Custo-efetividade de terapias anti-PD-1 comparadas com ipilimumabe para o tratamento de melanoma avançado sob a perspectiva do sistema de saúde suplementar brasileiro / Cost-effectiveness of anti-PD-1 therapies compared with ipilimumab for the treatment of advanced melanoma under the Brazilian supplementary health system perspective

Objetivo: Realizar uma análise de custo-efetividade das terapias imuno-oncológicas anti-PD-1 aprovadas no Brasil versus ipilimumabe no tratamento do paciente sem tratamento prévio com melanoma metastático (estádios III ou IV), independentemente da mutação BRAF sob a perspectiva do sistema de saúde suplementar brasileiro. Métodos: Foi desenvolvido um modelo com três estados de saúde mutuamente exclusivos (livre de progressão, progressão da doença e morte) para simular a condição clínica de pacientes tratados com nivolumabe ou pembrolizumabe comparado ao ipilimumabe. Os custos de medicamentos, materiais, exames e procedimentos foram calculados com base na lista oficial de preços no Brasil ­ CMED (março/2017), revistas Kairos e Simpro, Planserv 2008 e CBHPM 2015. O desfecho clínico considerado para a análise foi de anos de vida salvos. Resultados: O nivolumabe produziu uma razão de custo-efetividade incremental de R$ 37.231 e o pembrolizumabe, de R$ 72.760. Ambas as intervenções demonstraram benefício clínico dentro do limiar de disposição a pagar recomendado pela OMS (três vezes o PIB per capita), mostrando que as tecnologias são custoefetivas. Na análise de sensibilidade univariada foi demonstrado que as RCEIs para ambas as análises foram mais sensíveis aos parâmetros referentes à taxa de desconto anual e aos custos de acompanhamento. Entre as terapias imuno-oncológicas anti-PD-1, o nivolumabe apresentou benefício clínico maior a um custo menor. Conclusão: Ambas as terapias anti-PD-1 (nivolumabe e pembrolizumabe) são custo-efetivas versus ipilimumabe, sugerindo-se o nivolumabe como melhor opção para a alocação de recursos no tratamento de pacientes sem tratamento prévio com melanoma avançado, independentemente da mutação BRAF, sob a perspectiva do sistema de saúde suplementar brasileiro.

Objective: The aim of this study was to evaluate the cost-effectiveness of anti-PD-1 therapies approved in Brazil versus ipilimumab for the treatment of previously untreated patients with metastatic melanoma (stage III/IV) irrespective of BRAF status under the Brazilian supplementary health system perspective. Methods: A cost-effectiveness model with three mutually exclusive health state (pre-progression, post-progression and death) was developed to simulate the clinical condition of patients with metastatic melanoma treated with nivolumab or pembrolizumab compared with ipilimumab. The cost of drugs, materials, exams and procedures were obtained from official Brazilian price list ­ CMED, Kairos and Simpro magazines, Planserv 2008 and CBHPM 2015. The clinical outcome considered in the analysis was life years saved. Results: Nivolumab produced an incremental cost-effectiveness ratio of R$ 37,231 and pembrolizumab of R$ 72,760. Both interventions offered clinical benefit within the willingness-to-pay threshold recommended by World Health Organization (WHO) (three times per-capita GDP), showing that the technologies are cost-effective. It was demonstrated in the univariate sensitivity analyses that the parameters in which ICER of the comparison of nivolumab vs. ipilimumab and pembrolizumab vs. ipilimumab were more sensitive to annual discount rate (costs) and follow-up costs. Conclusion: Both nivolumab and pembrolizumab are cost-effective versus ipilimumab, suggesting that it would be more willing to be adopted for the treatment of previously untreated patients with advanced melanoma regardless of BRAF mutation under Brazilian supplementary health system perspective.

Primary squamous cell carcinoma of the thyroid diagnosed as anaplastic carcinoma: failure in fine-needle aspiration cytology?

A case of primary squamous-cell carcinoma (SCC) of the thyroid which had been initially diagnosed as an anaplastic carcinoma (ATC) is described: female, 73 years old, with a fast-growing cervical nodule on the left side and hoarseness for 3 months. Ultrasonography showed a 4.5 cm solid nodule. FNA was compatible with poorly differentiated carcinoma with immunoreactivity for AE1/AE3, EMA. Thyroidectomy was performed. Histopathological examination showed a nonencapsulated tumor. Immunohistochemistry disclosed positivity for AE1/AE3, p53,p63, and Ki67. The diagnosis was ATC. A second opinion reported tumor consisting of squamous cells, with intense inflammatory infiltrate both in tumor and in the adjacent thyroid, with final diagnosis of SCC, associated with Hashimoto thyroiditis. No other primary focus of SCC was found. Patient has shown a 48-month survival period. Clinically, primary SCCs of the thyroid and ATCs are similar. The distinction is often difficult particularly when based on the cytological analysis of FNA material.

Combinations of low doses of unfractionated heparin and of low-molecular-weight heparin prevent experimental venous thrombosis.

Synergism between low-molecular-weight heparin and low doses of unfractionated heparin (UH) enhancing anti-factor Xa activity and the release of tissue factor pathway inhibitor was observed. The aim of this study was to verify whether this association is effective in preventing experimental venous thrombosis. Seventy rats were allocated into 7 groups: the control group treated with distilled water, the H(350) group treated with UH 350 IU/kg, the E(2) group treated with enoxaparin 2 mg/kg, the H(175) group treated with UH 175 IU/kg, the E(1) group treated with enoxaparin 1 mg/kg, the H(175) + E(1) group treated with UH 175 IU/kg plus enoxaparin 1 mg/kg, and the H(100) + E(0.5) group treated with UH 100 IU/kg plus enoxaparin 0.5 mg/kg. Forty minutes after subcutaneous injection, thrombosis was induced in vena cava. Three hours later, if present, thrombi were withdrawn and weighed. Bleeding time, activated partial thromboplastin time, thrombin time (TT), and anti-factor Xa were measured at the beginning and end of the experiment. Forty-eight other animals were treated, but without inducing thrombus, and tests were performed 40 min after injection. Thrombus developed in 90.9% of control animals, 20% of the H(350) group, 22.2% of the E(2) group, 10% of the H(175) + E(1) group, and 30% of the H(100) + E(0.5) group; there was a difference between group C and the other groups. Only in the H(350) and H(175) + E(1) groups were TT and activated partial thromboplastin time prolonged in relation to control at the end of the experiment. Forty minutes after injection, TT was prolonged in the H(350) and H(175) + E(1) groups. In conclusion, combinations of low doses of low-molecular-weight heparin and low doses of UH were as effective as high doses of each one used alone in preventing thrombus development in rat vena cava.