Emotional and Clinical Aspects Observed in Women with Gestational Trophoblastic Disease: A Multidisciplinary Action / Aspectos emocionais e clínicos observados em mulheres com doença trofoblástica gestacional: Uma ação multidisciplinar

Abstract Objective To evaluate the emotional and clinical aspects observed in women with gestational trophoblastic disease (GTD) followed-up in a reference center (RC) by a multidisciplinary team. Methods Retrospective cohort study of the clinical records of 186 women with GTD and of the emotional aspects (EA) observed in these women by a teamof psychologists and reported by the 389 support groups conducted from 2014 to 2018. Results The women were young (mean age: 31.2 years), 47% had no living child, 60% had planned the pregnancy, and 50% participated in two or more SG. Most women (n=137; 73.6%) reached spontaneous remission ofmolar gestation in a median time of 10 weeks and had a total follow-up time of seven months. In the group of 49 women (26.3%) who progressed to gestational trophoblastic neoplasia (GTN), time to remission after chemotherapy was 18 weeks, and total follow-up time was 36 months. EA included different levels of anxiety and depression,more evident in 9.1% of the women; these symptoms tended to occur more frequently in women older than 40 years (p=0.067), less educated (p=0.054), and whose disease progressed to GTN (p=0.018), as well as in those who had to undergo multi-agent chemotherapy (p=0.028) or hysterectomy (p=0.001) adjuvant to clinical treatment. Conclusion This study found several EA in association with all types of GTD. It also highlights the importance of specialized care only found in a RC, essential to support the recovery of the mental health of these women.

Resumo Objetivo Avaliar aspectos emocionais e clínicos observados em mulheres com doença trofoblástica gestacional (DTG) acompanhadas em um centro de referência (CR), por equipe multiprofissional. Método Estudo de coorte retrospectivo nos prontuários clínicos de 186 mulheres comDTG, e dos aspectos emocionais (AE) observados nessas mulheres pela equipe de psicólogas e registrados nos 389 grupos de apoio (GAs), ocorridos de 2014 a 2018. Resultados As pacientes eram jovens (idade média 31,2 anos), 47% sem filhos vivos, 60% tinham desejado ou planejado esta gravidez e 50% delas participaram de dois ou mais GAs. A maioria (n=137-73,6%) apresentou remissão espontânea da gestação molar com mediana de 10 semanas e um tempo total de seguimento de 7 meses. Quarenta e nove mulheres (26,3%) evoluíram para neoplasia trofoblástica gestacional (NTG); amediana para atingir a remissão após tratamento comquimioterapia foi de 19 semanas e o tempo total de seguimento foi de 36 meses. Os AE incluíram variados graus de ansiedade e depressão, mais evidentes em 9,1% das nossas pacientes; tais AE tenderam a ocorrer mais em mulheres com idade acima de 40 anos (p=0,067), com menor escolaridade (p=0,054), com evolução para NTG (p=0,018), e nas que necessitaram de tratamento quimioterápico com regime de múltiplos agentes (p=0,028), ou de histerectomia complementar ao tratamento clínico (p=0,001). Conclusão Este estudo mostrou presença de vários AE associados em todos os tipos de DTG. Destaca tambéma importância de umatendimento psicológico especializado, somente encontrado nos CR, que é essencial para ajudar na recuperação da saúde mental dessas mulheres.

Emotional and Clinical Aspects Observed in Women with Gestational Trophoblastic Disease: A Multidisciplinary Action.

OBJECTIVE: To evaluate the emotional and clinical aspects observed in women with gestational trophoblastic disease (GTD) followed-up in a reference center (RC) by a multidisciplinary team. METHODS: Retrospective cohort study of the clinical records of 186 women with GTD and of the emotional aspects (EA) observed in these women by a team of psychologists and reported by the 389 support groups conducted from 2014 to 2018. RESULTS: The women were young (mean age: 31.2 years), 47% had no living child, 60% had planned the pregnancy, and 50% participated in two or more SG. Most women (n = 137; 73.6%) reached spontaneous remission of molar gestation in a median time of 10 weeks and had a total follow-up time of seven months. In the group of 49 women (26.3%) who progressed to gestational trophoblastic neoplasia (GTN), time to remission after chemotherapy was 18 weeks, and total follow-up time was 36 months. EA included different levels of anxiety and depression, more evident in 9.1% of the women; these symptoms tended to occur more frequently in women older than 40 years (p = 0.067), less educated (p = 0.054), and whose disease progressed to GTN (p = 0.018), as well as in those who had to undergo multi-agent chemotherapy (p = 0.028) or hysterectomy (p = 0.001) adjuvant to clinical treatment. CONCLUSION: This study found several EA in association with all types of GTD. It also highlights the importance of specialized care only found in a RC, essential to support the recovery of the mental health of these women.

OBJETIVO: Avaliar aspectos emocionais e clínicos observados em mulheres com doença trofoblástica gestacional (DTG) acompanhadas em um centro de referência (CR), por equipe multiprofissional. MéTODO: Estudo de coorte retrospectivo nos prontuários clínicos de 186 mulheres com DTG, e dos aspectos emocionais (AE) observados nessas mulheres pela equipe de psicólogas e registrados nos 389 grupos de apoio (GAs), ocorridos de 2014 a 2018. RESULTADOS: As pacientes eram jovens (idade média 31,2 anos), 47% sem filhos vivos, 60% tinham desejado ou planejado esta gravidez e 50% delas participaram de dois ou mais GAs. A maioria (n = 137­73,6%) apresentou remissão espontânea da gestação molar com mediana de 10 semanas e um tempo total de seguimento de 7 meses. Quarenta e nove mulheres (26,3%) evoluíram para neoplasia trofoblástica gestacional (NTG); a mediana para atingir a remissão após tratamento com quimioterapia foi de 19 semanas e o tempo total de seguimento foi de 36 meses. Os AE incluíram variados graus de ansiedade e depressão, mais evidentes em 9,1% das nossas pacientes; tais AE tenderam a ocorrer mais em mulheres com idade acima de 40 anos (p = 0,067), com menor escolaridade (p = 0,054), com evolução para NTG (p = 0,018), e nas que necessitaram de tratamento quimioterápico com regime de múltiplos agentes (p = 0,028), ou de histerectomia complementar ao tratamento clínico (p = 0,001). CONCLUSãO: Este estudo mostrou presença de vários AE associados em todos os tipos de DTG. Destaca também a importância de um atendimento psicológico especializado, somente encontrado nos CR, que é essencial para ajudar na recuperação da saúde mental dessas mulheres.

GLPG2737 in lumacaftor/ivacaftor-treated CF subjects homozygous for the F508del mutation: A randomized phase 2A trial (PELICAN).

BACKGROUND: Triple combinations of cystic fibrosis (CF) transmembrane conductance regulator (CFTR) modulators demonstrate enhanced clinical efficacy in CF patients with F508del mutation, compared with modest effects of dual combinations. GLPG2737 was developed as a novel corrector for triple combination therapy. METHODS: This multicenter, randomized, double-blind, placebo-controlled, phase 2a study evaluated GLPG2737 in F508del homozygous subjects who had been receiving lumacaftor 400mg/ivacaftor 250mg for ≥12weeks. The primary outcome was change from baseline in sweat chloride concentration. Other outcomes included assessment of pulmonary function, respiratory symptoms, safety, tolerability, and pharmacokinetics. RESULTS: Between November 2017 and April 2018, 22 subjects were enrolled and randomized to oral GLPG2737 (75mg; n=14) or placebo (n=8) capsules twice daily for 28days. A significant decrease from baseline in mean sweat chloride concentration occurred at day 28 for GLPG2737 versus placebo (least-squares-mean difference-19.6mmol/L [95% confidence interval (CI) -36.0, -3.2], p=.0210). The absolute improvement, as assessed by least-squares-mean difference in change from baseline, in forced expiratory volume in 1s (percent predicted) at day 28 for GLPG2737 versus placebo was 3.4% (95% CI -0.5, 7.3). Respiratory symptoms in both groups remained stable. Mild/moderate adverse events occurred in 10 (71.4%) and 8 (100%) subjects receiving GLPG2737 and placebo, respectively. Lower exposures of GLPG2737 (and active metabolite M4) were observed than would be expected if administered alone (as lumacaftor induces CYP3A4). Lumacaftor and ivacaftor exposures were as expected. CONCLUSIONS: GLPG2737 was well tolerated and yielded significant decreases in sweat chloride concentration versus placebo in subjects homozygous for F508del receiving lumacaftor/ivacaftor, demonstrating evidence of increased CFTR activity when added to a potentiator-corrector combination. FUNDING: Galapagos NV. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT03474042.

CFTR activity is enhanced by the novel corrector GLPG2222, given with and without ivacaftor in two randomized trials.

BACKGROUND: Several treatment approaches in cystic fibrosis (CF) aim to correct CF transmembrane conductance regulator (CFTR) function; the efficacy of each approach is dependent on the mutation(s) present. A need remains for more effective treatments to correct functional deficits caused by the F508del mutation. METHODS: Two placebo-controlled, phase 2a studies evaluated GLPG2222, given orally once daily for 29 days, in subjects homozygous for F508del (FLAMINGO) or heterozygous for F508del and a gating mutation, receiving ivacaftor (ALBATROSS). The primary objective of both studies was to assess safety and tolerability. Secondary objectives included assessment of pharmacokinetics, and of the effect of GLPG2222 on sweat chloride concentrations, pulmonary function and respiratory symptoms. RESULTS: Fifty-nine and 37 subjects were enrolled into FLAMINGO and ALBATROSS, respectively. Treatment-related treatment-emergent adverse events (TEAEs) were reported by 29.2% (14/48) of subjects in FLAMINGO and 40.0% (12/30) in ALBATROSS; most were mild to moderate in severity and comprised primarily respiratory, gastrointestinal, and infection events. There were no deaths or discontinuations due to TEAEs. Dose-dependent decreases in sweat chloride concentrations were seen in GLPG2222-treated subjects (maximum decrease in FLAMINGO: -17.6 mmol/L [GLPG2222 200 mg], p < 0.0001; ALBATROSS: -7.4 mmol/L [GLPG2222 300 mg], p < 0.05). No significant effects on pulmonary function or respiratory symptoms were reported. Plasma GLPG2222 concentrations in CF subjects were consistent with previous studies in healthy volunteers and CF subjects. CONCLUSIONS: GLPG2222 was well tolerated. Sweat chloride reductions support on-target enhancement of CFTR activity in subjects with F508del mutation(s). Significant improvements in clinical endpoints were not demonstrated. Observed safety results support further evaluation of GLPG2222, including in combination with other CFTR modulators. FUNDING: Galapagos NV. Clinical trial registration numbers FLAMINGO, NCT03119649; ALBATROSS, NCT03045523.