Hyaluronan (HA) is the major glycosaminoglycan present in the extracellular matrix. It is produced by some tumours and promotes proliferation, differentiation and migration among others cellular processes. Gestational trophoblastic disease (GTD) is composed by non-tumour entities, such as hydatidiform mole (HM), which is the most common type of GTD and also malignant entities such as choriocarcinoma (CC) and placental site trophoblastic tumour (PSTT), being CC the most aggressive tumour. Although there is a growing understanding of GTD biology, the role of HA in the pathogenesis of this group of diseases remains largely unknown. The aim of this work was to study the role of HA in the pathogenesis of GTD by defining the expression pattern of HA and its receptors CD44 and RHAMM, as well as to determine if HA can modulate proliferation, differentiation and migration of CC cells. Receptors and signalling pathways involved were also analyzed. We demonstrated that HA and RHAMM are differently expressed among GTD entities and even among trophoblast subtypes. We also showed that HA is able to enhance the expression of extravillous trophoblast markers and also to induce migration of JEG-3 cells, the latter mediated by RHAMM as well as PI3K and MAPK pathways. These findings indicate a novel regulatory mechanism for CC cell biology and also contribute to the understanding of GTD pathophysiology.

BackgroundSouth 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.MethodsThis 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.ResultsAmong 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).ConclusionTrophoblastic 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.

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Objective There are few multinational studies on gestational trophoblastic neoplasia (GTN) treatment outcomes in South America. The purpose of this study was to assess the clinical presentation, treatment outcomes, and factors associated with chemoresistance in low-risk postmolar GTN treated with first-line single-agent chemotherapy in three South American centers. Methods Multicentric, historical cohort study including women with International Federation of Gynecology and Obstetrics (FIGO)-staged low-risk postmolar GTN attending centers in Argentina, Brazil, and Colombia between 1990 and 2014. Data were obtained on patient characteristics, disease presentation, and treatment response. Logistic regression was used to assess the relationship between clinical factors and resistance to first-line single-agent treatment. A multivariate analysis of the clinical factors significant in univariate analysis was performed. Results A total of 163 women with low-risk GTN were included in the analysis. The overall rate of complete response to first-line chemotherapy was 80% (130/163). The rates of complete response to methotrexate or actinomycin-D as first-line treatment, and actinomycin-D as second-line treatment postmethotrexate failure were 79% (125/157), 83% (⅚), and 70% (23/33), respectively. Switching to second-line treatment due to chemoresistance occurred in 20.2% of cases (33/163). The multivariate analysis demonstrated that patients with a 5 to 6 FIGO risk score were 4.2-fold more likely to develop resistance to first-line single-agent treatment (p = 0.019). Conclusion 1) At presentation, most women showed clinical characteristics favorable to a good outcome, 2) the overall rate of sustained complete remission after first-line single-agent treatment was comparable to that observed in developed countries, 3) a FIGO risk score of 5 or 6 is associated with development of resistance to first-line single-agent chemotherapy.