Immune-checkpoint gene expression and BCG response in non-muscle invasive bladder cancer.

METHODS: One-hundred-six patients diagnosed with non-muscle invasive bladder cancer and treated with intravesical BCG were included and divided into two groups, BCG-responsive (n = 47) and -unresponsive (n = 59). Immunohistochemistry was used to evaluate PD-L1 expression and MSI was assessed by a commercial multiplex PCR kit. The mRNA expression profile of 15 immune checkpoints was performed using the nCounter technology. For in silico validation, two distinct cohorts sourced from the Gene Expression Omnibus (GEO) database were used. RESULTS: Among the 106 patients, only one (<1 %) exhibited MSI instability. PD-L1 expression was present in 9.4 % of cases, and no association was found with BCG-responsive status. We found low gene expression of canonic actionable immune checkpoints PDCD1 (PD-1), CD274 (PD-L1), and CTLA4, while high expression was observed for CD276 (B7-H3), CD47, TNFRSF14, IDO1 and PVR (CD155) genes. High IDO1 expression levels was associated with worst overall survival. The PDCD1, CTLA4 and TNFRSF14 expression levels were associated with BCG responsiveness, whereas TIGIT and CD276 were associated with unresponsiveness. Finally, CD276 was validated in silico cohorts. CONCLUSION: In NMIBC, MSI is rare and PD-L1 expression is present in a small subset of cases. Expression levels of PDCD1, CTLA4, TNFRSF14, TIGIT and CD276 could constitute predictive biomarkers of BCG responsiveness.

PD-L1 expression and microsatellite instability (MSI) in cancer of unknown primary site.

BACKGROUND: Cancer of unknown primary site (CUP) is a heterogeneous group of tumors for which the origin remains unknown. Clinical outcomes might be influenced by regulatory processes in its microenvironment. Microsatellite instability (MSI) is a predictive biomarker for cancer immunotherapy and its status, as well as co-occurrence with PD-L1 expression, is poorly evaluated. We aim to evaluate the expression of PD-L1 and the status of MSI in CUP and their possible associations with clinical-pathological features. METHODS: The combined positive score (CPS) PD-L1 expression was evaluated by immunohistochemistry. MSI status was assessed using a hexa-plex marker panel by polymerase chain reaction followed by fragment analysis. RESULTS: Among the 166 cases, MSI analysis was conclusive in 120, with two cases being MSI positive (1.6%). PD-L1 expression was positive in 18.3% of 109 feasible cases. PD-L1 expression was significantly associated with non-visceral metastasis and a dominance of nodal metastasis. The median overall survival (mOS) was 3.7 (95% CI 1.6-5.8) months and patients who expressed PD-L1 achieved a better mOS compared to those who did not express PD-L1 (18.7 versus 3.0 months, p-value: < .001). ECOG-PS equal to or more than two and PD-L1 expression were independent prognostic factors in multivariate analysis (2.37 and 0.42, respectively). CONCLUSION: PD-L1 is expressed in a subset (1/5) of patients with CUP and associated with improved overall survival, while MSI is a rare event. There is a need to explore better the tumor microenvironment as well as the role of immunotherapy to change such a bad clinical outcome.

Catabolismo muscular nos pacientes com infarto agudo do moicárdio / Muscular catabolism in patients with acute myocardial infarction

Introdução: O trauma e a sepse apresentam demanda metabólica aumentada devido à tríplice liberação hormonal com consequente aumento do catabolismo muscular. O infarto agudo do miocárdio(IAM) também pode ser considerado um trauma por apresentar as alterações hormonais características da fase aguda do estresse.Objetivo: Avaliar o grau de catabolismo muscular, quantificado pela excreção urinária de nitrogênio uréico em urina de 24 horas, nos pacientes admitidos com IAM.Métodos: Analisados prospectivamente 22 pacientes internados com IAM, sendo 12 de parede inferior e 10 de anterior, caracterizados elétrica e bioquimicamente com injúria e necrose transmural. A área do infarto foi diagnosticada pelo eletrocardiograma e confirmada pelas alterações no ecocardiograma. Foram excluídos os pacientes com insuficiência renal, IAM não transmural(ausência da onda Q evolutiva) e aqueles com mais de 48 horas de IAM. A coleta de urina de 24 horas foi realizada no 1º, 3º e 5º dias de internação para a quantificação da uréia excretada. O nitrogênio urinário foi calculado a partir da uréia, considerando-se um percentual nitrogendo de 46.66 por cento na molécula uréica. A avaliação estatística foi realizada pela análise de variância two way e pelo teste de Tukey, com nível de significância de 5 po cento.Resultados: O IAM, tanto anterior como inferior, apresenta catabolismo muscular evolutivo(terceiro dia) caracterizado como moderado(N2Dia3/Dia1, p igual 0,001). O catabolismo muscular foi idêntico mo IAM anterior e inferior (p igual 0,49). O catabolismo muscular é revertido no quinto dia.Conclusão: Os pacientes com IAM apresentaram um aumento reversível do catabolismo muscular