, in South America, awareness about the importance of diagnosing molar pregnancy early and considering CHM in the differential diagnosis in adolescents suspected to be pregnant should be raised.

Is chemotherapy necessary for patients with molar pregnancy and human chorionic gonadotropin serum levels raised but falling at 6months after uterine evacuation?

OBJECTIVE: To compare the outcomes of Brazilian patients with molar pregnancy who continue human chorionic gonadotropin (hCG) surveillance with those treated with chemotherapy when hCG was still positive, but falling at 6months after uterine evacuation. METHODS: Retrospective chart review of 12,526 patients with hydatidiform mole treated at one of nine Brazilian reference centers from January 1990 to May 2016. RESULTS: At 6months from uterine evacuation, 96 (0.8%) patients had hCG levels raised but falling. In 15/96 (15.6%) patients, chemotherapy was initiated immediately per FIGO 2000 criteria, while 81/96 (84.4%) patients were managed expectantly. Among the latter, 65/81 (80.2%) achieved spontaneous remission and 16 (19.8%) developed postmolar gestational trophoblastic neoplasia (GTN). Patients who received chemotherapy following expectant management required more time for remission (11 versus 8months; p=0.001), had a greater interval between uterine evacuation and initiating chemotherapy (8 versus 6months; p<0.001), and presented with a median WHO/FIGO risk score higher than women treated according to FIGO 2000 criteria (4 versus 2, p=0.04), but there were no significant differences in the need for multiagent treatment regimens (1/15 versus 3/16 patients, p=0.60). None of the women relapsed, and no deaths occurred in either group. CONCLUSION: In order to avoid unnecessary exposure of women to chemotherapy, we no longer follow the FIGO 2000 recommendation to treat all patients with molar pregnancy and hCG raised but falling at 6months after evacuation. Instead, we pursue close hormonal and radiological surveillance as the best strategy for these patients.

Apoptotic index for prediction of postmolar gestational trophoblastic neoplasia.

BACKGROUND: Although 85% of patients with a complete hydatidiform mole achieve spontaneous remission after a few months, 15% of them will experience gestational trophoblastic neoplasia, which requires chemotherapy. To date, there is no biomarker to predict post-molar gestational trophoblastic neoplasia before the initiation of human chorionic gonadotropin surveillance. OBJECTIVE: The purpose of this study was to assess the relationship between the expression of apoptosis markers in the molar villous trophoblasts and the subsequent development of gestational trophoblastic neoplasia after the evacuation of a complete hydatidiform mole. STUDY DESIGN: This was a retrospective cohort study of patients with complete hydatidiform mole who were diagnosed, treated, and followed at the Center of Trophoblastic Diseases (Botucatu/São Paulo State and Rio de Janeiro/Rio de Janeiro State, Brazil) from 1995-2014. Patients were divided temporally into derivation (1995-2004) and validation (2005-2014) cohorts. Immunohistochemistry was used to examine tissue expression of the apoptosis inhibitor survivin or the pro-apoptotic enzyme caspase-3. Survivin stains for cytoplasmic and nuclear expression were evaluated independently. Caspase-3 expression was measured as an apoptotic index of positive staining cells over negative staining cells multiplied by 100. Receiver operating characteristic curves were then constructed, and the area under the curve was calculated to test the performance characteristics of the staining to predict the subsequent development of gestational trophoblastic neoplasia. RESULTS: The final study population comprised 780 patients, with 390 patients in each temporal cohort: 590 patients entered spontaneous remission, and 190 patients experienced post-molar gestational trophoblastic neoplasia. Neither nuclear nor cytoplasmic survivin expression performed well as a predictor of subsequent gestational trophoblastic neoplasia. The caspase-3 apoptotic index was a strong risk factor for subsequent gestational trophoblastic neoplasia development. When the apoptotic index was <4%, the risk of gestational trophoblastic neoplasia had an odds ratio of 35.55 (95% confidence interval, 14.02-90.14; P < .0001) in the derivation cohort and an odds ratio of 25.71 (95% confidence interval, 10.13-65.29; P < .0001) in the validation cohort. However, in both cohorts, the positive predictive value for gestational trophoblastic neoplasia of an apoptotic index <4.0% was modest (49% in the derivation cohort and 41% in the validation cohort); the negative predictive value for gestational trophoblastic neoplasia of an apoptotic index ≥4.0% was high (97% in both cohorts). CONCLUSION: The subsequent development of gestational trophoblastic neoplasia after evacuation of complete hydatidiform mole is tied closely to the apoptotic index, which may be a useful biomarker for future prospective studies.

Changing Trends in the Clinical Presentation and Management of Complete Hydatidiform Mole Among Brazilian Women.

OBJECTIVE: The aim of the study was to evaluate potential changes in the clinical, diagnostic, and therapeutic parameters of complete hydatidiform mole in the last 25 years in Brazil. METHODS: A retrospective cohort study was conducted involving the analysis of 2163 medical records of patients diagnosed with complete hydatidiform mole who received treatment at the Rio de Janeiro Reference Center for Gestational Trophoblastic Disease between January 1988 and December 2012. For the statistical analysis of the natural history of the patients with complete molar pregnancies, time series were evaluated using the Cox-Stuart test and adjusted by linear regression models. RESULTS: A downward linear temporal trend was observed for gestational age of complete hydatidiform mole at diagnosis, which is also reflected in the reduced occurrence of vaginal bleeding, hyperemesis and pre-eclampsia. We also observed an increase in the use of uterine vacuum aspiration to treat molar pregnancy. Although the duration of postmolar follow-up was found to decline, this was not accompanied by any alteration in the time to remission of the disease or its progression to gestational trophoblastic neoplasia. CONCLUSIONS: Early diagnosis of complete hydatidiform mole has altered the natural history of molar pregnancy, especially with a reduction in classical clinical symptoms. However, early diagnosis has not resulted in a reduction in the development of gestational trophoblastic neoplasia, a dilemma that still challenges professionals working with gestational trophoblastic disease.

Centralized Coordination of Decentralized Assistance for Patients with Gestational Trophoblastic Disease in Brazil: A Viable Strategy for Developing Countries.

OBJECTIVE: To report on the Brazilian Association of Gestational Trophoblastic Disease's (GTD) formation of a network of regional care at specialized centers for women with GTD. STUDY DESIGN: We developed a questionnaire composed of 15 questions, which was sent by email to the 38 Brazilian GTD Reference Center (BGTDRC) Directors who are members of the Brazilian Association of GTD, in order to characterize the professionals involved in the care of patients with GTD and the type of assistance provided. RESULTS: The Directors of the BGTDRCs are usually specialists in Gynecology and Obstetrics (97%), with a median experience of a decade in treating women with GTD. The BGTDRCs are linked to university hospitals in 75% of centers and provide completely free medical care in 87%. However, 52% of centers do not perform chemotherapy in their reference center, and patients are referred elsewhere for chemotherapy. Despite some difficulties, the rate of patients lost to follow-up before human chorionic gonadotropin remission is 9%, and the GTD mortality rate is 0.9%. CONCLUSION: Due to large regional disparities, the BGTDRCs are not uniformly organized. However, under the coordination of the Brazilian Association of GTD there is now strong communication and collaboration among reference centers, which has significantly advanced both patient care and research into the management of these diseases.

Maternal Near Miss According to World Health Organization Classification Among Women with a Hydatidiform Mole: Experience at the New England Trophoblastic Disease Center, 1994-2013.

OBJECTIVE: To investigate the frequency of potentially life-threatening conditions (PLTCs) and maternal near misses (MNMs) at the New England Trophoblastic Disease Center (NETDC) in recent years, when there has been earlier diagnosis of molar pregnancy. STUDY DESIGN: This study included patients with molar pregnancy at the NETDC between 1994 and 2013. Clinical and pathologic reports were reviewed. PLTC and MNM criteria and maternal deaths were searched in medical records using the World Health Organization criteria and classification. RESULTS: We identified 375 patients with molar pregnancy and no patient developed a MNM or maternal death. Only 6 (1.6%) had PLTCs (hemorrhage with hemodynamic instability, severe preeclampsia, respiratory distress, blood transfusion, and ICU admission). CONCLUSION: We observed a low rate of PLTC and no cases of MNMs or maternal deaths related to molar pregnancy, likely due to earlier diagnosis at the NETDC in recent years.

Relationship between race and clinical characteristics, extent of disease, and response to chemotherapy in patients with low-risk gestational trophoblastic neoplasia.

OBJECTIVE: To evaluate the potential effects of race on clinical characteristics, extent of disease, and response to chemotherapy in women with postmolar low-risk gestational trophoblastic neoplasia (GTN). METHODS: This non-concurrent cohort study was undertaken including patients with FIGO-defined postmolar low-risk GTN treated with comparable doses and schedules of chemotherapy at the New England Trophoblastic Disease Center (NETDC) between 1973 and 2012. Racial groups investigated included whites, African American and Asians. Information on patient characteristics and response to chemotherapy (need for second line chemotherapy, reason for changing to an alternative chemotherapy, number of cycles/regimens, need for combination chemotherapy, and time to hCG remission) was obtained. RESULTS: Of 316 women, 274 (86.7%) were white, 19 (6%) African American, and 23 (7.3%) Asian. African Americans were significantly younger than white and Asian women (p=0.008). Disease presentation, and extent of disease, including antecedent molar histology, median time to persistence, median hCG level at persistence, rate of D&C at persistence, presence of metastatic disease, and FIGO stage and risk score were similar among races. Need for second line chemotherapy (p=0.023), and median number of regimens (p=0.035) were greater in Asian women than in other races. CONCLUSIONS: Low-risk GTN was more aggressive in Asian women, who were significantly more likely to need second line chemotherapy and a higher number of chemotherapy regimens to achieve complete remission than women of African American and Asian descent. Further studies involving racial differences related to clinical, biological and environmental characteristics are needed.