8554 Background: Surgery is standard of care for patients with stage I non-small cell lung cancer (NSCLC). However, 5-year mortality can reach up to 30%. For patients with contraindication to surgery, treatment with stereotactic ablative radiotherapy (SABR) leads to adequate local tumor control, but has a high rate of regional and distant failure. SABR as neoadjuvant therapy for stage I NSCLC produced a pathologic complete response (pCR) rate of only 60% when surgery was performed after 10 weeks of treatment, demanding improvement in the management of both operable and inoperable early-stage NSCLC. Immune checkpoint inhibitors (ICI) are routinely used in stages III-IV NSCLC, with recent approvals in the peri-operative setting, and may be synergistic with radiotherapy. We hypothesized that neoadjuvant nivolumab plus SABR may improve pCR rate and provide insight to its changes in the tumor microenvironment. Methods: This is a phase 2, single arm, open label study evaluating neoadjuvant treatment for patients with NSCLC of up to 4 cm, with no lymph node involvement (AJCC 8th edition: up to cT2aN0), and adequate surgical conditions. Treatment consisted of nivolumab 360 mg every 3 weeks for 3 doses or unacceptable toxicity. SABR started on D1 of nivolumab, with a duration of 2 to 3 weeks, depending on the lesion size and location (3 x 18 Gy; or 5 x 10 Gy; or 8 x 7.5 Gy). Standard-of-care surgery was performed at 10 (+- 2) weeks after the last radiotherapy dose. The primary endpoint of the study is pCR rate at surgery. Tissue, blood, and stool samples were collected during treatment. Results: We included 25 patients. All but one were cared for in the Brazilian public system. Mean age was 68 years. Mean tumor size was 2.45 cm. Only 3 patients were never-smokers. Surgery was performed as scheduled in all but one patient. pCR rate was 80% (19/24) and MPR rate was 83% (20/24) of patients who underwent surgery. Twenty-nine treatment-emergent adverse events occurred in 13 patients (23 grade 1-2 events, two grade 3 and two grade 5 events, being only one grade 3 diarrhea related to experimental treatment). The single patient who was not operated died during study treatment from relapsed acute alcoholic hepatitis. The other grade 5 event was due to a respiratory infection, both unrelated to treatment. Two patients died from surgical complications 185 and 72 days after surgery, respectively (one with pulmonary artery lesion with subsequent clinical complications and other with thromboembolic events), deemed unrelated to experimental treatment. During follow-up, two additional patients died due to comorbidities, and none relapsed to date. Conclusions: In this trial with patients with significant comorbidities and smoking history from the public system in Brazil, we demonstrated a pCR rate of 80% with SABR + nivolumab. Further studies are warranted to evaluate this strategy versus surgery in operable patients with stage I disease. Clinical trial information: NCT04271384 .
AGRADECIMENTOSPrimeiramente à Deus pela vida, por sempre me abençoar e dar capacidade, força e disposição para superar todos os obstáculos e conseguir alcançar meus objetivos! Ao meu pai Oswaldo Gomes Sobrinho que sempre estará presente em minha memória sendo meu maior exemplo de dignidade, responsabilidade e coragem. Seus conselhos e broncas foram essenciais para minha formação pessoal.A minha mãe Edna Luiza Gomes, pelo amor, cuidado, carinho e por sempre estar ao meu lado dando todo apoio necessário.A todos meus familiares, irmão e irmãs que sempre me apoiaram a todo momento, especialmente a minha irmã Kerley Gomes da Silva que sempre acreditou no meu potencial, me incentivou, e por ter proporcionado todo suporte que precisei durante esses anos. Ao meu orientador Prof. Dr. Alam Gustavo Trovó pelo apoio e confiança, amizade, dedicação, e principalmente por tudo que me ensinou durante todos esses anos de convivência e por viabilizar o desenvolvimento deste trabalho. A todos os meus amigos integrantes de grupo: Bárbara, Arlene, Valdislaine, Nayara, Vinícius, Jader, Ivo, Cleiseano, Eduardo e Maria Gabriela pelas sugestões, ajuda, amizade, atenção e por tornar esse período mais agradável e proveitoso possível. Aos Profs. Dr. Waldomiro Borges Neto e Dr. Antonio Eduardo da Hora Machado pela parceria e disponibilidade em auxiliar no que necessário. A pesquisadora Dra. Daniela Daniel pela parceria e colaboração nas análises de HPLC-ESI-Q-TOF-MS. Aos professores e membros da banca de qualificação Dr. Sérgio Antônio Lemos de Morais e Dr. Sebastião de Paula Eiras pelas contribuições realizadas no trabalho. À CAPES, pela bolsa concedida, e à FAPEMIG e CNPq pelo suporte financeiro. Aos docentes e funcionários do Instituto de Química que muito contribuíram para minha formação acadêmica, e ao Laboratório Multiusuário do Instituto de Química da Universidade Federal de Uberlândia por fornecer acesso e uso do equipamento HPLC-DAD. A todos aqueles que contribuíram direta ou indiretamente para a concretização desta pesquisa, meus mais sinceros agradecimentos! PDs identificados têm baixa toxicidade em relação a bactéria Vibrio fischeri, sugerindo que a fotocatálise heterogênea pode ser uma boa alternativa para o tratamento de águas residuais contendo FIP e seus PDs, principalmente quando radiação solar é utilizada como fonte de radiação, uma vez que sob esta condição o consumo de energia durante o tratamento pode ser significativamente reduzido.Palavras chave: fotocatálise heterogênea, dióxido de titânio, Vibrio fischeri, pesticidas, metodologia da superfície de resposta, DFT, radiação solar. ABSTRACTIn this work it was evaluated the degradation of the insecticide fipronil (FIP) by heterogeneous photocatalysis induced by TiO 2 -P25. Using chemometric methods (Fatorial Design and Response Surface methodology), it was possible to evaluate the role of interaction between pH of the reaction medium, the reaction time and concentration of TiO 2 , optimizing the conditions for degradation of FIP using artificial radiation. At optimized con...
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