Prognostic value of programmed cell death ligand 1 (PD-L1) expression in patients with stage III non-small cell lung cancer under different treatment types: a retrospective study

ABSTRACT Objective Currently programmed cell death protein 1 (PD-1) inhibitors in combination with other therapies are being evaluated to determine their efficacy in cancer treatment. However, the effect of PD-ligand (L) 1 expression on disease outcomes in stage III (EC III) non-small cell lung cancer is not completely understood. Therefore, this study aimed to assess the influence of PD-L1 expression on the outcomes of EC III non-small cell lung cancer. Methods This study was conducted on patients diagnosed with EC III non-small cell lung cancer who underwent treatment at a tertiary care hospital. PD-L1 expression was determined using immunohistochemical staining, all patients expressed PD-L1. Survival was estimated using the Kaplan-Meier method. Relationships between variables were assessed using Cox proportional regression models. Results A total of 49 patients (median age=69 years) with EC III non-small cell lung cancer and PD-L1 expression were evaluated. More than half of the patients were men, and most were regular smokers. The patients were treated with neoadjuvant chemotherapy, surgery, or sequential or combined chemotherapy and radiotherapy. The median progression-free survival of the entire cohort was 14.2 months, and the median overall survival was 20 months. There was no significant association between PD-L1 expression and disease progression, clinical characteristics, or overall survival. Conclusions PD-L1 expression was not correlated with EC III non-small cell lung cancer outcomes. Whether these findings differ from the association with immune checkpoint inhibitors remains to be addressed in future studies.

Sepse no pós-operatório de cirurgia cardíaca: descrição do problema / Sepsis in the postoperative period of cardiac surgery: problem description

FUNDAMENTOS: A despeito do avanço no diagnóstico e na terapêutica da sepse nos últimos anos, a morbidade e mortalidade são elevadas. OBJETIVO: Avaliar a prevalência, a evolução hospitalar e o prognóstico de pacientes que apresentaram sepse no pós- operatório de cirurgia cardíaca. MÉTODOS: Trata-se de um registro prospectivo que incluiu pacientes (n = 7.332) submetidos à cirurgia cardíaca (valvar ou coronariana) entre janeiro de 1995 e dezembro de 2007. Utilizamos os critérios clássicos de diagnóstico de sepse para identificar os pacientes que evoluíram com tal enfermidade e avaliamos as comorbidades pré-operatórias, a evolução hospitalar e o prognóstico. RESULTADOS: A sepse ocorreu em 29 pacientes (prevalência = 0,39 por cento). O sexo masculino predominou sobre o feminino (79 por cento vs. 21 por cento). A idade média foi de 69 ± 6,5 anos. As principais comorbidades pré-operatórias eram: hipertensão arterial sistêmica (79 por cento), dislipidemia (48 por cento) e antecedente familiar de doença arterial coronariana (38 por cento). O índice Apache médio foi de 18 ± 7, enquanto o Sofa indicou 14,2 ± 3,8. O foco infeccioso primário foi pulmonar em 19 pacientes (55 por cento). Houve 19 culturas positivas, e a média de hidratação endovenosa nas primeiras 24 horas foi de 1.016 ± 803 ml. As principais complicações foram: insuficiência renal aguda (65 por cento), síndrome de baixo débito cardíaco (55 por cento) e arritmia ventricular maligna (55 por cento). A mortalidade foi de 79 por cento (23 pacientes). CONCLUSÃO: A sepse após cirurgia cardíaca foi um evento raro, porém com desfechos clínicos catastróficos. O índice elevado de morbidade e mortalidade revelou a necessidade de um aprimoramento no tratamento, visando melhorar a evolução clínica dos pacientes.

BACKGROUND: In spite of the advances in sepsis diagnosis and treatment in the last years, the morbidity and mortality are still high. OBJECTIVE: To assess the prevalence, in-hospital evolution and prognosis of patients that presented sepsis in the postoperative period of cardiac surgery. METHODS: This is a prospective study that included patients (n = 7,332) submitted to cardiac surgery (valvular or coronary) between January 1995 and December 2007. The classic criteria of sepsis diagnosis were used to identify the patients that developed such condition and the preoperative comorbidities, in-hospital evolution and prognosis were evaluated. RESULTS: Sepsis occurred in 29 patients (prevalence = 0.39 percent). There was a predominance of the male when compared to the female sex (79 percent vs. 21 percent). Mean age was 69 ± 6.5 years. The main preoperative comorbidities were: systemic arterial hypertension (79 percent), dyslipidemia (48 percent) and family history of coronary artery disease (38 percent). The mean Apache score was 18 ± 7, whereas the Sofa score was 14.2 ± 3.8. The primary infectious focus was pulmonary in 19 patients (55 percent). There were 19 positive cultures and the mean IV hydration during the first 24 hours was 1,016 ± 803 ml. The main complications were acute renal failure (65 percent), low cardiac output syndrome (55 percent) and malignant ventricular arrhythmia (55 percent). Mortality was 79 percent (23 patients). CONCLUSION: The occurrence of sepsis after cardiac surgery was a rare event; however, its occurrence showed catastrophic clinical outcomes. The high morbidity and mortality showed the need to improve treatment, aiming at patients' better clinical evolution.

Mutação em NRAS causa uma síndrome autoimune linfoproliferativa humana / NRAS mutation causes a human autoimmune lymphoproliferative syndrome

A subfamília p21 RAS de pequenas GTPases, incluindo KRAS, HRAS e NRAS, participa de muitas redes de sinalização, incluindo proliferação celular, organização do citoesqueleto e apoptose, e é o alvo mais freqüente de mutações ativadoras em câncer. Mutações germinativas em KRAS e HRAS causam graves anormalidades desenvolvimentais levando às síndromes de Noonan, cárdio-facial-cutânea e Costello, porem mutações ativadoras germinativas em NRAS não foram descritas até hoje. A síndrome autoimune linfoproliferativa (ALPS) é o mais comum defeito genético de apoptose linfocitária, cursando com autoimunidade e acúmulo excessivo de linfócitos, particularmente do tipo T + CD4- CD8-. As mutações causadoras de ALPS descritas até hoje afetam a apoptose mediada por Fas, uma das vias extrínsecas de apoptose. Nós demonstramos aqui que os principais achados clínicos de ALPS, bem como uma predisposição para tumores hematológicos, podem ser causados por uma mutação heterozigota ativadora G13D no oncogene NRAS, sem causar prejuízo na apoptose mediada por Fas. O aumento na quantidade intracelular de NRAS ativo, ligado a GTP, induziu a um aumento da sinalização na via RAF/MEK/ERK, o que suprimiu a expressão da proteína pró-apoptótica BIM, e atenuou a apoptose intrínseca mitocondrial. Desta forma, uma mutação germinativa ativadora em NRAS causou um fenótipo clinico diferente do visto em pacientes com mutações em outros membros da família p21 RAS, cursando com um defeito imunológico seletivo, sem distúrbios generalizados do desenvolvimento.

The p21 RAS subfamily of small GTPases, including KRAS, HRAS, and NRAS, regulates cell proliferation, cytoskeletal organization and other signaling networks, and is the most frequent target of activating mutations in cancer. Activating germline mutations of KRAS and HRAS cause severe developmental abnormalities leading to Noonan, cardio-facial-cutaneous and Costello syndrome, but activating germline mutations of NRAS have not been reported. Autoimmune lymphoproliferative syndrome (ALPS) is the most common genetic disease of lymphocyte apoptosis and causes autoimmunity as well as excessive lymphocyte accumulation, particularly of CD4-, CD8- ab T cells. Mutations in ALPS typically affect Fas-mediated apoptosis, but certain ALPS individuals have no such mutations. We show here that the salient features of ALPS as well as a predisposition to hematological malignancies can be caused by a heterozygous germline Gly13Asp activating mutation of the NRAS oncogene that does not impair Fas-mediated apoptosis. The increase in active, GTP-bound NRAS augmented RAF/MEK/ERK signaling which markedly decreased the pro-apoptotic protein BIM and attenuated intrinsic, nonreceptor-mediated mitochondrial apoptosis. Thus, germline activating mutations in NRAS differ from other p21 Ras oncoproteins by causing selective immune abnormalities without general developmental defects.