Geographical Health District and Distance Traveled Influence on Clinical Status at Admission of Patients with Gestational Trophoblastic Disease.

OBJECTIVE: To assess the potential relationship of clinical status upon admission and distance traveled from geographical health district in women with gestational trophoblastic disease (GTD). METHODS: This is a cross-sectional study including women with GTD from the 17 health districts from the São Paulo state (I-XVII), Brazil, referred to the Botucatu Trophoblastic Disease Center (specialized center, district VI), between 1990 and 2018. At admission, hydatidiform mole was assessed according to the risk score system of Berkowitz et al. Gestational trophoblastic neoplasia was evaluated using the International Federation of Gynecology and Obstetrics / World Health Organization (FIGO/WHO) staging/risk score. Data on demographics, clinical status and distance traveled were collected. Multiple regression analyses were performed. RESULTS: This study included 366 women (335 hydatidiform mole, 31 gestational trophoblastic neoplasia). The clinical status at admission and distance traveled significantly differed between the specialized center district and other districts. Patients referred from health districts IX (ß = 2.38 [0.87-3.88], p = 0.002) and XVI (ß = 0.78 [0.02-1.55], p = 0.045) had higher hydatidiform mole scores than those from the specialized center district. Gestational trophoblastic neoplasia patients from district XVI showed a 3.32 increase in FIGO risk scores compared with those from the specialized center area (ß = 3.32, 95% CI = 0.78-5.87, p = 0.010). Distance traveled by patients from districts IX (200km) and XVI (203.5km) was significantly longer than that traveled by patients from the specialized center district (76km). CONCLUSION: Patients from health districts outside the specialized center area had higher risk scores for both hydatidiform mole and gestational trophoblastic neoplasia at admission. Long distances (>80 km) seemed to adversely influence gestational trophoblastic disease clinical status at admission, indicating barriers to accessing specialized centers.

OBJETIVO: Avaliar a possível relação entre estado clínico na apresentação e distância percorrida a partir do distrito de saúde em mulheres com doença trofoblástica gestacional. MéTODOS: Estudo transversal incluindo mulheres com doença trofoblástica gestacional dos 17 distritos de saúde do estado de São Paulo (I­XVII), Brasil, encaminhadas ao Centro de Doenças Trofoblásticas de Botucatu (distrito VI), entre 1990 e 2018. Na admissão, avaliaram-se mola hidatiforme pelo sistema de pontuação de risco de Berkowitz et al. e neoplasia trofoblástica gestacional pelo escore de risco/estadiamento Federação Internacional de Ginecologia e Obstetrícia / Organização Mundial da Saúde (FIGO/OMS). Coletaram-se dados demográficos, clínicos e distância percorrida e análises de regressão múltipla foram realizadas. RESULTADOS: Este estudo incluiu 366 mulheres (335 mola hidatiforme, 31 neoplasia trofoblástica gestacional). O estado clínico na apresentação e distância percorrida diferiram significativamente entre o centro especializado e demais distritos. Nas pacientes encaminhadas pelos distritos IX (ß = 2,38 [0,87­3,88], p = 0,002) e XVI (ß = 0,78 [0,02­1,55], p = 0,045), os escores de mola hidatiforme foram maiores que no centro especializado. As pacientes com neoplasia trofoblástica gestacional do distrito XVI apresentaram escores FIGO 3,32 vezes maior que no centro especializado (ß = 3,32, 95% CI = 0,78­5,87, p = 0,010). A distância percorrida pelas pacientes dos distritos IX (200km) e XVI (203,5km) foi significativamente maior do que a percorrida pelas pacientes do centro especializado (76km). CONCLUSãO: Pacientes de distritos de saúde fora da cobertura do centro especializado apresentaram escores de risco mais alto para mola hidatiforme e para neoplasia trofoblástica gestacional na admissão. Longas distâncias (>80 km) pareceram influenciar negativamente o estado clínico da doença trofoblástica gestacional na apresentação, indicando barreiras no acesso a centros especializados.

Immunotherapy in the treatment of chemoresistant gestational trophoblastic neoplasia - systematic review with a presentation of the first 4 Brazilian cases.

OBJECTIVE: To evaluate the efficacy of immunotherapy for GTN treatment after methotrexate-resistance or in cases of multiresistant disease, through a systematic review, as well as to present the first 4 Brazilian cases of immunotherapy for GTN treatment. METHODS: Three independent researchers searched five electronic databases (EMBASE, LILACS, Medline, CENTRAL and Web of Science), for relevant articles up to February/2023 (PROSPERO CRD42023401453). The quality assessment was performed using the Newcastle Ottawa scale for case series and case reports. The primary outcome of this study was the occurrence of complete remission. The presentation of the case reports was approved by the Institutional Review Board. RESULTS: Of the 4 cases presented, the first was a low-risk GTN with methotrexate resistance unsuccessfully treated with avelumab, which achieved remission with sequential multiagent chemotherapy. The remaining 3 cases were high-risk multiagent-resistant GTN that were successfully treated with pembrolizumab, among which there were two subsequent gestations, one of them with normal pregnancy and healthy conceptus. Regarding the systematic review, 12 studies were included, only one of them on avelumab, showing a 46.7% complete remission rate. The remaining 11 studies were on pembrolizumab, showing an 86.7% complete remission rate, regardless of tumor histology. Both immunotherapies showed good tolerability, with two healthy pregnancies being recorded: one after avelumb and another after pembrolizumab. CONCLUSION: Immunotherapy showed effectiveness for GTN treatment and may be especially useful in cases of high-risk disease, where pembrolizumab achieves a high therapeutic response, regardless of the histological type, and despite prior chemoresistance to multiple lines of treatment.

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.

Geographical Health District and Distance Traveled Influence on Clinical Status at Admission of Patients with Gestational Trophoblastic Disease / A influência do distrito de saúde e da distância viajada sobre o estado clínico na apresentação de pacientes com doença trofoblástica gestacional

Abstract Objective To assess the potential relationship of clinical status upon admission and distance traveled from geographical health district in women with gestational trophoblastic disease (GTD). Methods This is a cross-sectional study including women with GTD from the 17 health districts from the São Paulo state (I-XVII), Brazil, referred to the Botucatu Trophoblastic Disease Center (specialized center, district VI), between 1990 and 2018. At admission, hydatidiform mole was assessed according to the risk score system of Berkowitz et al. Gestational trophoblastic neoplasia was evaluated using the International Federation of Gynecology and Obstetrics / World Health Organization (FIGO/WHO) staging/risk score. Data on demographics, clinical status and distance traveled were collected. Multiple regression analyses were performed. Results This study included 366 women (335 hydatidiform mole, 31 gestational trophoblastic neoplasia). The clinical status at admission and distance traveled significantly differed between the specialized center district and other districts. Patients referred from health districts IX (β = 2.38 [0.87-3.88], p = 0.002) and XVI (β = 0.78 [0.02-1.55], p = 0.045) had higher hydatidiform mole scores than those from the specialized center district. Gestational trophoblastic neoplasia patients from district XVI showed a 3.32 increase in FIGO risk scores compared with those from the specialized center area (β = 3.32, 95% CI = 0.78-5.87, p = 0.010). Distance traveled by patients from districts IX (200km) and XVI (203.5km) was significantly longer than that traveled by patients from the specialized center district (76km). Conclusion Patients from health districts outside the specialized center area had higher risk scores for both hydatidiform mole and gestational trophoblastic neoplasia at admission. Long distances (>80 km) seemed to adversely influence gestational trophoblastic disease clinical status at admission, indicating barriers to accessing specialized centers.

Resumo Objetivo Avaliar a possível relação entre estado clínico na apresentação e distância percorrida a partir do distrito de saúde em mulheres com doença trofoblástica gestacional. Métodos Estudo transversal incluindo mulheres com doença trofoblástica gestacional dos 17 distritos de saúde do estado de São Paulo (I-XVII), Brasil, encaminhadas ao Centro de Doenças Trofoblásticas de Botucatu (distrito VI), entre 1990 e 2018. Na admissão, avaliaram-se mola hidatiforme pelo sistema de pontuação de risco de Berkowitz et al. e neoplasia trofoblástica gestacional pelo escore de risco/estadiamento Federação Internacional de Ginecologia e Obstetrícia / Organização Mundial da Saúde (FIGO/OMS). Coletaram-se dados demográficos, clínicos e distância percorrida e análises de regressão múltipla foram realizadas. Resultados Este estudo incluiu 366 mulheres (335 mola hidatiforme, 31 neoplasia trofoblástica gestacional). O estado clínico na apresentação e distância percorrida diferiram significativamente entre o centro especializado e demais distritos. Nas pacientes encaminhadas pelos distritos IX (β = 2,38 [0,87-3,88], p = 0,002) e XVI (β = 0,78 [0,02-1,55], p = 0,045), os escores de mola hidatiforme foram maiores que no centro especializado. As pacientes com neoplasia trofoblástica gestacional do distrito XVI apresentaram escores FIGO 3,32 vezes maior que no centro especializado (β = 3,32, 95% CI = 0,78-5,87, p = 0,010). A distância percorrida pelas pacientes dos distritos IX (200km) e XVI (203,5km) foi significativamente maior do que a percorrida pelas pacientes do centro especializado (76km). Conclusão Pacientes de distritos de saúde fora da cobertura do centro especializado apresentaram escores de risco mais alto para mola hidatiforme e para neoplasia trofoblástica gestacional na admissão. Longas distâncias (>80 km) pareceram influenciar negativamente o estado clínico da doença trofoblástica gestacional na apresentação, indicando barreiras no acesso a centros especializados.

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.

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.

Current chemotherapeutic options for the treatment of gestational trophoblastic disease.

INTRODUCTION: Gestational trophoblastic neoplasia (GTN) is a rare tumor that arises from trophoblastic tissues with high remission rates after chemotherapy treatment. GTN can develop from any gestational events, such as miscarriage, ectopic pregnancy, and preterm/term pregnancy, but is more frequent after hydatidiform mole. The sensitivity of this tumor to chemotherapy and the presence of an exceptional tumor marker allow high remission rates, especially when patients are treated in referral centers. AREAS COVERED: Observational, retrospective, prospective, systematic reviews, and meta-analysis studies focusing on GTN treatment. We searched PubMed, Medline, and the Library of Congress from January 1965 to May 2022. EXPERT OPINION: Early GTN diagnosis allows low-toxic and highly effective treatment. Even multimetastatic disease has high rates of remission with multiagent regimen chemotherapy. Surgery is reserved for uterine disease in patients who have completed childbearing, in cases of chemoresistance to multiagent regimens or in the rare cases of placental site trophoblastic tumor or epithelioid trophoblastic tumor. While resistance is managed by salvage chemotherapy, cases with limited clinical response to sequential regimens have been successfully treated with immunotherapy.

Influence of COVID-19 pandemic on molar pregnancy and postmolar gestational trophoblastic neoplasia: An observational study.

OBJECTIVE: To assess whether the incidence and aggressiveness of molar pregnancy (MP) and postmolar gestational trophoblastic neoplasia (GTN) changed during the COVID-19 pandemic. DESIGN: Observational study with two separate designs: retrospective multicentre cohort of patients with MP/postmolar GTN and a cross-sectional analysis, with application of a questionnaire. SETTING: Six Brazilian Reference Centres on gestational trophoblastic disease. POPULATION: 2662 patients with MP/postmolar GTN treated from March-December/2015-2020 were retrospectively evaluated and 528 of these patients answered a questionnaire. METHODS: Longitudinal retrospective multicentre study of patients diagnosed with MP/ postmolar GTN at presentation and a cross-sectional analysis, with application of a questionnaire, exclusive to patients treated during the period of study, to assess living and health conditions during the COVID-19 pandemic compared with previous years. MAIN OUTCOME MEASURES: The incidence of MP/postmolar GTN. RESULTS: Compared with the last 5 pre-pandemic years, MP/postmolar GTN incidence remained stable during 2020 (COVID-19 pandemic). Multivariable logistic regression, adjusted for the patient age, showed that during 2020, presentation with MP was more likely to be >10 weeks of gestation (adjusted odds ratio [aOR] 2.50, 95% confidence interval [CI] 1.90-3.29, P < 0.001), have a pre-evacuation hCG level ≥100 000 iu/l (aOR 1.77, 95% CI 1.38-2.28, P < 0.001) and time to the initiation of chemotherapy ≥7 months (aOR 1.86, 95% CI 1.01-3.43, P = 0.047) when compared with 2015-2019. CONCLUSIONS: Although the incidence of MP/postmolar GTN remained stable during the COVID-19 pandemic in Brazil, the pandemic was associated with greater gestational age at MP diagnosis and more protracted delays in initiation of chemotherapy for postmolar GTN.

Immunotherapy in the treatment of chemoresistant gestational trophoblastic neoplasia - systematic review with a presentation of the first 4 Brazilian cases

Abstract Objective To evaluate the efficacy of immunotherapy for GTN treatment after methotrexate-resistance or in cases of multiresistant disease, through a systematic review, as well as to present the first 4 Brazilian cases of immunotherapy for GTN treatment. Methods Three independent researchers searched five electronic databases (EMBASE, LILACS, Medline, CENTRAL and Web of Science), for relevant articles up to February/2023 (PROSPERO CRD42023401453). The quality assessment was performed using the Newcastle Ottawa scale for case series and case reports. The primary outcome of this study was the occurrence of complete remission. The presentation of the case reports was approved by the Institutional Review Board. Results Of the 4 cases presented, the first was a low-risk GTN with methotrexate resistance unsuccessfully treated with avelumab, which achieved remission with sequential multiagent chemotherapy. The remaining 3 cases were high-risk multiagent-resistant GTN that were successfully treated with pembrolizumab, among which there were two subsequent gestations, one of them with normal pregnancy and healthy conceptus. Regarding the systematic review, 12 studies were included, only one of them on avelumab, showing a 46.7% complete remission rate. The remaining 11 studies were on pembrolizumab, showing an 86.7% complete remission rate, regardless of tumor histology. Both immunotherapies showed good tolerability, with two healthy pregnancies being recorded: one after avelumb and another after pembrolizumab. Conclusion Immunotherapy showed effectiveness for GTN treatment and may be especially useful in cases of high-risk disease, where pembrolizumab achieves a high therapeutic response, regardless of the histological type, and despite prior chemoresistance to multiple lines of treatment.

Neutrophil/lymphocyte ratio and other blood cell component counts are not associated with the development of postmolar gestational trophoblastic neoplasia.

OBJECTIVE: To relate preevacuation platelet count and leukogram findings, especially neutrophil/lymphocyte ratios (NLR) and platelet/lymphocyte ratios with the occurrence of gestational trophoblastic neoplasia (GTN) after complete hydatidiform mole (CHM) among Brazilian women. METHODS: Retrospective cohort study of patients with CHM followed at Rio de Janeiro Federal University, from January/2015-December/2020. Before molar evacuation, all patients underwent a medical evaluation, complete blood count and hCG measurement, in addition to other routine preoperative tests. The primary outcome was the occurrence of postmolar GTN. RESULTS: From 827 cases of CHM treated initially at the Reference Center, 696 (84.15%) had spontaneous remission and 131 (15.85%) developed postmolar GTN. Using optimal cut-offs from receiver operating characteristic curves and multivariable logistic regression adjusted for the possible confounding variables of age and preevacuation hCG level (already known to be associated with the development of GTN) we found that ≥2 medical complications at presentation (aOR: 1.96, CI 95%: 1.29-2.98, p<0.001) and preevacuation hCG ≥100,000 IU/L (aOR: 2.16, CI 95%: 1.32-3.52, p<0.001) were significantly associated with postmolar GTN after CHM. However, no blood count profile findings were able to predict progression from CHM to GTN. CONCLUSION: Although blood count is a widely available test, being a low-cost test and mandatory before molar evacuation, and prognostic for outcome in other neoplasms, its findings were not able to predict the occurrence of GTN after CHM. In contrast, the occurrence of medical complications at presentation and higher preevacuation hCG levels were significantly associated with postmolar GTN and may be useful to guide individualized clinical decisions in post-molar follow-up and treatment of these patients.

Clinical Presentation, Treatment Outcomes, and Resistance-related Factors in South American Women with Low-risk Postmolar Gestational Trophoblastic Neoplasia / Apresentação clínica, resultados do tratamento e fatores relacionados à resistência em mulheres sul-americanas com neoplasia trofoblástica gestacional pós-molar de baixo risco

Abstract 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.

Resumo Objetivo Existem poucos estudos multinacionais sobre os resultados do tratamento da neoplasia trofoblástica gestacional (NTG) na América do Sul. O objetivo deste estudo foi avaliar a apresentação clínica, os resultados do tratamento e os fatores associados a casos de quimiorresistência em NTG pós-molar de baixo risco tratados com quimioterapia de agente único de primeira linha em três centros sul-americanos. Métodos Estudo multicêntrico de coorte histórica incluindo mulheres com NTG pós-molar de baixo risco com estadiamento International Federation of Gynecology and Obstetrics (FIGO) em centros de atendimento na Argentina, Brasil e Colômbia entre 1990 e 2014. Foram obtidos dados sobre as características do paciente, apresentação da doença e resposta ao tratamento. A regressão logística foi usada para avaliar a relação entre fatores clínicos e resistência ao tratamento de primeira linha com agente único. Foi realizada uma análise multivariada dos fatores clínicos significativos na análise univariada. Resultados Cento e sessenta e três mulheres com NTG de baixo risco foram incluídas na análise. A taxa global de resposta completa à quimioterapia de primeira linha foi de 80% (130/163). As taxas de resposta completa ao metotrexato ou actinomicina-D como tratamento de primeira linha e actinomicina-D como tratamento de segunda linha após falha do metotrexato foram 79% (125/157), 83% (⅚) e 70% (23/33), respectivamente. A mudança para o tratamento de segunda linha por quimiorresistência ocorreu em 20,2% dos casos (33/163). A análise multivariada demonstrou que pacientes com pontuação de risco FIGO de 5 a 6 foram 4,2 vezes mais propensos a desenvolver resistência ao tratamento com agente único de primeira linha (p= 0,019). Conclusão 1) Na apresentação, a maioria das mulheres demonstrou características clínicas favoráveis a um bom resultado, 2) a taxa geral de remissão completa sustentada após o tratamento de primeira linha com agente único foi comparável à de países desenvolvidos, 3) um escore de risco FIGO de 5 ou 6 está associado ao desenvolvimento de resistência à quimioterapia de agente único de primeira linha.

Clinical Presentation, Treatment Outcomes, and Resistance-related Factors in South American Women with Low-risk Postmolar Gestational Trophoblastic Neoplasia.

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.

OBJETIVO: Existem poucos estudos multinacionais sobre os resultados do tratamento da neoplasia trofoblástica gestacional (NTG) na América do Sul. O objetivo deste estudo foi avaliar a apresentação clínica, os resultados do tratamento e os fatores associados a casos de quimiorresistência em NTG pós-molar de baixo risco tratados com quimioterapia de agente único de primeira linha em três centros sul-americanos. MéTODOS: Estudo multicêntrico de coorte histórica incluindo mulheres com NTG pós-molar de baixo risco com estadiamento International Federation of Gynecology and Obstetrics (FIGO) em centros de atendimento na Argentina, Brasil e Colômbia entre 1990 e 2014. Foram obtidos dados sobre as características do paciente, apresentação da doença e resposta ao tratamento. A regressão logística foi usada para avaliar a relação entre fatores clínicos e resistência ao tratamento de primeira linha com agente único. Foi realizada uma análise multivariada dos fatores clínicos significativos na análise univariada. RESULTADOS: Cento e sessenta e três mulheres com NTG de baixo risco foram incluídas na análise. A taxa global de resposta completa à quimioterapia de primeira linha foi de 80% (130/163). As taxas de resposta completa ao metotrexato ou actinomicina-D como tratamento de primeira linha e actinomicina-D como tratamento de segunda linha após falha do metotrexato foram 79% (125/157), 83% (⅚) e 70% (23/33), respectivamente. A mudança para o tratamento de segunda linha por quimiorresistência ocorreu em 20,2% dos casos (33/163). A análise multivariada demonstrou que pacientes com pontuação de risco FIGO de 5 a 6 foram 4,2 vezes mais propensos a desenvolver resistência ao tratamento com agente único de primeira linha (p = 0,019). CONCLUSãO: 1) Na apresentação, a maioria das mulheres demonstrou características clínicas favoráveis a um bom resultado, 2) a taxa geral de remissão completa sustentada após o tratamento de primeira linha com agente único foi comparável à de países desenvolvidos, 3) um escore de risco FIGO de 5 ou 6 está associado ao desenvolvimento de resistência à quimioterapia de agente único de primeira linha.

The role of natural killer cells in the immune homeostasis of the maternal fetal interface / A természetes ölosejtek szerepe az anyai-magzati immunhomeostasis fenntartásában

Successful conception, implantation and pregnancy require a complex and organized communication between the embryonal (allograft) and the maternal (host) immune system. Different leukocyte subsets have an important role in orchestrating the immune response at the fetal-maternal interface. There are certain similarities between the immune invasion of tumor cells and the physiological invasion of the trophoblastic cells of embryonic origin into the maternal decidua. The decidual natural killer cells are a special subset of natural killer cells and alongside with macrophages and dendritic cells, they are part of the innate immune system therefore they are the first immune cells contacting any intruder whether it is a tumor or embryonic tissue. Interestingly decidual natural killer cells not only do not eliminate invasive trophoblastic cells, but specifically promote their progression. Their angiogenic activity facilitates and coordinates local vascular remodeling of the forming placenta. In this article we review the different nature of trophoblastic cell and decidual natural killer cell interaction, the role of decidual natural killer cells in the vascularization and immune homeostasis of the decidua.

ATR and CDK4/6 inhibition target the growth of methotrexate-resistant choriocarcinoma.

Low-risk gestational trophoblastic neoplasia including choriocarcinoma is often effectively treated with Methotrexate (MTX) as a first line therapy. However, MTX resistance (MTX-R) occurs in at least ≈33% of cases. This can sometimes be salvaged with actinomycin-D but often requires more toxic combination chemotherapy. Moreover, additional therapy may be needed and, for high-risk patients, 5% still die from the multidrug-resistant disease. Consequently, new treatments that are less toxic and could reverse MTX-R are needed. Here, we compared the proteome/phosphoproteome of MTX-resistant and sensitive choriocarcinoma cells using quantitative mass-spectrometry to identify therapeutically actionable molecular changes associated with MTX-R. Bioinformatics analysis of the proteomic data identified cell cycle and DNA damage repair as major pathways associated with MTX-R. MTX-R choriocarcinoma cells undergo cell cycle delay in G1 phase that enables them to repair DNA damage more efficiently through non-homologous end joining in an ATR-dependent manner. Increased expression of cyclin-dependent kinase 4 (CDK4) and loss of p16Ink4a in resistant cells suggested that CDK4 inhibition may be a strategy to treat MTX-R choriocarcinoma. Indeed, inhibition of CDK4/6 using genetic silencing or the clinically relevant inhibitor, Palbociclib, induced growth inhibition both in vitro and in an orthotopic in vivo mouse model. Finally, targeting the ATR pathway, genetically or pharmacologically, re-sensitised resistant cells to MTX in vitro and potently prevented the growth of MTX-R tumours in vivo. In short, we identified two novel therapeutic strategies to tackle MTX-R choriocarcinoma that could rapidly be translated into the clinic.

Consolidation chemotherapy in postmolar low-risk gestational trophoblastic neoplasia: a systematic review protocol.

INTRODUCTION: Current evidence remains insufficient to strongly demonstrate the benefits of consolidation chemotherapy to all women with low-risk gestational trophoblastic neoplasia (GTN). This protocol outlines a systematic review to investigate whether consolidation chemotherapy is necessary for all patients with postmolar low-risk GTN after human chorionic gonadotropin normalisation with first-line single-agent chemotherapy. METHODS AND ANALYSIS: A search string will be used to search the PubMed (MEDLINE), EMBASE, Web of Sciences, Scopus, LILACS and Cochrane Central Register of Controlled Trials databases. Articles will be screened at the title and abstract level, and then at the full article level by two independent reviewers using inclusion/exclusion criteria. Randomised and non-randomised study designs will be included, while case studies, commentaries, editorials, review articles, animal studies, basic science studies and cross-sectional studies, as well as studies not reporting relapse/recurrence rates and/or whether consolidation chemotherapy was delivered will be excluded. There will be no restrictions on date of publication, geographical location, study setting, or language of publication. The primary outcome is rate of recurrence/relapse. The assessments of randomised controlled trials will be performed using the risk of bias tool from the Cochrane Collaboration. Non-randomised studies will be assessed using the Newcastle-Ottawa scale. The quality of evidence will be assessed using the Grading quality of evidence and strength of recommendations (Grades of Recommendations, Assessment, Development and Evaluation) guidelines. ETHICS AND DISSEMINATION: No formal ethical approval is required as all data collected will be secondary data and analysed anonymously. Results will be disseminated through a peer-reviewed publication and at scientific events. PROSPERO REGISTRATION NUMBER: CRD42020164822.

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.

Isolation and culture of decidual natural killer cells from term placenta and complete hydatidiform mole.

Decidual natural killer cells (dNK) have been the focus of many studies because of their unique roles in both the anti-tumor immune response and healthy placental formation. Revealing the immunological mechanisms by which they interact with their target cells may lead to a better understanding of immune evasion of certain tumor cells, including abnormal cells of the different forms of gestational trophoblast disease and miscarriages of immunologic origin. Efforts to perform functional immunological studies on dNK cells have been limited by difficulty obtaining sufficent quantities of cells and sustaining the dNK phenotype. A novel protocol was developed to isolate and culture dNK cells from fresh, term placentas and complete hydatidiform moles.The placental samples were collected from healthy women undergoing scheduled elective cesarean delivery. The molar samples were collected after evacuation and curettage. Tissue samples were made into single cell suspensions using mechanical and enzymatic degradation, followed by fluorescence-activated cell sorting (FACS) using surface markers. The dNK cells were then expanded in cell culture. Their surface markers and cytotoxicity were reassessed by flow cytometry and functional assays. The protocol produces high quantities of enriched dNK cells which can be sustained in cell culture for at least a month, preserving their phenotype and funcionality for a week.

Perinatal outcomes of first pregnancy after chemotherapy for gestational trophoblastic neoplasia: a systematic review of observational studies and meta-analysis.

OBJECTIVE: To assess perinatal outcomes of first pregnancy after remission from gestational trophoblastic neoplasia and the impact of the time between the end of chemotherapy and the subsequent pregnancy. DATA SOURCES: The Medical Subject Headings related to perinatal outcomes, chemotherapy, and gestational trophoblastic neoplasia were used alone or in combination to retrieve relevant articles. We searched all references registered until April, 2019 in Embase, LILACS, MEDLINE, the Cochrane Central Register of Controlled Trials, and Web of Science. STUDY ELIGIBILITY CRITERIA: We included any observational or interventional studies that evaluated perinatal outcomes of first pregnancy after chemotherapy for gestational trophoblastic neoplasia. Animal studies, narrative reviews, expert opinions, and previous treatments with potential risks for future perinatal outcomes which may introduce confounding bias were excluded. STUDY APPRAISAL AND SYNTHESIS METHODS: Two reviewers independently screened all identified references for eligibility and data extraction. Methodological quality and bias of included studies were assessed using the Quality Assessment Tool for Observational Cohort and Cross-Sectional Studies from the National Institutes of Health. For the meta-analysis, the measures of association were calculated using bivariate random-effects models. Statistical heterogeneity was evaluated with I2 statistics and explored through sensitivity analysis. Publication bias was assessed by visual inspection of the funnel plot or Egger's test, according to the number of articles included. For all analyses, a P value of <.05 indicated statistical significance. This study was registered on PROSPERO (CRD42018116513). RESULTS: A total of 763 studies were identified after literature search and 23 original studies were included in the systematic review and in the meta-analysis. The combined data from the subgroup meta-analysis (outcome vs time after chemotherapy) showed an incidence of spontaneous abortion of 15.28% (95% confidence interval, 12.37-18.74; I2=73%), 3.30% of malformation (95% confidence interval, 2.27-4.79; I2=31%), 6.19% of prematurity (95% confidence interval, 5.03-7.59; I2=0), and 1.73% of stillbirth (95% confidence interval, 1.17-2.55; I2=0%). These results were not influenced by the time between the end of chemotherapy and the subsequent pregnancy in most of the studied outcomes, including malformation (P=.14, I2=31%), prematurity (P=.46, I2=0), and stillbirth (P=.66, I2=0). However, there was a higher occurrence of spontaneous abortion (P<.01, I2=73%) in pregnancies that occurred ≤6 months after chemotherapy. CONCLUSION: Chemotherapy for gestational trophoblastic neoplasia does not appear to increase the chance of unfavorable perinatal outcomes, except for the higher occurrence of spontaneous abortion in pregnancies occurring ≤6 months after chemotherapy.

Diagnosis and management of gestational trophoblastic disease: 2021 update.

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