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.

Age-dependent impairment in antibody responses elicited by a homologous CoronaVac booster dose.

The emergence of the SARS-CoV-2 Omicron sublineages resulted in increased transmission rates and reduced protection from vaccines. To counteract these effects, multiple booster strategies were used in different countries, although data comparing their efficiency in improving protective immunity remain sparse, especially among vulnerable populations, including older adults. The inactivated CoronaVac vaccine was among the most widely distributed vaccine worldwide and was essential in the early control of SARS-CoV-2-related hospitalizations and deaths. However, it is not well understood whether homologous versus heterologous booster doses in those fully vaccinated with CoronaVac induce distinct humoral responses or whether these responses vary across age groups. We analyzed plasma antibody responses from CoronaVac-vaccinated younger or older individuals who received a homologous CoronaVac or heterologous BNT162b2 or ChAdOx1 booster vaccine. All three evaluated boosters resulted in increased virus-specific IgG titers 28 days after the booster dose. However, we found that both IgG titers against SARS-CoV-2 Spike or RBD and neutralization titers against Omicron sublineages were substantially reduced in participants who received homologous CoronaVac compared with the heterologous BNT162b2 or ChAdOx1 booster. This effect was specifically prominent in recipients >50 years of age. In this group, the CoronaVac booster induced low virus-specific IgG titers and failed to elevate neutralization titers against any Omicron sublineage. Our results point to the notable inefficiency of CoronaVac immunization and boosting in mounting protective antiviral humoral immunity, particularly among older adults, during the Omicron wave. These observations also point to benefits of heterologous regimens in high-risk populations fully vaccinated with CoronaVac.

Expressão do receptor tirosina quinase AXL em pacientes com carcinoma de células renais metastáticos tratados com sunitinibe e sua associação com desfechos clínico-patológicos / Expression of tyrosine kinase AXL receptor in patients with metastatic renal cell carcinoma treated with sunitinib and its association with clinical and pathological outcomes

JUSTIFICATIVA: Carcinoma de células renais representa 2-3% de todos dos cânceres. Em 2012, a incidência de câncer de rim no Brasil foi de 6.200 brasileiros, e metade desses pacientes morreram da doença naquele ano. Novas terapias alvo-moleculares, como o sunitinibe, emergiram nos últimos anos para pacientes com câncer de rim metastático, com aumento de sobrevida global. No entanto, existe uma grande heterogeneidade inter-paciente e falta de biomarcadores específicos preditivos de resposta terapêutica ou fatores prognósticos. Estudos recentes, inclusive do nosso grupo tem sugerido que a expressão do receptor de tirosina-quinase AXL, pode condicionar a resposta ao sunitinibe. OBJETIVOS: Avaliar a expressão proteica de AXL através da técnica de imuno-histoquímica em 114 pacientes com carcinoma de células renais metastático tratados com sunitinibe no Hospital de Câncer de Barretos, e correlacionar o perfil de expressão com as características clínicas e patológicas e resposta terapêutica ao uso desta medicação. MATERIAIS E MÉTODOS: Através de análise retrospectiva de prontuários desses pacientes, determinar o perfil epidemiológico e características clínicas e patológicas. Revisão histopatológica dos casos e realização de um tissue microarray (TMA) dos casos selecionados, contendo tecido normal, tumor primário e metastático renal para posterior análise de expressão proteica. Após a otimização da técnica de imuno-histoquímica para a proteína AXL, procedemos à avaliação da sua expressão. Por último, correlacionamos o perfil de expressão de AXL com as características epidemiológicas e clínico-patológicas dos pacientes, em particular o seu impacto no prognóstico e resposta terapêutica ao uso desta medicação...

BACKGROUND: Renal cell carcinoma represents 2-3% of all cancers of the Western countries. In 2012 it was estimated that the incidence of kidney cancer in Brazil was approximately in 6,200 Brazilians, and half of these patients died from the disease that year. New targeted molecular therapies emerged in recent years for patients with metastatic kidney cancer, with objective tumor responses in approximately 30%, with a significant increase in overall survival. However, there is great heterogeneity inter-patient and the lack of predictive or prognostic biomarkers. The search for those biomarkers aims to better characterize the patient with kidney cancer and provide a more sensitive guide to medical management. Recent studies in our group have even suggested that the expression of tyrosine kinase AXL receptor may affect the response to the molecular target drug, sunitinib, currently used in the treatment of patients with renal cell carcinoma. OBJECTIVE: To evaluate the protein expression of AXL by immunohistochemistry technique in 114 patients with metastatic renal cell carcinoma treated with sunitinib in Barretos Cancer Hospital, and to correlate the expression profile with clinical and pathological features and therapeutic response to use of this medication. MATERIALS AND METHODS: To determine the epidemiological and clinical and pathological characteristics of patients with metastatic renal cell carcinoma who have made use of sunitinib; histopathologic review of cases and conducting a tissue-microarray (TMA) of the selected cases; optimizing the immunohistochemistry technique to evaluate the AXL protein and its expression; correlate the profile AXL expression with the epidemiological and clinical-pathological characteristics of the patients, in particular its impact on prognosis and therapeutic response to this drug...