Avaliação da eficácia do 5‐fluorouracil 5% tópico intermitente e da nicotinamida oral no tratamento do campo de cancerização cutâneo: um ensaio clínico randomizado

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Entretanto, os efeitos colaterais decorrentes do uso diário podem levar a má adesão e prejuízo no resultado.<a class="elsevierStyleCrossRef" href="#bib0070">4</a> Apesar da descrição de inúmeros regimes terapêuticos, seu uso para a estabilização do CCC sob forma intermitente ainda não foi testado adequadamente.A nicotinamida é uma vitamina do complexo B que atua no reparo do DNA, reduzindo os efeitos da imunossupressão cutânea causados pela radiação ultravioleta (RUV), modulando a produção de citocinas inflamatórias e restaurando os níveis de energia celular pós‐exposição à RUV. Ademais, a nicotinamida oral parece apresentar efeito fotoprotetor em humanos, reduzindo a contagem de CAs e a incidência de neoplasias cutâneas em pacientes de alto risco.<a class="elsevierStyleCrossRef" href="#bib0075">5</a>Conduziu‐se um ensaio clínico aberto, randomizado, comparativo, fatorial, autocontrolado, duplo cego (para nicotinamida) no qual 36 pacientes, cujos antebraços apresentavam de três a dez CAs cada, foram randomizados em dois grupos. Um grupo recebeu nicotinamida oral 500mg a cada 12 horas durante 120 dias, e o outro grupo recebeu placebo na mesma posologia. Seus antebraços foram, subsequentemente, randomizados para receber 5FU tópico, à noite, três vezes na semana, ou filtro solar com fator de proteção solar 30 (FPS), três vezes ao dia. Em uma área padronizada dos antebraços, os pacientes foram avaliados clinicamente quanto à contagem de CAs e à Escala de Fotoenvelhecimento dos Antebraços (EFA), que avalia os antebraços quanto a aspectos do fotoenvelhecimento, como rugas, melanoses, púrpura visível, elastose e cicatrizes estelares, associados à presença de CAs.<a class="elsevierStyleCrossRef" href="#bib0080">6</a>Além disso, os pacientes foram biopsiados na região central do antebraço, em pele sem CA clinicamente evidente, para avaliação de displasia epitelial a partir do KIN (Keratinocyte Intraepithelial Neoplasia) e imuno‐histoquímica dos marcadores p53 e Ki67, na inclusão e após 120 dias. O desfecho primário foi o clearance completo de CAs, e os secundários foram clearance parcial (> 50%) e redução da EFA, do KIN e da expressão de p53 e Ki67.A unidade de análise deste estudo foi cada antebraço. Os resultados foram analisados por intenção de tratamento, e os dropouts foram imputados pelo modelo misto. As variáveis foram comparadas de acordo com o tempo e com os grupos pelo modelo (multinível) linear de efeitos mistos com matriz de covariância robusta. A análise post hoc foi realizada pelo procedimento sequencial de Sidak. Considerou‐se significativo p <0,05.Os dados demográficos dos pacientes encontram‐se na <a class="elsevierStyleCrossRef" href="#tbl0005">tabela 1</a>. Dos 36 pacientes analisados, houve três dropouts: um por óbito (não relacionado às intervenções do estudo), um por melhora das lesões e uma desistência por efeito adverso do 5FU.<elsevierMultimedia ident="tbl0005"></elsevierMultimedia>A <a class="elsevierStyleCrossRef" href="#tbl0010">tabela 2</a> apresenta os principais resultados clínicos e histopatológicos do estudo. A melhora na contagem de CA e na escala de fotoenvelhecimento foi maior com 5FU em comparação ao filtro solar, sem diferença entre os grupos quanto ao clearance total de CAs (<a class="elsevierStyleCrossRef" href="#fig0005">fig. 1</a>). Embora a nicotinamida não tenha promovido melhorias clínicas adicionais em comparação ao uso de 5FU ou filtro solar, houve redução significativa da expressão de Ki67 no grupo nicotinamida em comparação aos outros grupos. Não houve diferença entre nicotinamida e 5FU na redução da expressão de p53 ou na melhora do escore KIN. A <a class="elsevierStyleCrossRef" href="#tbl0015">tabela 3</a> apresenta os eventos adversos relatados. Apenas um participante apresentou eritema grave secundário ao 5FU, com consequente interrupção do uso.<elsevierMultimedia ident="tbl0010"></elsevierMultimedia><elsevierMultimedia ident="fig0005"></elsevierMultimedia><elsevierMultimedia ident="tbl0015"></elsevierMultimedia>Estudos prévios com 5FU tópico demonstraram maior redução na contagem de CAs nos grupos que utilizaram esquemas de uso diário, porém, com maior irritação e efeitos adversos em comparação ao uso intermitente. Em tempo, o 5FU foi o único tratamento de CCC que demonstrou redução na incidência de neoplasias malignas.<a class="elsevierStyleCrossRef" href="#bib0085">7</a> O uso intermitente, duas vezes por dia, semanalmente, levou à redução de 66% na contagem de CA após 12 semanas, mostrando que pode melhorar a aderência e a tolerabilidade, promovendo menos efeitos adversos locais.<a class="elsevierStyleCrossRef" href="#bib0090">8</a>Houve eventos adversos previsíveis e controláveis no grupo 5FU de intensidade leve ou moderada, que não causaram a descontinuação do tratamento. Apenas um paciente desenvolveu erupção generalizada após o uso local de 5FU, levando à suspensão do tratamento e destacando a significativa variabilidade individual na suscetibilidade ao 5FU, cuja toxicidade foi relatada em casos de deficiência de di‐hidropirimidina desidrogenase ou com baixos níveis de timidilato sintase.<a class="elsevierStyleCrossRef" href="#bib0095">9</a>Estudos prévios que empregaram nicotinamida oral demonstraram redução na contagem de CA em pacientes de alto risco. Neste estudo, não foi identificada melhora clínica em comparação ao placebo, tampouco efeito aditivo ao uso de 5FU. É mister, entretanto, salientar que o uso de nicotinamida no presente estudo teve a duração de 120 dias, enquanto o maior estudo prévio usou o medicamento, em média, por cerca de 12 meses.<a class="elsevierStyleCrossRef" href="#bib0075">5</a> Contudo, apesar da diferença no tempo de tratamento e do maior número de participantes (n=386), a redução na contagem de CA foi de apenas 13% após 12 meses de tratamento.<a class="elsevierStyleCrossRef" href="#bib0075">5</a>Variabilidade no fototipo, dieta pobre em vitamina B3, menor taxa de metabolismo hepático e menor idade podem estar associados a diferentes respostas clínicas à nicotinamida oral. A topografia estudada (p. ex., face, membros superiores ou couro cabeludo) e diferentes graus de CA também podem justificar a variabilidade na resposta aos tratamentos do CCC.Houve uma melhora na expressão de Ki67 para ambos os tratamentos, com diferença significativa no grupo nicotinamida. Assim, apesar de não haver resposta clínica adicional da nicotinamida aos tratamentos instituídos neste estudo, há evidências de efeito na redução da proliferação do CCC.<a class="elsevierStyleCrossRef" href="#bib0100">10</a> Regimes mais longos de nicotinamida podem levar a resultados clínicos mais robustos.O presente estudo apresenta algumas limitações: é monocêntrico, com acompanhamento limitado e apresenta participantes idosos de instituição pública, o que minimiza a generalização dos resultados. Além disso, uma posologia do 5FU tópico diferente do habitual foi utilizada, o que também pode dificultar a comparação dos resultados com outros estudos anteriores.Evidenciamos a eficácia do tratamento do CCC com 5FU tópico, em regime intermitente, por 120 dias. Nossos resultados devem estimular ensaios clínicos com 5FU tópico em regime intermitente a fim de explorar seu papel na estabilização do CCC, reduzindo a incidência de CAs e neoplasias cutâneas.Suporte financeiroNenhum.Contribuição dos autoresEliane Roio Ferreira: Concepção e planejamento do estudo; obtenção, análise e interpretação dos dados; revisão crítica da literatura; elaboração e redação do manuscrito; aprovação da versão final do manuscrito.Anna Carolina Miola: Obtenção, análise e interpretação dos dados; revisão crítica da literatura; elaboração e redação do manuscrito; revisão crítica do manuscrito; aprovação da versão final do manuscrito.Thania Rios Rossi Lima: Obtenção, análise e interpretação dos dados; revisão crítica da literatura; revisão crítica do manuscrito; aprovação da versão final do manuscrito.Juliano Vilaverde Schmitt: Concepção e planejamento do estudo; revisão crítica da literaturar; revisão crítica do manuscrito; aprovação da versão final do manuscrito.Luciana Patricia Fernandes Abbade: Concepção e planejamento do estudo; revisão crítica da literatura; revisão crítica do manuscrito; aprovação da versão final do manuscrito.Hélio Amante Miot: Concepção e planejamento do estudo; participação efetiva na orientação da pesquisa; análise estatística; revisão crítica da literatura; revisão crítica do manuscrito; aprovação da versão final do manuscrito.Conflito de interessesNenhum." "textoCompletoSecciones" => array:1 [ "secciones" => array:4 [ 0 => array:2 [ "identificador" => "sec0005" "titulo" => "Suporte financeiro" ] 1 => array:2 [ "identificador" => "sec0010" "titulo" => "Contribuição dos autores" ] 2 => array:2 [ "identificador" => "sec0015" "titulo" => "Conflito de interesses" ] 3 => array:1 [ "titulo" => "Referências" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2020-06-16" "fechaAceptado" => "2020-09-14" "NotaPie" => array:2 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "Como citar este artigo: Ferreira ER, Miola AC, Lima TRR, Schmitt JV, Abbade LPF, Miot HA. Efficacy of intermittent topical 5‐fluorouracil 5% and oral nicotinamide in the skin field cancerization: a randomized clinical trial. An Bras Dermatol. 2021;96:784–7." ] 1 => array:2 [ "etiqueta" => "☆☆" "nota" => "Trabalho realizado no Ambulatório de Dermatologia, Faculdade de Medicina, Universidade Estadual Paulista, São Paulo, SP, Brasil." ] ] "multimedia" => array:4 [ 0 => array:7 [ "identificador" => "fig0005" "etiqueta" => "Figura 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1440 "Ancho" => 2167 "Tamanyo" => 135747 ] ] "descripcion" => array:1 [ "pt" => "Contagem das ceratoses actínicas no T0 e no T120 para os grupos nicotinamida oral, placebo, 5FU e filtro solar tópicos: melhora em todos os grupos com o tempo, com superioridade ao grupo em uso de 5FU tópico." ] ] 1 => array:8 [ "identificador" => "tbl0005" "etiqueta" => "Tabela 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at1" "detalle" => "Tabela " "rol" => "short" ] ] "tabla" => array:1 [ "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Variáveis \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Valores \t\t\t\t\t\t\n \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Idade (anos), média (DP) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">71,6 (8,6) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " colspan="2" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Sexo, n (%)</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Masculino \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">14 (39) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Feminino \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">22 (61) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " colspan="2" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Fototipo de Fitzpatrick, n (%)</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">I \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">13 (36) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">II \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">21 (58) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">III \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">2 (6) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Exposição crônica ao sol, n (%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">34 (94) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Contagem de CAs, mediana (p25–p75) em cada antebraço \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">6 (5–8) \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab2750908.png" ] ] ] ] "descripcion" => array:1 [ "pt" => "Dados demográficos e clínicos dos participantes do estudo" ] ] 2 => array:8 [ "identificador" => "tbl0010" "etiqueta" => "Tabela 2" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at2" "detalle" => "Tabela " "rol" => "short" ] ] "tabla" => array:2 [ "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col"> \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " colspan="2" align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Nicotinamida</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " colspan="2" align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Placebo</th></tr><tr title="table-row"><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">5FU (n=18) \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">FPS (n=18) \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">5FU (n=18) \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">FPS (n=18) \t\t\t\t\t\t\n \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " colspan="5" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">T0</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">EFA \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">99 (90–104) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">100 (86–103) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">99 (81–99) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">97 (81–103) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Contagem de CA<a class="elsevierStyleCrossRef" href="#tblfn0020">d</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">7 (5–8) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">7 (5–9) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">6,5 (5–8) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">5 (5–7) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">p53<a class="elsevierStyleCrossRef" href="#tblfn0020">d</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">4,3 (1,2–9,5) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">10,5 (3,2–12,7) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">4,4 (2,4–5,3) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">4,8 (2,6–7,6) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Ki67<a class="elsevierStyleCrossRef" href="#tblfn0020">d</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">7,1 (4,0–8,1) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">7,75 (4,9–10,3) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">6,76 (4,5–8,5) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">5,9 (5,0–9,0) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " colspan="5" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"></td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " colspan="5" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">KIN<a class="elsevierStyleCrossRef" href="#tblfn0025">e</a></td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0 (0,0) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">2 (11,1) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0 (0,0) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">2 (11,1) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">I \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">9 (50,0) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">6 (33,3) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">7 (38,9) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">7 (38,9) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">II \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">9 (50,0) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">10 (55,6) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">11 (61,1) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">9 (50,0) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " colspan="5" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"></td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " colspan="5" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">T120</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">EFA<a class="elsevierStyleCrossRef" href="#tblfn0020">d</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">90 (74–100)<a class="elsevierStyleCrossRefs" href="#tblfn0005">a,b</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">94 (75–97)<a class="elsevierStyleCrossRef" href="#tblfn0005">a</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">78 (63–95)<a class="elsevierStyleCrossRefs" href="#tblfn0005">a,b</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">89 (74–95)<a class="elsevierStyleCrossRef" href="#tblfn0005">a</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Contagem de CA<a class="elsevierStyleCrossRef" href="#tblfn0020">d</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">2 (1–4)<a class="elsevierStyleCrossRefs" href="#tblfn0005">a,b</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">3,5 (2–7)<a class="elsevierStyleCrossRef" href="#tblfn0005">a</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1,5 (1–3)<a class="elsevierStyleCrossRefs" href="#tblfn0005">a,b</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">2 (1–6)<a class="elsevierStyleCrossRef" href="#tblfn0005">a</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">p53<a class="elsevierStyleCrossRef" href="#tblfn0020">d</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">4,7 (3,8–14,4) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">4,8 (3,8–9,6) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">6,5 (4,5–9,0) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">5,4 (3,8–8,0) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Ki67<a class="elsevierStyleCrossRef" href="#tblfn0020">d</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">4,3 (3,5–6,7)<a class="elsevierStyleCrossRefs" href="#tblfn0005">a,c</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">4,4 (3,1–7,1)<a class="elsevierStyleCrossRefs" href="#tblfn0005">a,c</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">6,7 (5,1–7,6)<a class="elsevierStyleCrossRef" href="#tblfn0005">a</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">6,5 (4,5–7,5)<a class="elsevierStyleCrossRef" href="#tblfn0005">a</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " colspan="5" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"></td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " colspan="5" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">KIN<a class="elsevierStyleCrossRef" href="#tblfn0025">e</a></td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">7 (38,9)<a class="elsevierStyleCrossRef" href="#tblfn0005">a</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">6 (33,3)<a class="elsevierStyleCrossRef" href="#tblfn0005">a</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">6 (33,3)<a class="elsevierStyleCrossRef" href="#tblfn0005">a</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">4 (22,2)<a class="elsevierStyleCrossRef" href="#tblfn0005">a</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">I \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">9 (50,0) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">7 (38,9) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">8 (44,4) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">8 (44,4) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">II \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">2 (11,1) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">5 (27,8) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">4 (22,2) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">6 (33,3) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Clearance total de CAs<a class="elsevierStyleCrossRef" href="#tblfn0025">e</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">4 (23,5) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">2 (11,8) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">4 (26,7) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">3 (20) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Clearance parcial de CAs<a class="elsevierStyleCrossRef" href="#tblfn0025">e</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">15 (83,3)<a class="elsevierStyleCrossRef" href="#tblfn0010">b</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">10 (55,5) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">13 (72,2)<a class="elsevierStyleCrossRef" href="#tblfn0010">b</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">11 (61,1) \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab2750907.png" ] ] ] "notaPie" => array:5 [ 0 => array:3 [ "identificador" => "tblfn0005" "etiqueta" => "a" "nota" => "p <0,05 (T0 vs. T120)" ] 1 => array:3 [ "identificador" => "tblfn0010" "etiqueta" => "b" "nota" => "p <0,05 (5‐FU vs. FPS)" ] 2 => array:3 [ "identificador" => "tblfn0015" "etiqueta" => "c" "nota" => "p <0,05 (nicotinamida vs. placebo)" ] 3 => array:3 [ "identificador" => "tblfn0020" "etiqueta" => "d" "nota" => "mediana (p25–p75)" ] 4 => array:3 [ "identificador" => "tblfn0025" "etiqueta" => "e" "nota" => "n (%)." ] ] ] "descripcion" => array:1 [ "pt" => "Principais desfechos clínicos e histopatológicos" ] ] 3 => array:8 [ "identificador" => "tbl0015" "etiqueta" => "Tabela 3" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at3" "detalle" => "Tabela " "rol" => "short" ] ] "tabla" => array:1 [ "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Nicotinamida (n=18 pacientes) \t\t\t\t\t\t\n \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Náuseas \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1 (5%) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Epigastralgia \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1 (5%) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Vômitos \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0 (‐) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Cefaleia \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0 (‐) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Rubor cutâneo \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0 (‐) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">5‐FU (n=36 antebraços) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Eritema \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">18 (50%) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Dor \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">3 (8%) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Edema \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1 (2%) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Ulcerações \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1 (2%) \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab2750909.png" ] ] ] ] "descripcion" => array:1 [ "pt" => "Eventos adversos após 15 dias de tratamento" ] ] ] "bibliografia" => array:2 [ "titulo" => "Referências" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0015" "bibliografiaReferencia" => array:10 [ 0 => array:3 [ "identificador" => "bib0055" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Profile of dermatological consultations in Brazil (2018)" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "H.A. Miot" 1 => "G.O. Penna" 2 => "A.M.C. Ramos" 3 => "M.L.F. Penna" 4 => "S.M. Schmidt" 5 => "F.B. Luz" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1590/abd1806-4841.20188802" "Revista" => array:6 [ "tituloSerie" => "An Bras Dermatol." "fecha" => "2018" "volumen" => "93" "paginaInicial" => "916" "paginaFinal" => "928" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/30484547" "web" => "Medline" ] ] ] ] ] ] ] ] 1 => array:3 [ "identificador" => "bib0060" "etiqueta" => "2" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Actinic keratoses: review of clinical, dermoscopic and therapeutic aspects" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "C.P.H. Reinehr" 1 => "R.M. Bakos" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.abd.2019.10.004" "Revista" => array:6 [ "tituloSerie" => "An Bras Dermatol." 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Avaliação da eficácia do 5‐fluorouracil 5% tópico intermitente e da nicotinamida oral no tratamento do campo de cancerização cutâneo: um ensaio clínico randomizado

Eliane Roio Ferreira, Anna Carolina Miola

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anna.c.miola@unesp.br

Autor para correspondência.

, Thania Rios Rossi Lima, Juliano Vilaverde Schmitt, Luciana Patricia Fernandes Abbade, Hélio Amante Miot

Departamento de Dermatologia, Faculdade de Medicina, Universidade Estadual Paulista, São Paulo, SP, Brasil

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em atividade&#46;<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">3</span></a> Recentemente&#44; estrat&#233;gias de estabiliza&#231;&#227;o do CCC s&#227;o estudadas&#44; com o objetivo de prevenir a incid&#234;ncia de tumores cut&#226;neos&#44; sua recorr&#234;ncia ou a evolu&#231;&#227;o de les&#245;es j&#225; existentes&#46;</p><p id="par0015" class="elsevierStylePara elsevierViewall">O 5&#8208;fluorouracil &#40;5FU&#41; &#233; um quimioter&#225;pico t&#243;pico de excelente resposta terap&#234;utica&#44; com redu&#231;&#227;o de at&#233;&#160;80&#37; da contagem de CAs e estabiliza&#231;&#227;o do CCC&#46; Entretanto&#44; os efeitos colaterais decorrentes do uso di&#225;rio podem levar a m&#225; ades&#227;o e preju&#237;zo no resultado&#46;<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">4</span></a> Apesar da descri&#231;&#227;o de in&#250;meros regimes terap&#234;uticos&#44; seu uso para a estabiliza&#231;&#227;o do CCC sob forma intermitente ainda n&#227;o foi testado adequadamente&#46;</p><p id="par0020" class="elsevierStylePara elsevierViewall">A nicotinamida &#233; uma vitamina do complexo B que atua no reparo do DNA&#44; reduzindo os efeitos da imunossupress&#227;o cut&#226;nea causados pela radia&#231;&#227;o ultravioleta &#40;RUV&#41;&#44; modulando a produ&#231;&#227;o de citocinas inflamat&#243;rias e restaurando os n&#237;veis de energia celular p&#243;s&#8208;exposi&#231;&#227;o &#224; RUV&#46; Ademais&#44; a nicotinamida oral parece apresentar efeito fotoprotetor em humanos&#44; reduzindo a contagem de CAs e a incid&#234;ncia de neoplasias cut&#226;neas em pacientes de alto risco&#46;<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">5</span></a></p><p id="par0025" class="elsevierStylePara elsevierViewall">Conduziu&#8208;se um ensaio cl&#237;nico aberto&#44; randomizado&#44; comparativo&#44; fatorial&#44; autocontrolado&#44; duplo cego &#40;para nicotinamida&#41; no qual&#160;36&#160;pacientes&#44; cujos antebra&#231;os apresentavam de tr&#234;s a dez CAs cada&#44; foram randomizados em dois grupos&#46; Um grupo recebeu nicotinamida oral 500<span class="elsevierStyleHsp" style=""></span>mg a cada 12 horas durante 120 dias&#44; 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sem diferen&#231;a entre os grupos quanto ao <span class="elsevierStyleItalic">clearance</span> total de CAs &#40;<a class="elsevierStyleCrossRef" href="#fig0005">fig&#46; 1</a>&#41;&#46; Embora a nicotinamida n&#227;o tenha promovido melhorias cl&#237;nicas adicionais em compara&#231;&#227;o ao uso de 5FU ou filtro solar&#44; houve redu&#231;&#227;o significativa da express&#227;o de Ki67 no grupo nicotinamida em compara&#231;&#227;o aos outros grupos&#46; N&#227;o houve diferen&#231;a entre nicotinamida e 5FU na redu&#231;&#227;o da express&#227;o de p53 ou na melhora do escore KIN&#46; A <a class="elsevierStyleCrossRef" href="#tbl0015">tabela 3</a> apresenta os eventos adversos relatados&#46; Apenas um participante apresentou eritema grave secund&#225;rio ao 5FU&#44; com consequente interrup&#231;&#227;o do uso&#46;</p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia><elsevierMultimedia ident="fig0005"></elsevierMultimedia><elsevierMultimedia ident="tbl0015"></elsevierMultimedia><p id="par0050" class="elsevierStylePara elsevierViewall">Estudos pr&#233;vios com 5FU t&#243;pico demonstraram maior redu&#231;&#227;o na contagem de CAs nos grupos que utilizaram esquemas de uso di&#225;rio&#44; por&#233;m&#44; com maior irrita&#231;&#227;o e efeitos adversos em compara&#231;&#227;o ao uso intermitente&#46; Em tempo&#44; o 5FU foi o &#250;nico tratamento de CCC que demonstrou redu&#231;&#227;o na incid&#234;ncia de neoplasias malignas&#46;<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">7</span></a> O uso intermitente&#44; duas vezes por dia&#44; semanalmente&#44; levou &#224; redu&#231;&#227;o de&#160;66&#37; na contagem de CA ap&#243;s&#160;12&#160;semanas&#44; mostrando que pode melhorar a ader&#234;ncia e a tolerabilidade&#44; promovendo menos efeitos adversos locais&#46;<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">8</span></a></p><p id="par0055" class="elsevierStylePara elsevierViewall">Houve eventos adversos previs&#237;veis e control&#225;veis no grupo 5FU de intensidade leve ou moderada&#44; que n&#227;o causaram a descontinua&#231;&#227;o do tratamento&#46; Apenas um paciente desenvolveu erup&#231;&#227;o generalizada ap&#243;s o uso local de 5FU&#44; levando &#224; suspens&#227;o do tratamento e destacando a significativa variabilidade individual na suscetibilidade ao 5FU&#44; cuja toxicidade foi relatada em casos de defici&#234;ncia de di&#8208;hidropirimidina desidrogenase ou com baixos n&#237;veis de timidilato sintase&#46;<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">9</span></a></p><p id="par0060" class="elsevierStylePara elsevierViewall">Estudos pr&#233;vios que empregaram nicotinamida oral demonstraram redu&#231;&#227;o na contagem de CA em pacientes de alto risco&#46; Neste estudo&#44; n&#227;o foi identificada melhora cl&#237;nica em compara&#231;&#227;o ao placebo&#44; tampouco efeito aditivo ao uso de 5FU&#46; &#201; mister&#44; entretanto&#44; salientar que o uso de nicotinamida no presente estudo teve a dura&#231;&#227;o de 120 dias&#44; enquanto o maior estudo pr&#233;vio usou o medicamento&#44; em m&#233;dia&#44; por cerca de 12 meses&#46;<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">5</span></a> Contudo&#44; apesar da diferen&#231;a no tempo de tratamento e do maior n&#250;mero de participantes &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>386&#41;&#44; a redu&#231;&#227;o na contagem de CA foi de apenas&#160;13&#37; ap&#243;s&#160;12&#160;meses de tratamento&#46;<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">5</span></a></p><p id="par0065" class="elsevierStylePara elsevierViewall">Variabilidade no fototipo&#44; dieta pobre em vitamina&#160;B<span class="elsevierStyleInf">3</span>&#44; menor taxa de metabolismo hep&#225;tico e menor idade podem estar associados a diferentes respostas cl&#237;nicas &#224; nicotinamida oral&#46; A topografia estudada &#40;p&#46; ex&#46;&#44; face&#44; membros superiores ou couro cabeludo&#41; e diferentes graus de CA tamb&#233;m podem justificar a variabilidade na resposta aos tratamentos do CCC&#46;</p><p id="par0070" class="elsevierStylePara elsevierViewall">Houve uma melhora na express&#227;o de Ki67 para ambos os tratamentos&#44; com diferen&#231;a significativa no grupo nicotinamida&#46; Assim&#44; apesar de n&#227;o haver resposta cl&#237;nica adicional da nicotinamida aos tratamentos institu&#237;dos neste estudo&#44; h&#225; evid&#234;ncias de efeito na redu&#231;&#227;o da prolifera&#231;&#227;o do CCC&#46;<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">10</span></a> Regimes mais longos de nicotinamida podem levar a resultados cl&#237;nicos mais robustos&#46;</p><p id="par0075" class="elsevierStylePara elsevierViewall">O presente estudo apresenta algumas limita&#231;&#245;es&#58; &#233; monoc&#234;ntrico&#44; com acompanhamento limitado e apresenta participantes idosos de institui&#231;&#227;o p&#250;blica&#44; o que minimiza a generaliza&#231;&#227;o dos resultados&#46; Al&#233;m disso&#44; uma posologia do 5FU t&#243;pico diferente do habitual foi utilizada&#44; o que tamb&#233;m pode dificultar a compara&#231;&#227;o dos resultados com outros estudos anteriores&#46;</p><p id="par0080" class="elsevierStylePara elsevierViewall">Evidenciamos a efic&#225;cia do tratamento do CCC com 5FU t&#243;pico&#44; em regime intermitente&#44; por&#160;120 dias&#46; Nossos resultados devem estimular ensaios cl&#237;nicos com 5FU t&#243;pico em regime intermitente a fim de explorar seu papel na estabiliza&#231;&#227;o do CCC&#44; reduzindo a incid&#234;ncia de CAs e neoplasias cut&#226;neas&#46;</p><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0005">Suporte financeiro</span><p id="par0085" class="elsevierStylePara elsevierViewall">Nenhum&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Contribui&#231;&#227;o dos autores</span><p id="par0090" class="elsevierStylePara elsevierViewall">Eliane Roio Ferreira&#58; Concep&#231;&#227;o e planejamento do estudo&#59; obten&#231;&#227;o&#44; an&#225;lise e interpreta&#231;&#227;o dos dados&#59; revis&#227;o cr&#237;tica da literatura&#59; elabora&#231;&#227;o e reda&#231;&#227;o do manuscrito&#59; aprova&#231;&#227;o da vers&#227;o final do manuscrito&#46;</p><p id="par0095" class="elsevierStylePara elsevierViewall">Anna Carolina Miola&#58; Obten&#231;&#227;o&#44; an&#225;lise e interpreta&#231;&#227;o dos dados&#59; revis&#227;o cr&#237;tica da literatura&#59; elabora&#231;&#227;o e reda&#231;&#227;o do manuscrito&#59; revis&#227;o cr&#237;tica do manuscrito&#59; aprova&#231;&#227;o da vers&#227;o final do manuscrito&#46;</p><p id="par0100" class="elsevierStylePara elsevierViewall">Thania Rios Rossi Lima&#58; Obten&#231;&#227;o&#44; an&#225;lise e interpreta&#231;&#227;o dos dados&#59; revis&#227;o cr&#237;tica da literatura&#59; revis&#227;o cr&#237;tica do manuscrito&#59; aprova&#231;&#227;o da vers&#227;o final do manuscrito&#46;</p><p id="par0105" class="elsevierStylePara elsevierViewall">Juliano Vilaverde Schmitt&#58; Concep&#231;&#227;o e planejamento do estudo&#59; revis&#227;o cr&#237;tica da literaturar&#59; revis&#227;o cr&#237;tica do manuscrito&#59; aprova&#231;&#227;o da vers&#227;o final do manuscrito&#46;</p><p id="par0110" class="elsevierStylePara elsevierViewall">Luciana Patricia Fernandes Abbade&#58; Concep&#231;&#227;o e planejamento do estudo&#59; revis&#227;o cr&#237;tica da literatura&#59; revis&#227;o cr&#237;tica do manuscrito&#59; aprova&#231;&#227;o da vers&#227;o final do manuscrito&#46;</p><p id="par0115" class="elsevierStylePara elsevierViewall">H&#233;lio Amante Miot&#58; Concep&#231;&#227;o e planejamento do estudo&#59; participa&#231;&#227;o efetiva na orienta&#231;&#227;o da pesquisa&#59; an&#225;lise estat&#237;stica&#59; revis&#227;o cr&#237;tica da literatura&#59; revis&#227;o cr&#237;tica do manuscrito&#59; aprova&#231;&#227;o da vers&#227;o final do manuscrito&#46;</p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Conflito de interesses</span><p id="par0120" class="elsevierStylePara elsevierViewall">Nenhum&#46;</p></span></span>"
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        "nota" => "<p class="elsevierStyleNotepara" id="npar0030">Como citar este artigo&#58; Ferreira ER&#44; Miola AC&#44; Lima TRR&#44; Schmitt JV&#44; Abbade LPF&#44; Miot HA&#46; Efficacy of intermittent topical 5&#8208;fluorouracil 5&#37; and oral nicotinamide in the skin field cancerization&#58; a randomized clinical trial&#46; An Bras Dermatol&#46; 2021&#59;96&#58;784&#8211;7&#46;</p>"
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        "nota" => "<p class="elsevierStyleNotepara" id="npar0035">Trabalho realizado no Ambulat&#243;rio de Dermatologia&#44; Faculdade de Medicina&#44; Universidade Estadual Paulista&#44; S&#227;o Paulo&#44; SP&#44; Brasil&#46;</p>"
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                  \t\t\t\t">99 &#40;90&#8211;104&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">100 &#40;86&#8211;103&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">99 &#40;81&#8211;99&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">97 &#40;81&#8211;103&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Contagem de CA<a class="elsevierStyleCrossRef" href="#tblfn0020"><span class="elsevierStyleSup">d</span></a>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>p53<a class="elsevierStyleCrossRef" href="#tblfn0020"><span class="elsevierStyleSup">d</span></a>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Ki67<a class="elsevierStyleCrossRef" href="#tblfn0020"><span class="elsevierStyleSup">d</span></a>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">5&#44;9 &#40;5&#44;0&#8211;9&#44;0&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " colspan="5" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">KIN</span><a class="elsevierStyleCrossRef" href="#tblfn0025"><span class="elsevierStyleSup">e</span></a></td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>0&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">90 &#40;74&#8211;100&#41;<a class="elsevierStyleCrossRefs" href="#tblfn0005"><span class="elsevierStyleSup">a&#44;b</span></a>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">94 &#40;75&#8211;97&#41;<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></a>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
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                      "titulo" => "Profile of dermatological consultations in Brazil &#40;2018&#41;"
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                            0 => "H&#46;A&#46; Miot"
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                            3 => "M&#46;L&#46;F&#46; Penna"
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                        "tituloSerie" => "An Bras Dermatol&#46;"
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                    0 => array:2 [
                      "titulo" => "Actinic keratoses&#58; review of clinical&#44; dermoscopic and therapeutic aspects"
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                          "etal" => false
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                      "doi" => "10.1016/j.abd.2019.10.004"
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Article information

ISSN: 26662752
Original language: Portuguese

DOI:10.1016/j.abdp.2021.09.012

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Year/Month	Html	Pdf	Total

2024 November	96	4	100
2024 October	1432	87	1519
2024 September	1184	95	1279
2024 August	968	136	1104
2024 July	1775	123	1898
2024 June	1158	76	1234
2024 May	788	82	870
2024 April	713	90	803
2024 March	789	87	876
2024 February	632	91	723
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2023 December	640	64	704
2023 November	583	100	683
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2023 September	724	75	799
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2023 July	673	50	723
2023 June	442	59	501
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2023 April	247	34	281
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2023 February	149	39	188
2023 January	104	40	144
2022 December	106	35	141
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2022 September	129	89	218
2022 August	108	59	167
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2022 April	77	71	148
2022 March	76	96	172
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