Clinical and prognostic implications of CD47 and PD-L1 expression in surgically resected small-cell lung cancer.

BACKGROUND: Pharmacological inhibition of the immune-checkpoint molecule CD47 has shown promising results in preclinical small-cell lung cancer (SCLC) models, whereas anti-programmed death-ligand 1 (PD-L1) inhibitors have been recently implemented in the standard of care of advanced-stage SCLC patients. Nevertheless, the expression pattern, clinical relevance and prognostic implication of both CD47 and PD-L1 are rather controversial in surgically treated SCLC patients. MATERIALS AND METHODS: In total, 104 Caucasian SCLC patients from two Central European thoracic centers were included in this study. CD47 and PD-L1 expression as well as the expression of the four major SCLC molecular subtype markers (ASCL1, NEUROD1, YAP1 and POU2F3) were measured by immunohistochemistry. Expression levels were independently evaluated and statistically correlated with clinicopathological data and survival. RESULTS: Positive CD47 and PD-L1 expressions were seen in 84.6% and 9.6% of the samples, respectively. Meanwhile, the tumor-associated stroma was positive for PD-L1 in 59.6% of the cases. Stromal PD-L1 expression correlated with longer overall survival (OS) (versus PD-L1-negative stroma; median OS was 42 versus 14 months, respectively, P = 0.003) and was confirmed as an independent predictor of favorable outcome upon multivariate analysis (hazard ratio 0.530, 95% confidence interval 0.298-0.943, P = 0.031). Notably, neither CD47 nor PD-L1 presence was related to a distinct molecular SCLC subtype. CONCLUSION: CD47 shows a remarkably high expression while tumoral PD-L1 expression is generally low in surgically treated SCLC. Importantly, stromal PD-L1 expression may indicate a favorable clinical outcome and serve as a novel prognostic factor in these patients. Additional studies are warranted to further investigate the clinical impact of CD47 and PD-L1 expression in SCLC.

Analysis of microRNA expression in brush cytology specimens improves the diagnosis of pancreatobiliary cancer.

BACKGROUND/OBJECTIVES: Malignant pancreatobiliary strictures are in many cases clinically indistinguishable and present a major problem to endoscopy specialists. Intraductal sampling procedures such as brush cytology are commonly used for diagnosis with a sensitivity that is low for a diagnostic test used in daily clinical practice. MicroRNA (miR) alterations detected in many cancers are disease-specific, which can be utilized in clinical applications. The aim of the present study was to analyze whether determination of miR expression levels in intraductal brush cytology specimens is a feasible approach to improve the diagnosis of pancreatobiliary cancer. METHODS: Brush cytology specimens have been collected during endoscopic retrograde cholangio-pancreatography (ERCP) and analyzed by routine cytology and ancillary miR assays. Total RNA was extracted using the miRNeasy Mini Kit and the expression of miRs frequently dysregulated in pancreatobiliary cancer (miR-16, miR-21, miR-196a, miR-221) were analyzed by quantitative real-time PCR using RNU6B as internal control. RESULTS: Routine cytology resulted in no false positive diagnoses, however, the combined sensitivity remained at 53.8%. Expression (ΔCt values) of miR-16 (p = 0.0039), miR-196a (p = 0.0003) and miR-221 (p = 0.0049) showed a clear statistical significance between malignant and benign pancreatobiliary specimens (n = 35). Malignancy could be detected combining routine cytology and the miR-196a single marker expression levels with a sensitivity of 84.6% (92.9% in biliary strictures) with no false positives. CONCLUSIONS: The results offer the first direct demonstration that microRNAs are readily detectable in brush cytology specimens obtained during ERCP, and have the potential to help the cytological diagnosis of pancreatobiliary malignancy.

IGF1 activates cell cycle arrest following irradiation by reducing binding of ΔNp63 to the p21 promoter.

Radiotherapy for head and neck tumors often results in persistent loss of function in salivary glands. Patients suffering from impaired salivary function frequently terminate treatment prematurely because of reduced quality of life caused by malnutrition and other debilitating side-effects. It has been previously shown in mice expressing a constitutively active form of Akt (myr-Akt1), or in mice pretreated with IGF1, apoptosis is suppressed, which correlates with maintained salivary gland function measured by stimulated salivary flow. Induction of cell cycle arrest may be important for this protection by allowing cells time for DNA repair. We have observed increased accumulation of cells in G2/M at acute time-points after irradiation in parotid glands of mice receiving pretreatment with IGF1. As p21, a transcriptional target of the p53 family, is necessary for maintaining G2/M arrest, we analyzed the roles of p53 and p63 in modulating IGF1-stimulated p21 expression. Pretreatment with IGF1 reduces binding of ΔNp63 to the p21 promoter after irradiation, which coincides with increased p53 binding and sustained p21 transcription. Our data indicate a role for ΔNp63 in modulating p53-dependent gene expression and influencing whether a cell death or cell cycle arrest program is initiated.

Fatal pulmonary fibrosis induced by paclitaxel: a case report and review of the literature.

Fatal lung fibrosis caused by paclitaxel toxicity has not been reported In this report, we describe the case of a 62-year-old woman who received six cycles of paclitaxel and carboplatin as combination chemotherapy for advanced ovarian cancer. Four weeks after the end of the chemotherapy she developed interstitial pneumonitis and irreversible lung fibrosis. Despite treatment with corticosteroids, she had rapid deterioration and died of respiratory failure. Pulmonary fibrosis is a complication of paclitaxel therapy that may occur despite treatments with corticosteroids. While reviewing the literature, we found few less severe pulmonary injuries after intravenous use of paclitaxel, but none of these cases had a fatal outcome. Physicians should keep in mind that taxanes such as paclitaxel have the potential to cause pneumonitis and lung fibrosis.