DSpace Collection:
https://hdl.handle.net/10171/12202
2024-03-28T22:09:45ZImmunotherapy and lung cytopathology: Overview and possibilities
https://hdl.handle.net/10171/69173
Title: Immunotherapy and lung cytopathology: Overview and possibilities
Abstract: Immunotherapy has become a promising cancer treatment in the past decade, and IHC is the most commonly used testing method for PDL-1/PD1 evaluation. In general, PD-L1 assays can be performed on both FFPE specimens and cytological samples. However, their use on smears is not yet well-established or validated. Nowadays, digital images and advanced algorithms can aid in interpreting PD-L1 in cytological samples. Understanding the immune environment of non-small cell lung cancer (NSCLC) is critical in developing successful anticancer immunotherapies. The use of a multiplexed immunofluorescence (mIF) assay on cytological samples obtained through minimally invasive methods appears to be a viable option for investigating the immune environment of NSCLC. This review aims to briefly summarize the knowledge of the role of cytopathology in the analysis of PD-L1 by immunocytochemistry (ICC) and future directions of cytopathology in the immunotherapy setting.2023-01-01T00:00:00ZPD-1/PD-L1 blockers in NSCLC brain metastases: Challenging paradigms and clinical practice
https://hdl.handle.net/10171/68687
Title: PD-1/PD-L1 blockers in NSCLC brain metastases: Challenging paradigms and clinical practice
Abstract: Immune checkpoint inhibitors (ICI) have revolutionized the management of advanced non-small cell lung cancer (NSCLC). However, most pivotal phase III trials systematically excluded patients with active brain metastases, precluding the generalization of the results. Although theoretically restricted from crossing the blood-brain barrier, the novel pharmacokinetic/pharmacodynamic profiles of anti-PD-1/PD-L1 drugs have prompted studies to evaluate their activity in patients with NSCLC with active central nervous system (CNS) involvement. Encouraging results have suggested that ICI could be active in the CNS in selected patients with driver-negative advanced NSCLC with high PD-L1 expression and low CNS disease burden. Single-agent CNS response rates around 30% have been reported. Beyond this particular setting, anti-PD-1/PD-L1 antibodies have been evaluated in patients receiving local therapy for brain metastases (BM), addressing concerns about potential neurologic toxicity risks associated with radiotherapy, more specifically, radionecrosis (RN). Accordingly, a variety of clinical and imaging strategies are being appropriately developed to evaluate tumor response and to rule out pseudoprogression or radionecrosis. Our purpose is to critically summarize the advances regarding the role of systemic anti-PD-1/PD-L1 antibodies for the treatment of NSCLC BM. Data were collected from the PubMed database, reference lists, and abstracts from the latest scientific meetings. Recent reports suggest anti-PD-1/PD-L1 agents are active in a subset of patients with NSCLC with BM showing acceptable toxicity. These advances are expected to change soon the management of these patients but additional research is required to address concerns regarding radionecrosis and the appropriate sequencing of local and systemic therapy combinations.2020-01-01T00:00:00ZSignature-driven repurposing of Midostaurin for combination with MEK1/2 and KRASG12C inhibitors in lung cancer
https://hdl.handle.net/10171/68095
Title: Signature-driven repurposing of Midostaurin for combination with MEK1/2 and KRASG12C inhibitors in lung cancer
Abstract: Drug combinations are key to circumvent resistance mechanisms compromising response to single anti-cancer targeted therapies. The implementation of combinatorial approaches involving MEK1/2 or KRASG12C inhibitors in the context of KRAS-mutated lung cancers focuses fundamentally on targeting KRAS proximal activators or effectors. However, the antitumor effect is highly determined by compensatory mechanisms arising in defined cell types or tumor subgroups. A potential strategy to find drug combinations targeting a larger fraction of KRAS-mutated lung cancers may capitalize on the common, distal gene expression output elicited by oncogenic KRAS. By integrating a signature-driven drug repurposing approach with a pairwise pharmacological screen, here we show synergistic drug combinations consisting of multi-tyrosine kinase PKC inhibitors together with MEK1/2 or KRASG12C inhibitors. Such combinations elicit a cytotoxic response in both in vitro and in vivo models, which in part involves inhibition of the PKC inhibitor target AURKB. Proteome profiling links dysregulation of MYC expression to the effect of both PKC inhibitor-based drug combinations. Furthermore, MYC overexpression appears as a resistance mechanism to MEK1/2 and KRASG12C inhibitors. Our study provides a rational framework for selecting drugs entering combinatorial strategies and unveils MEK1/2- and KRASG12C-based therapies for lung cancer.2023-01-01T00:00:00ZImpact of perineural invasion on the outcome of patients with synchronous colorectal liver metastases treated with neoadjuvant chemotherapy and surgery
https://hdl.handle.net/10171/67911
Title: Impact of perineural invasion on the outcome of patients with synchronous colorectal liver metastases treated with neoadjuvant chemotherapy and surgery
Abstract: Purpose: To analyze the prognostic value of variables of the primary tumor in patients with synchronous liver metastases in colorectal cancer (CLRMs) treated with neoadjuvant chemotherapy and surgery.
Methods/patients: From a prospective database, we retrospectively identified all patients with synchronous CLRMs who were treated with neoadjuvant chemotherapy and liver resection. Using univariate and multivariate analyses, we identified the variables associated with tumor recurrence. Overall survival and disease-free survival were calculated using the Kaplan-Meier method with differences determined by the Cox multiple hazards model. Results were compared using the log-rank test.
Results: Ninety-eight patients with synchronous CLRMs were identified. With a median follow-up of 39.8 months, overall survival and disease-free survival at 5 and 10 years were 53%, 41.7%, 29% and 29%, respectively. Univariate analysis identified three variables associated with tumor recurrence: location in the colon (p = 0.025), lymphovascular invasion (p = 0.011) and perineural invasion (p = 0.005). Multivariate analysis identified two variables associated with worse overall survival: perineural invasion (HR 2.36, 95% CI 1.162-4.818, p = 0.018) and performing frontline colectomy (HR 3.286, 95% CI 1.256-8.597, p = 0.015). Perineural invasion remained as the only variable associated with lower disease-free survival (HR 1.867, 95% CI 1.013-3.441, p = 0.045). Overall survival at 5 and 10 years in patients with and without perineural invasion was 68.2%, 54.4% and 29.9% and 21.3%, respectively (HR 5.920, 95% CI 2.241-15.630, p < 0.001).
Conclusions: Perineural invasion in the primary tumor is the variable with most impact on survival in patients with synchronous CLRMs treated with neoadjuvant chemotherapy and surgery.2023-01-01T00:00:00Z