Neil S. Horowitz

ObjectiveTo characterize the natural history of persistent low-level real human chorionic gonadotropin (hCG) after gestational trophoblastic disease (GTD) and identify predictors of subsequent gestational trophoblastic neoplasia (GTN).MethodsRetrospective cohort study included patients with persistent low-level real hCG (≤100 IU/L for ≥3 months) during postmolar surveillance or after GTN remission at specialized GTD referral centers in Rio de Janeiro, Brazil, between 2000 and 2022. Clinical characteristics, hCG patterns, and oncologic outcomes were analyzed. Risk differences (RD) and 95% confidence intervals (CI) were calculated to identify factors associated with subsequent GTN.ResultsAmong 7,304 patients with GTD managed during the study period, 72 (0.9%) developed persistent low-level real hCG. Spontaneous hCG normalization occurred in 88.4% (38/43) of patients during postmolar surveillance and 75.9% (22/29) after GTN remission. During postmolar surveillance, vaginal hemorrhage (RD:35.7%, 95%CI:10.6–60.8), preevacuation hCG ≥100,000 IU/L (RD:22.7%, 95%CI:5.2–40.2), and delayed onset of persistent low-level real hCG ≥7 weeks (RD:16.6%, 95%CI:3.3–30.0) were associated with an increased risk of postmolar GTN. Among patients monitored after GTN remission, age ≥34 years (RD:19.1%, 95%CI:11.0–49.1), preevacuation hCG ≥100,000 IU/L (RD:30.4%, 95%CI:11.6–49.2), and delayed onset of persistent low-level real hCG ≥14 weeks (RD:43.8%, 95%CI:19.4–68.1) were associated with relapsed GTN.ConclusionsPersistent low-level real hCG after GTD frequently resolves spontaneously and does not necessarily represent active malignancy. Careful surveillance until fulfillment of FIGO criteria appears to be the most appropriate management strategy, minimizing unnecessary interventions.

Gestational trophoblastic disease (GTD) comprises a heterogeneous group of disorders arising from abnormal proliferation of placental trophoblastic tissue. This spectrum includes benign forms, prim...

Introduction Gestational trophoblastic neoplasia (GTN) is a highly curable malignancy arising from placental trophoblasts, yet a small subset of patients develops multidrug resistance with limited therapeutic options. The discovery of high programmed death-ligand 1 (PD-L1) expression across trophoblastic tumors has provided a compelling biological rationale for immunotherapy, particularly immune checkpoint blockade targeting the PD-1/PD-L1 axis. Objective To summarize current evidence on immunotherapy in GTN, integrating biological foundations, clinical experiences, and ongoing clinical trials, and to discuss future perspectives toward individualized, fertility-preserving management. Methods A narrative review was conducted according to structured PRISMA-based principles. Literature was retrieved from PubMed, Scopus, and Web of Science from 2000 to 2025 using predefined descriptors related to GTN and immunotherapy. Eligible studies included clinical trials, case series, case reports, and translational research addressing immune checkpoint inhibitors in GTN. Results GTN exhibits high PD-L1 expression, mirroring the immune-privileged nature of the placenta. Checkpoint inhibitors alone, such as pembrolizumab, avelumab, or the combination of camrelizumab plus apatinib (that potently suppresses the kinase activity of vascular endothelial growth factor 2), have demonstrated complete and durable responses in approximately 70–80% of patients with multidrug-resistant GTN, with acceptable safety and preserved fertility. Conclusions Immunotherapy has expanded therapeutic GTN, transforming refractory disease as a result of its immune responsiveness. Checkpoint inhibition not only achieves high remission rates but also offers fertility preservation and long-term survivorship. The future challenge lies in optimizing combination strategies, refining biomarkers, and ensuring equitable global access to these emerging treatments.

Objectives: To evaluate the potential associations of the type of complete hydatidiform mole (CHM) initial treatment (hysterectomy or uterine evacuation) with GTN development, need for chemotherapy, and treatment outcome in women aged ≥ 40 years. Methods: This multicentric retrospective cohort study included women ≥ 40 years with CHM, initially treated between 1990 and 2018, at four different centers. Data collected included patient demographics and clinical characteristics. The outcome variables were post-CHM GTN development, need for chemotherapy for hCG normalization, surgical complications, and time to remission. Univariate and multivariate analyses were performed using chi-square, Mann–Whitney, Fisher’s exact tests, and Poisson regression. Results: 275 women with CHM aged ≥ 40 years were included in the analysis. Median patient age was significantly higher among hysterectomy patients (47 × 44 years, p = 0.01). Multivariate analysis showed that compared with uterine evacuation (244/275, 89%), hysterectomy (31/275, 11%) was associated with an 83% lower risk of GTN [RR = 0.17 95% CI = (0.04–0.71); p = 0.015] and a 92% lower risk of requiring chemotherapy [RR: 0.08 (0.01–0.64), p = 0.016]. Median time to hCG normalization did not statistically differ between treatments. No significant differences were observed between hysterectomy and uterine evacuation in terms of FIGO staging (p = 0.221) or prognostic risk score (p = 0.576). Resistance to first-line chemotherapy (17/72; 23.6%) and relapse (3/72; 4.1%) were observed only in patients undergoing initial uterine evacuation. Hysterectomy complications occurred in 45.1% (14) of the patients. Conclusions: CHM initial treatment with hysterectomy was associated with a lower risk for GTN occurrence and need for chemotherapy in women aged 40 years or older. However, shared decision-making about surgery should be tailored to each patient and their risk factors and preferences. Further, larger controlled studies are required to support our findings.

Hydatidiform mole is a trophoblastic disorder resulting from abnormal fertilization. Diagnosis is established through a combination of clinical findings, elevated serum human chorionic gonadotropin (hCG) levels, and characteristic features on transvaginal ultrasound. Timely and accurate diagnosis is essential for initiating prompt treatment and preventing medical complications. Uterine evacuation, preferably via vacuum aspiration, is the treatment of choice due to its high efficacy and safety profile. Adjunctive techniques, such as hysteroscopy and intraoperative ultrasonography, enhance the safety and effectiveness of uterine evacuation and should be available to patients, especially at specialized referral centers equipped to manage this diagnosis. In selected cases, particularly in women with fulfilled reproductive goals or those at a high risk of developing post-molar gestational trophoblastic neoplasia (GTN), total abdominal hysterectomy is appropriate. Postoperative follow-up with serial measurements of hCG is essential for monitoring remission and for the early detection of post-molar GTN, which develops in approximately 20% of cases of complete molar pregnancies and 1–4% of partial molar pregnancies. This article provides a comprehensive review of the diagnosis of hydatidiform mole and the surgical techniques employed in the treatment of this condition, emphasizing individualized care and the use of appropriate surgical strategies to treat complications associated with this trophoblastic disease.

Molar pregnancy is a rare reproductive anomaly that globally affects 1:1,000–1,500 pregnancies. It is caused by aberrant fertilization and can be associated with medical complications or progress to postmolar gestational trophoblastic neoplasia. Molar pregnancy presents with two distinct entities, complete and partial hydatidiform mole, which differ in their clinical, genetic, and prognostic aspects. Maternal age and history of molar pregnancy are the main risk factors for the occurrence of molar pregnancy. Early diagnosis of molar pregnancy by ultrasonography is associated with a decrease in medical complications but not decreased postmolar gestational trophoblastic neoplasia. After the diagnosis of a presumed molar pregnancy, patients should be referred to an expert with experience taking care of molar pregnancy or to a reference center for uterine evacuation and postmolar follow-up, which facilitates early diagnosis of gestational trophoblastic neoplasia. Weekly human chorionic gonadotropin measurement is essential to confirm remission and to identify cases of gestational trophoblastic neoplasia that will require further treatment. To maintain the reliability of this tumor marker, hormonal contraception is indicated during postmolar follow-up. The postmolar follow-up should extend for 1 month and from 3 to 6 months after remission in cases of partial and complete hydatidiform mole, respectively. The reproductive outcomes after molar pregnancy are comparable with those of the general population, except for the higher occurrence of recurrent molar pregnancy, affecting 1.0–2.0% of subsequent pregnancies. The considerable psychosocial repercussions of molar pregnancy require a multidisciplinary approach to minimize the repercussions of this disease on mental health.

PURPOSE: In a phase II study, letrozole/abemaciclib demonstrated an objective response rate of 30% and a median progression-free survival (PFS) of 9.1 months in recurrent estrogen receptor–positive endometrial cancer (EC). While tissue-based tumor profiling revealed several mechanistically relevant candidate baseline genomic predictors of response, circulating tumor DNA (ctDNA) is a less invasive alternative to monitor therapeutic efficacy and define acquired resistance. METHODS: Serial plasma specimens were obtained at baseline, C2D1, C3D1, C8D1, the time of objective response, and the time of progression. Samples were analyzed using the Guardant Reveal assay to assess methylation-based tumor fraction (TF), with the Guardant360 assay providing genotyping of >700 genes in samples with detectable ctDNA. Treatment response was assessed using a measure of the relative change in TF pre- versus on-treatment. RESULTS: A total of 99 of 102 (97%) samples from 28 patients were successfully analyzed. Patients with above median baseline TF exhibited worse median PFS (2.0 months v 16.5 months, P < .005, hazard ratio [HR], 24.1) and worse overall survival (OS) (10.7 months v not yet reached, P < .005, HR, 14.8). Patients with molecular response (MR) after the first or second cycle of letrozole/abemaciclib therapy had significantly better median PFS and OS regardless of the cutoff used for definition of MR. ctDNA analysis of postprogression specimens identified several acquired genomic alterations associated with resistance to letrozole/abemaciclib therapy in more than half of the patients, including PI3K pathway, receptor tyrosine kinase ( FGFR1 , 2 and ERBB2 alterations), cell cycle pathway ( RB1 and CCNE1 alterations), and ESR1 and MAPK pathway alterations. Two of the three patients with mismatch repair–deficient ECs acquired ESR1 mutations at the time of progression. CONCLUSION: Baseline and on-treatment ctDNA dynamics may provide an early indication of benefit from letrozole/abemaciclib in EC. ctDNA at the time of progression may identify resistance alterations that may inform subsequent therapy.