IntroductionImmune checkpoint inhibition has shifted treatment paradigms in non-small cell lung cancer (NSCLC). Conflicting results have been reported regarding the immune infiltrate and programmed death-ligand 1 (PD-L1) as a prognostic marker. We correlated the immune infiltrate and PD-L1 expression with clinicopathologic characteristics in a cohort of resected NSCLC.MethodsA tissue microarray was constructed using triplicate cores from consecutive resected NSCLC. Immunohistochemistry was performed for CD8, FOXP3 and PD-L1. Strong PD-L1 expression was predefined as greater than 50% tumor cell positivity. Matched nodal samples were assessed for concordance of PD-L1 expression.ResultsOf 522 patients, 346 were node-negative (N0), 72 N1 and 109 N2; 265 were adenocarcinomas (AC), 182 squamous cell cancers (SCC) and 75 other. Strong PD-L1 expression was found in 24% cases. In the overall cohort, PD-L1 expression was not associated with survival. In patients with N2 disease, strong PD-L1 expression was associated with significantly improved disease-free (DFS) and overall survival (OS) in multivariate analysis (HR 0.49, 95%CI 0.36–0.94, p = 0.031; HR 0.46, 95%CI 0.26–0.80, p = 0.006). In this resected cohort only 5% harboured EGFR mutations, whereas 19% harboured KRAS and 23% other. KRAS mutated tumors were more likely to highly express PD-L1 compared to EGFR (22% vs 3%). A stromal CD8 infiltrate was associated with significantly improved DFS in SCC (HR 0.70, 95%CI 0.50–0.97, p = 0.034), but not AC, whereas FOXP3 was not prognostic. Matched nodal specimens (N = 53) were highly concordant for PD-L1 expression (89%).ConclusionPD-L1 expression was not prognostic in the overall cohort. PD-L1 expression in primary tumor and matched nodal specimens were highly concordant. The observed survival benefit in N2 disease requires confirmation.
There is a large unmet need for effective therapies for cholestatic disorders, including primary sclerosing cholangitis (PSC), a disease that commonly results in liver failure. Angiotensin (Ang) II of the renin Ang system (RAS) is a potent profibrotic peptide, and Ang converting enzyme 2 (ACE2) of the alternate RAS breaks down Ang II to antifibrotic peptide Ang‐(1‐7). In the present study, we investigated long‐term effects of ACE2 delivered by an adeno‐associated viral vector and short‐term effects of Ang‐(1‐7) peptide in multiple drug‐resistant gene 2‐knockout (Mdr2‐KO) mice. These mice develop progressive biliary fibrosis with pathologic features closely resembling those observed in PSC. A single intraperitoneal injection of ACE2 therapy markedly reduced liver injury (P < 0.05) and biliary fibrosis (P < 0.01) at both established (3‐6 months of age) and advanced (7‐9 months of age) disease compared to control vector‐injected Mdr2‐KO mice. This was accompanied by increased hepatic Ang‐(1‐7) levels (P < 0.05) with concomitant reduction in hepatic Ang II levels (P < 0.05) compared to controls. Moreover, Ang‐(1‐7) peptide infusion improved liver injury (P < 0.05) and biliary fibrosis (P < 0.0001) compared to saline‐infused disease controls. The therapeutic effects of both ACE2 therapy and Ang‐(1‐7) infusion were associated with significant (P < 0.01) reduction in hepatic stellate cell (HSC) activation and collagen expression. While ACE2 therapy prevented the loss of epithelial characteristics of hepatocytes and/or cholangiocytes in vivo, Ang‐(1‐7) prevented transdifferentiation of human cholangiocytes (H69 cells) into the collagen‐secreting myofibroblastic phenotype in vitro. We showed that an increased ratio of hepatic Ang‐(1‐7) to Ang II levels by ACE2 therapy results in the inhibition of HSC activation and biliary fibrosis. Conclusion: ACE2 therapy has the potential to treat patients with biliary diseases, such as PSC.
Background:Bevacizumab prolongs progression-free survival (PFS) in patients with metastatic colorectal cancer. We analysed the protein expression levels of vascular endothelial growth factor (VEGF) ligands and receptors to determine their prognostic and predictive effects.Methods:We graded expression of VEGF-A, VEGF-B, VEGF-C, VEGF-D, VEGF-R1, and VEGF-R2 to assess whether overexpression predicted bevacizumab resistance in samples from 268 of 471 patients randomised to capecitabine (C), capecitabine and bevacizumab (CB), or CB and mitomycin (CBM) in the MAX trial and extended the analysis to the CAIRO-2 population.Results:Patients with low expression of VEGF-D (0, 1+) benefited from bevacizumab treatment (PFS hazard ratio (HR) (C vs CB+CBM), 0.21; 95% CI, 0.08–0.55; overall survival (OS) HR, 0.35; 95% CI, 0.13–0.90). Patients with higher VEGF-D expression received less benefit (VEGF-D 2+ PFS HR, 0.67; 95% CI, 0.45–1.00; OS HR, 0.82; 95% CI, 0.52–1.30; VEGF-D 3+ PFS HR, 0.77; 95% CI, 0.50–1.17; OS HR, 1.28; 95% CI, 0.79–2.09) (P interaction <0.05). In CAIRO-2, there was no difference in PFS or OS according to VEGF-D expression.Conclusions:The predictive value of VEGF-D expression for bevacizumab may depend on the chemotherapy backbone used. Further evaluation is required before clinical utilisation.
HighlightsUpper oesophageal adenocarcinomas are rare, and can occur in the setting of ectopic gastric mucosa (EGM).Adenocarcinomas arising within EGM have been treated successfully via a wide range of approaches (including endomucosal resection and open surgical resection) depending upon their clinical staging.The patient in our case report was successfully treated with no detectable disease recurrence at 18months follow up with neoadjuvant chemotherapy and surgical resection.
Nivolumab is an immune checkpoint inhibitor used to treat multiple solid-organ malignancies. While many of its immune-related adverse events are well established, nivolumab-induced sclerosing cholangitis remains poorly characterised, with no defined diagnostic criteria. Moreover, data regarding long-term outcomes are particularly lacking. We present a biopsy-proven case of nivolumab-induced sclerosing cholangitis, which uniquely captures 18 months of follow-up post-treatment. Our case highlights key features of intrahepatic subtype sclerosing cholangitis and suggests durable response to corticosteroid therapy.
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