RESUMEN
BACKGROUND: Programmed death ligand-1 (PD-L1) expression is a well-known predictive biomarker of response to immune checkpoint blockade in non-small cell lung cancer (NSCLC). However, there is limited evidence of the relationship between PD-L1 expression, clinicopathological features, and their association with major driver mutations in NSCLC patients in Latin America. METHODS: This retrospective study included patients from Argentina with advanced NSCLC, and centralized evaluation of PD-L1 expression concurrently with genomic alterations in the driver genes EGFR, ALK, ROS1, BRAF, and/or KRAS G12C in FFPE tissue samples. RESULTS: A total of 10 441 patients with advanced NSCLC were analyzed. Adenocarcinoma was the most frequent histological subtype (71.1%). PD-L1 expression was categorized as PD-L1 negative (45.1%), PD-L1 positive low-expression 1%-49% (32.3%), and PD-L1 positive high-expression ≥50% (22.6%). Notably, current smokers and males were more likely to have tumors with PD-L1 tumor proportion score (TPS) ≥50% and ≥ 80% expression, respectively (p < 0.001 and p = 0.013). Tumors with non-adenocarcinoma histology had a significantly higher median PD-L1 expression (p < 0.001). Additionally, PD-L1 in distant nodes was more likely ≥50% (OR 1.60 [95% CI: 1.14-2.25, p < 0.01]). In the multivariate analysis, EGFR-positive tumors were more commonly associated with PD-L1 low expression (OR 0.62 [95% CI: 0.51-0.75], p < 0.01), while ALK-positive tumors had a significant risk of being PD-L1 positive (OR 1.81 [95% CI: 1.30-2.52], p < 0.01). CONCLUSIONS: PD-L1 expression was associated with well-defined clinicopathological and genomic features. These findings provide a comprehensive view of the expression of PD-L1 in patients with advanced NSCLC in a large Latin American cohort.
Asunto(s)
Adenocarcinoma , Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Masculino , Humanos , Carcinoma de Pulmón de Células no Pequeñas/patología , Neoplasias Pulmonares/patología , Proteínas Tirosina Quinasas/genética , Antígeno B7-H1/genética , Antígeno B7-H1/metabolismo , Estudios Retrospectivos , Quinasa de Linfoma Anaplásico/genética , Proteínas Proto-Oncogénicas/genética , Adenocarcinoma/genética , Mutación , Receptores ErbB/genéticaRESUMEN
Osteomyelitis caused by Staphylococcus aureus is an important and current health care problem worldwide. Treatment of this infection frequently fails not only due to the increasing incidence of antimicrobial-resistant isolates but also because of the ability of S. aureus to evade the immune system, adapt to the bone microenvironment, and persist within this tissue for decades. We have previously demonstrated the role of staphylococcal protein A (SpA) in the induction of exacerbated osteoclastogenesis and increased bone matrix degradation during osteomyelitis. The aim of this study was to evaluate the potential of using anti-SpA antibodies as an adjunctive therapy to control inflammation and bone damage. By using an experimental in vivo model of osteomyelitis, we demonstrated that the administration of an anti-SpA antibody by the intraperitoneal route prevented excessive inflammatory responses in the bone upon challenge with S. aureus. Ex vivo assays indicated that blocking SpA reduced the priming of osteoclast precursors and their response to RANKL. Moreover, the neutralization of SpA was able to prevent the differentiation and activation of osteoclasts in vivo, leading to reduced expression levels of cathepsin K, reduced expression of markers associated with abnormal bone formation, and decreased trabecular bone loss during osteomyelitis. Taken together, these results demonstrate the feasibility of using anti-SpA antibodies as an antivirulence adjunctive therapy that may prevent the development of pathological conditions that not only damage the bone but also favor bacterial escape from antimicrobials and the immune system.
Asunto(s)
Osteomielitis , Infecciones Estafilocócicas , Humanos , Osteoclastos/metabolismo , Osteoclastos/patología , Staphylococcus aureus , Proteína Estafilocócica A/metabolismo , Osteomielitis/tratamiento farmacológico , Osteomielitis/microbiología , Osteogénesis , Infecciones Estafilocócicas/microbiologíaRESUMEN
Objective: To analyze the frequency of KRAS, NRAS and BRAF hotspot mutations in circulating tumor DNA (ctDNA) from patients with metastatic colorectal cancer (mCRC). Methods: Observational, descriptive and retrospective study in mCRC patients with available ctDNA-based genotype of KRAS, NRAS and BRAF. Results: The frequencies of plasma mutations for KRAS, NRAS and BRAF were 34% (± 7), 4% (± 3) and 4% (± 3), respectively. Median overall survival of plasma-tested RAS/BRAF-mutated patients was 26.6 months (95% CI: 14.4-not estimable [NE]), while RAS/BRAF wild-type patients did not reach the median survival during follow-up. Median progression-free survival for RAS/BRAF wild-type and RAS/BRAF-mutated patients was 12 (95% CI: 7-NE) and 4 months (95% CI: 4-NE), respectively. Conclusion: Our work supports the utility of KRAS, NRAS and BRAF analysis in liquid biopsy from mCRC patients.