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.

Outcomes for relapsed versus resistant low risk gestational trophoblastic neoplasia following single-agent chemotherapy.

OBJECTIVE: To compare outcomes for relapsed versus resistant low risk gestational trophoblastic neoplasia (GTN) following single-agent chemotherapy. METHODS: This was a single center retrospective study of low risk GTN. Cases failing to achieve a normal hCG with first-line therapy were defined as chemotherapy resistance. Cases achieving hCG remission, but recurring, were defined as relapse. Primary endpoints were remission rate with second-line therapy and time to remission. Univariate and multivariate analyses were performed to define prognostic factors. RESULTS: Among 877 low risk GTN patients there were 124 (14.8%) chemotherapy resistant and 22 (2.6%) relapse cases. Complete remission rates with second-line therapy were similar between relapse (77.3%) and resistant (76.6%) cases (p = 0.95), but resistance was associated with a longer time to reach complete remission with second-line therapy (median 8.3 vs 4.9 weeks; p = 0.024). In multivariate analysis, the significant prognostic factors for second-line therapy remission and time to second-line therapy remission were use of multi-agent chemotherapy (OR of 9.45; 95%CI, 2.13-41.97; p = 0.003) and primary chemo-resistance (HR of 0.27; 95%CI, 0.12-0.59; p = 0.001), respectively. With additional therapies, sustained remission rates rose to 90% (18/20) for relapse and 99.2% (120/121) for chemo-resistance (p = 0.053). CONCLUSIONS: Although second-line therapy for resistant or relapsed low risk GTN is able to achieve complete remission in most cases, time to complete remission for relapsed disease was shorter than for resistant disease. Further studies on the biologic differences between resistant and relapsed disease may clarify the optimal treatment for these clinical situations.

EMA vs EMACO in the treatment of gestational trophoblastic neoplasia.

OBJECTIVE: To compare experiences with EMA versus EMACO in the treatment of gestational trophoblastic neoplasia. METHODS: The medical records of women diagnosed with GTN at the New England Trophoblastic Disease Center from 1986 to 2019 were reviewed, and women receiving EMA or EMACO as their first multiagent regimen were eligible. Clinical characteristics, treatment, outcomes, and adverse events were compared between the two groups. RESULTS: We identified 44 and 39 patients who received EMA and EMACO, respectively. The complete remission rate was significantly higher in the EMA group (97.7%) than in the EMACO group (71.8%) (p = 0.001). However, patients receiving EMACO were more likely to have adverse prognostic factors such as higher median prognostic risk score (8 vs 4, p < 0.001), non-molar antecedent pregnancy (59 vs 27.3%, p = 0.014) and distant metastasis (64.1 vs 47.7%, p = 0.017). Time to complete remission was also similar (p = 0.947) with a median of 12 weeks with EMA and 13.1 weeks with EMACO. There was no significant difference in treatment delays or use of adjuvant surgery. After multivariate analysis, chemotherapy regimen (EMA or EMACO) did not retain prognostic significance for remission. Overall toxicities were more frequent in EMA (60.2 vs 32.7%, p < 0.001), especially neutropenia, but this did not delay treatment and likely resulted from less growth factor support (18.2 vs 48.7%, p = 0.003). CONCLUSIONS: When controlling for other prognostic factors, outcomes with EMA appear similar to EMACO. It may be worthwhile to investigate whether EMA, a simpler and less costly regimen, may be as effective as EMACO in the treatment of GTN.

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.

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.

Gestational Trophoblastic Disease Electronic Consults: What Do Patients and Physicians Want to Know?

OBJECTIVES: Given the rarity of gestational trophoblastic disease (GTD), specialized regional and national centers for GTD have been established. These centers serve at least 3 purposes: to improve care for women with GTD, to enhance research though collaboration, and to educate other clinicians. This study was undertaken to understand the potential GTD knowledge gap by examining both patient and physician inquiries received at a specialized GTD center. METHODS: All electronic consults received by specialists at our center between March 2016 and March 2017 were analyzed. Information collected included source of inquiry, reason for the consult, type of GTD, and the advice provided. Descriptive statistics were used to analyze the major trends. RESULTS: We analyzed 102 electronic consults. Physicians sent 49 (48%) and patients sent 53 (52%) consults. Most e-consults were sent by physicians and patients within the United States; however, 11% of the consults were directed from international locations. Among physicians, gynecologic oncologists (65%) were the most common specialty to consult our institution followed by medical oncologists (18%) and obstetrician gynecologists (16%).Most questions from gynecologic (62%) and medical oncologists (77%) concerned treatment regimens. This was contrasted by general obstetrician gynecologists who more commonly asked about human chorionic gonadotropin monitoring (62%). Difficulty with appropriate Federation of Gynecology and Obstetrics staging and World Health Organization risk score assignment were common themes. Most of the confusion centered on the use of chest computed tomography rather than plain chest x-ray for the assessment of lung metastases. Unlike physicians, patient e-consults were most concerned with the duration of human chorionic gonadotropin monitoring (51%) and timing of future conceptions. CONCLUSIONS: Both physicians and patients in the United States and abroad frequently use electronic consults to improve their knowledge about GTD management and follow-up. Although the type of inquires varied, they highlight fundamental gaps in understanding and potential opportunities for formal education.

Placental site trophoblastic tumors and epithelioid trophoblastic tumors: Biology, natural history, and treatment modalities.

Placental site (PSTT) and epithelioid trophoblastic tumor (ETT) are rare types of gestational trophoblastic neoplasia (GTN) that arise from intermediate trophoblast. Given that this cell of origin is different from other forms of GTN, it is not surprising that the clinical presentation, tumor marker profile, and treatment paradigm for PSTT and ETT are quite different as well. The mainstay for therapy for stage I PSTT and ETT is hysterectomy with adjuvant chemotherapy reserved for those presenting greater than four years from the antecedent pregnancy. Surgery is also important for metastatic disease. There is no standardized chemotherapy regimen for advanced stage disease but often consists of a platinum-containing combination therapy, usually EMA-EP or TE/TP. Despite its rarity, PSTT and ETT account for a disproportionate percentage of mortality from GTN likely resulting from their relative chemotherapy resistance. Novel therapeutic modalities therefore are needed to improve the outcomes of women with advanced stage or resistant PSTT and ETT.

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.

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.

The effect of adolescence and advanced maternal age on the incidence of complete and partial molar pregnancy.

OBJECTIVE: To compare the age-specific incidence of complete (CM) and partial molar (PM) pregnancy in a large tertiary care center in the United States. METHODS: Incidence rates of CM and PM per 10,000 live births were calculated using databases from Brigham and Women's Hospital, between 2000 and 2013. Age-specific rates were calculated for women younger than 20 years old (adolescents), 20-39 years old (average age), and 40 years and older (advanced maternal age). Pearson χ(2) test was used to evaluate potential differences among groups. Rate ratios (RR) and 95% confidence intervals (CI) were used to compare risk of molar pregnancy among average age women with that of adolescents and women of advanced age. Holm-Bonferonni adjustment was used to correct for multiple comparisons. RESULTS: Between 2000 and 2013, there were 255 molar pregnancies (140 CM and 115 PM) and 105,942 live births, corresponding to a molar pregnancy rate of 24 per 10,000 live births (95% CI 21-27). Rates of CM and PM were 13 (95% CI 11-16) and 11 (95% CI 9-14) per 10,000 live births respectively. The incidence of CM differed significantly among maternal age groups (p<0.001). Compared to average age women, adolescents were 7.0 times as likely to develop CM (95% CI 3.6-8.9, p<0.001), and women with advanced maternal age were nearly twice as likely (1.9, 95% CI 1.8-4.7, p=0.002). The rate of PM did not vary significantly among age groups (p=0.26). CONCLUSIONS: Adolescence and advanced maternal age were associated with increased risk of complete mole, but not partial mole.

Effect of race/ethnicity on risk of complete and partial molar pregnancy after adjustment for age.

OBJECTIVE: To quantify the effect of race/ethnicity on risk of complete and partial molar pregnancy. METHODS: We conducted a cross-sectional study including women who were followed for complete or partial mole and those who had a live singleton birth in a teaching hospital in the northeastern United States between 2000 and 2013. We calculated race/ethnicity-specific risk of complete and partial mole per 10,000 live births, and used logistic regression to estimate crude and age-adjusted relative risks (RR) of complete and partial mole. RESULTS: We identified 140 cases of complete mole, 115 cases of partial mole, and 105,942 live births. The risk of complete mole was 13 cases per 10,000 live births (95% confidence interval [CI] 11-16) and that of partial mole was 11 cases per 10,000 live births (95% CI 9-13). After age-adjustment, Asians were more likely to develop complete mole (RR 2.3 95% CI 1.4-3.8, p<0.001) but less likely to develop partial mole (RR 0.2; 95% CI 0.04-0.7, p=0.02) than whites. Blacks were significantly less likely than whites to develop partial mole (RR 0.4; 95% CI 0.2-0.8, p=0.01) but only marginally less likely to develop complete mole (RR 0.6; 95% CI 0.3-1.0, p=0.07). Hispanics were less likely than whites to develop complete mole (RR 0.4; 95% CI 0.2-0.7, p=0.002) and partial mole (RR 0.4; 95% CI 0.2-0.9, p=0.02). CONCLUSION: Race/ethnicity is a significant risk factor for both complete and partial molar pregnancy in the northeastern United States.

Effect of race/ethnicity on clinical presentation and risk of gestational trophoblastic neoplasia in patients with complete and partial molar pregnancy at a tertiary care referral center.

BACKGROUND: The reported incidence of molar pregnancy varies widely among different geographic locations. This variation has been attributed, at least in part, to racial/ethnic differences. While the incidence of molar pregnancies is decreasing, certain ethnic groups such as Hispanics, Asians, and American Indians continue to have an increased risk of developing gestational trophoblastic disease across the globe. OBJECTIVE: We sought to describe the potential effect of ethnicity/race on the presentation and clinical course of complete mole and partial mole. STUDY DESIGN: All patients followed up for complete mole and partial mole at a single institution referral center from 1994 through 2013 were identified. Variables including age, race, gravidity, parity, gestational age, presenting signs/symptoms, serum human chorionic gonadotropin values, and development of gestational trophoblastic neoplasia were extracted from medical records and patient surveys. Patients with complete mole and partial mole were categorized into race/ethnicity groups defined as white, black, Asian, or Hispanic. Due to low numbers of non-white patients with partial mole in each non-white category, patients with partial mole were grouped as white or non-white. Continuous variables were compared using the Kruskal-Wallis test and binary variables were compared using the Fisher exact test. RESULTS: A total of 167 complete mole patients with known race/ethnicity status were included (57.48% white, 14.97% Asian, 14.37% black, 13.17% Hispanic). Hispanics presented at younger age (median 24.5 years) compared to whites (median 32.0 years, P = .04) and Asians (median 31.0 years, P = .03). Blacks had higher gravidity than whites (P < .001) and Hispanics (P = .05). There was no significant difference in presenting symptoms, gestational age at diagnosis, and preevacuation serum human chorionic gonadotropin level by race/ethnicity. Hispanics were significantly less likely than whites to develop gestational trophoblastic neoplasia (absolute risk difference, 28.6%; 95% confidence interval, 8.1-39.2%; P = .02). A total of 144 patients with partial mole were analyzed. There were 108 white and 36 non-white patients. Median age was 31 years for white and 29 years for non-white patients (P = .006). Median gravidity was 2 for white and 3 for non-white patients (P < .001), and median parity was 0 for white patients and 1 for non-white patients (P = .003). There were no significant differences with respect to presenting signs and symptoms, gestational age, preevacuation human chorionic gonadotropin level, or risk of progression to gestational trophoblastic neoplasia. CONCLUSION: Hispanic patients with complete molar pregnancy had a significantly lower risk of developing gestational trophoblastic neoplasia than white patients. There were no significant differences among groups in terms of presenting symptoms, gestational age at diagnosis, or preevacuation human chorionic gonadotropin levels for either complete mole or partial mole patients.

Clinical Presentation of Complete Hydatidiform Mole and Partial Hydatidiform Mole at a Regional Trophoblastic Disease Center in the United States Over the Past 2 Decades.

OBJECTIVE: The aim of this study was to compare the clinical presentation and incidence of postmolar gestational trophoblastic neoplasia (GTN) among cases of complete mole (CM) and partial mole (PM) from 1994 to 2013. METHODS: This study included all cases of patients with CM and PM from our trophoblastic disease center between 1994 and 2013. Their clinical and pathologic reports were reviewed. Gestational age at evacuation, features of clinical presentation, human chorionic gonadotropin levels, and the rate of progression to GTN were compared. RESULTS: The median gestational age at evacuation was 9 weeks for CM and 12 weeks for PM (P < 0.001). Patients with PM had lower pre-evacuation serum human chorionic gonadotropin levels (P < 0.001), and they were also less likely to present with vaginal bleeding (P < 0.001), biochemical hyperthyroidism (P < 0.001), anemia (P < 0.001), uterine size greater than dates (P < 0.001), and hyperemesis (P = 0.002). Consequently, patients with PM were less likely to have been clinically diagnosed as moles compared with CM prior to uterine evacuation (P < 0.001). The development of GTN occurred in 17.7% (33/186) and 4.1% (7/169) of patients with CM and PM, respectively (P < 0.001). CONCLUSIONS: This study indicates that, at our center over the past 20 years, both CM and PM were usually evacuated in the first trimester of pregnancy. Because CM more commonly presents with the signs and symptoms of molar disease than PM, CM is more commonly diagnosed prior to evacuation.

Timing of Referral to the New England Trophoblastic Disease Center: Does Referral with Molar Pregnancy Versus Postmolar Gestational Trophoblastic Neoplasia Affect Outcomes?

OBJECTIVE: To assess if referral of patients with molar pregnancy who then developed postmolar gestational trophoblastic neoplasia (PMGTN) is associated with different outcomes when compared to referral of patients already with a diagnosis of PMGTN. STUDY DESIGN: The records of the New England Trophoblastic Disease Center (NETDC) were queried for all patients with molar pregnancy or PMGTN from 1993-2013. Retrospective chart review was performed to extract relevant clinical and demographic data. Parametric and nonparametric tests were utilized to compare variables. RESULTS: From 1993-2013, 429 women with molar disease were evaluated at the NETDC. Of those, 68% were referred with molar pregnancy and 32% were referred with PMGTN. Comparing women with PMGTN who were referred with a molar pregnancy versus referred with PMGTN, the women were of equivalent stage and World Health Organization (WHO) score. Additionally, referral with molar pregnancy or PMGTN did not associate with time to persistence, time to remission, or number of lines of chemotherapy administered. CONCLUSION: In this trophoblastic disease specialty center in the United States, referral at the time of PMGTN as opposed to at diagnosis of molar pregnancy did not appear to affect the stage or WHO score at diagnosis, the need for multiple chemotherapy lines, or time to remission.

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.

Changing presentation of complete hydatidiform mole at the New England Trophoblastic Disease Center over the past three decades: does early diagnosis alter risk for gestational trophoblastic neoplasia?

OBJECTIVE: To compare the clinical presentation and incidence of postmolar gestational trophoblastic neoplasia (GTN) among recent (1994-2013) and historical (1988-1993) cases of complete hydatidiform mole (CHM). METHODS: This study included two non-concurrent cohorts (1988-1993 versus 1994-2013) of patients from the New England Trophoblastic Disease Center (NETDC). Clinical and pathologic reports of patients diagnosed with CHM between 1994 and 2013 were reviewed. Gestational age at evacuation, features of clinical presentation, human chorionic gonadotropin (hCG) levels, and the rate of progression to GTN were compared. RESULTS: In the current cohort (1994 to 2013) the median gestational age at diagnosis continued to decline compared to our prior cohort (1988-1993) (9weeks versus 12weeks). Patients from the current cohort were significantly more likely to be diagnosed prior to the 11th week of gestation (56 versus 41%, p=0.04). Patients in the current cohort were also significantly less likely to present with vaginal bleeding (46 versus 84%, p<0.001). Earlier diagnosis of complete mole did not result in a decrease in the rate of postmolar GTN. The frequencies of postmolar GTN in the current (1994-2013) and prior (1988-1993) cohorts were 19 and 23%, respectively. In the current cohort, even diagnosis prior to ten weeks gestation did not decrease the risk of developing GTN. CONCLUSIONS: This study indicates that complete mole continues to be diagnosed progressively earlier resulting in a further decrease in some classical presenting symptoms. However, despite earlier detection, the risk of development of postmolar GTN has not been affected.

Response to chemotherapy in overweight/obese patients with low-risk gestational trophoblastic neoplasia.

OBJECTIVE: Despite rising global obesity rates, the impact of obesity on gestational trophoblastic neoplasia (GTN) remains uninvestigated. This study aimed at investigating whether overweight/obesity relates to response to chemotherapy in low-risk GTN patients. METHODS: This nonconcurrent cohort study included 300 patients with International Federation of Gynecology and Obstetrics-defined postmolar low-risk GTN treated with a single-agent chemotherapy­methotrexate or actinomycin-D (actD)­between 1973 and 2012 at the New England Trophoblastic Disease Center. Chemotherapy dosing was based on actual body weight regardless of obesity status, except for 5-day courses or pulse regimens of actD. Patients were classified as overweight/obese (body mass index [BMI] ≥25 kg/m²) or non-overweight/obese (BMI <25 kg/m²). Information on patient characteristics and response to chemotherapy (need for second-line chemotherapy, reason for changing to an alternative chemotherapy, number of cycles, need for combination chemotherapy, and time to human chorionic gonadotropin remission) was obtained. RESULTS: Of 300 low-risk GTN patients, 81 (27%) were overweight/obese. Overweight/obese patients were older than the non-overweight/obese patients (median age: 30 vs 28 years, P = 0.004). First-line therapy using actD was more frequent in overweight/obese patients (6.2% vs 1.4%, P = 0.036). Resistance and toxicity were similar between groups. No significant difference in the number of chemotherapy cycles needed for remission or time required to achieve remission was found between groups. CONCLUSIONS: No association between overweight/obesity and low-risk GTN outcomes was found. Current chemotherapy dosing using BMI seems to be appropriate for overweight/obese patients with low-risk GTN.

Women with a partial mole during their first pregnancy and diagnosed earlier in gestation are at increased risk of developing gestational trophoblastic neoplasia.

OBJECTIVE: The aim of this study is to identify factors associated with gestational trophoblastic neoplasia (GTN) after partial molar pregnancy. METHODS: We retrospectively evaluated clinical data from 111 patients with a partial molar pregnancy between 1995 and 2010. RESULTS: A total of 111 patients with a partial molar pregnancy were available for analysis. There was no significant difference between patients who did and did not develop GTN with respect to patient age, parity, history of prior molar pregnancy, presenting signs/symptoms, uterine size greater than gestational age, clinical diagnosis, preevacuation sonogram findings, or the preevacuation human chorionic gonadotropin value. Patients who developed GTN had fewer prior pregnancies (median, 2 vs 3; P = 0.02) and were more likely to have had a partial molar pregnancy as their first gestational event (37.1% vs 17.1%; P = 0.03). Among the 35 patients who developed GTN, the median time to diagnosis of GTN was 47 days (range, 25-119 days), and the median human chorionic gonadotropin value at the time of GTN diagnosis was 475 mIU/mL (range, 20-52,630 mIU/mL). All women (100%) who developed GTN had stage I disease, and all patients (100%) had low-risk GTN. All 35 women (100%) were able to achieve remission, and most (85.7%) of these patients received methotrexate as first-line chemotherapy. CONCLUSIONS: Women with a partial molar pregnancy as their first gestational event and diagnosed earlier in gestation are more likely to develop postmolar GTN.

Subsequent pregnancy outcomes after complete and partial molar pregnancy, recurrent molar pregnancy, and gestational trophoblastic neoplasia: an update from the New England Trophoblastic Disease Center.

OBJECTIVE: To review and update the subsequent reproductive outcomes in patients with complete, partial, and recurrent hydatidiform moles, as well as gestational trophoblastic neoplasia (GTN) at the New England Trophoblastic Disease Center. STUDY DESIGN: Patients with complete and partial hydatidiform mole, recurrent hydatidiform mole, and GTN were identified from the Donald P. Goldstein, M.D., Trophoblastic Tumor Registry. Questionnaires regarding subsequent pregnancies were mailed to patients with current mailing addresses available. Additional patient data was obtained from electronic medical records. RESULTS: A total of 2,432 subsequent pregnancies have been reported since 1965. Of those, 1,388 pregnancies were after complete mole, 357 after partial mole, and 667 after GTN. The subsequent reproductive outcomes in patients with complete and partial molar pregnancies and persistent GTN remain similar to those in the general population. However, approximately 1.7% of patients with a prior molar pregnancy had a molar pregnancy in a later gestation. Furthermore, after successful chemotherapy for GTN the incidence of stillbirth was slightly increased to 1.3% in later pregnancies. CONCLUSION: Patients with molar pregnancies and GTN should expect similar reproductive outcomes as compared to the general population. However, patients receiving chemotherapy for GTN have a slightly increased risk stillbirth in subsequent pregnancies.