Pancreatic ductal adenocarcinoma: tumour regression grading following neoadjuvant FOLFIRINOX and radiation.

AIMS: In the adjuvant setting, when compared to gemcitabine, patients with pancreatic ductal adenocarcinoma (PDAC) treated with FOLFIRINOX (Folinic Acid, Fluorouracil, Irinotecan, and Oxaliplatin) show superior survival. In this study, we quantitatively assess the pathological tumour response to chemoradiation in pancreatectomy specimens and reassess guidelines for tumour regression grading. METHODS AND RESULTS: We evaluated 92 patients with borderline resectable/locally advanced PDAC following pancreatectomy and neoadjuvant treatment with FOLFIRINOX and radiation. Demographic data, CAP tumour regression grade (TRG) and overall survival (OS) were recorded. A quantitative analysis of residual tumour was performed on the slide with the highest tumour burden to derive a tumour-to-tumour bed ratio. On univariate analysis, only lymph node status (P = 0.043) and CAP TRG (P = 0.038) correlated with OS. Sixteen per cent of patients showed a complete pathological response. The optimal tumour-to-tumour bed ratio cut-point was 11.6%, and on a multivariate model was the only pathological parameter that correlated with OS (P = 0.016) (hazard ratio = 2.27). CONCLUSIONS: The high proportion of patients with PDAC showing complete and near-complete pathological responses supports the use of FOLFIRINOX and radiation in the neoadjuvant setting. Several traditional pathology parameters fail to predict OS in patients treated with chemoradiation, while a quantitative tumour-to-tumour bed ratio is a powerful predictor of OS. The data support a two-tiered approach to TRG based on tumour-to-tumour bed ratio, and quantitative analysis merits further consideration.

Tumor necrosis factor-α confers cardioprotection through ectopic expression of keratins K8 and K18.

Tumor necrosis factor-α (TNF-α), one of the major stress-induced proinflammatory cytokines, is upregulated in the heart after tissue injury, and its sustained expression can contribute to the development of heart failure. Whether TNF-α also exerts cytoprotective effects in heart failure is not known. Here we provide evidence for a cardioprotective function of TNF-α in a genetic heart failure model, desmin-deficient mice. The cardioprotective effects of TNF-α are a consequence of nuclear factor-κB (NF-κB)-mediated ectopic expression in cardiomyocytes of keratin 8 (K8) and keratin 18 (K18), two epithelial-specific intermediate filament proteins. In cardiomyocytes, K8 and K18 (K8/K18) formed an alternative cytoskeletal network that localized mainly at intercalated discs (IDs) and conferred cardioprotection by maintaining normal ID structure and mitochondrial integrity and function. Ectopic induction of K8/K18 expression in cardiomyocytes also occurred in other genetic and experimental models of heart failure. Loss of the K8/K18 network resulted in a maladaptive cardiac phenotype following transverse aortic constriction. In human failing myocardium, where TNF-α expression is upregulated, K8/K18 were also ectopically expressed and localized primarily at IDs, which did not contain detectable amounts of desmin. Thus, TNF-α- and NF-κB-mediated formation of an alternative, stress-induced intermediate filament cytoskeleton has cardioprotective function in mice and potentially in humans.