Proper grading of the cribriform prostate cancer pattern has not previously been supported by outcome-based evidence. Among 153 men who underwent radical prostatectomy, 76 with prostate-specific antigen (PSA) failure (≥0.2 ng/mL [0.2 µg/L]) were matched to 77 without failure. Frequencies of high-grade patterns included fused small acini, 83.7%; papillary, 52.3%; large cribriform, 37.9%; small (≤12 lumens) cribriform, 17.0%; and individual cells, 22.9%. A cribriform pattern was present in 61% (46/76) of failures but 16% (12/77) of nonfailures (P < .0001). Multivariate analysis showed the cribriform pattern had the highest odds ratio for PSA failure, 5.89 (95% confidence interval, 2.53–13.70; P < .0001). The presence of both large and small cribriform patterns was significantly linked to failure. The cumulative odds ratio of failure per added square millimeter of cribriform pattern was 1.173 (P = .008), higher than for any other pattern. All 8 men with a cribriform area sum of 25 mm2 or more had failure (range, 33–930). Regrading cribriform cancer as Gleason 5 improved the grade association with failure, although half of all cases with individual cells also had a cribriform pattern, precluding a precise determination of the independent importance of the latter. The cribriform pattern has particularly adverse implications for outcome.

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Background and Aims Hepatic ischemia reperfusion injury (IRI) is a critical component of hepatic surgery. Oxidative stress has long been implicated as a key player in IRI. In this study, we examine the cell-specific role of the Nrf2-antioxidant response element pathway in warm hepatic IRI. Methods Nrf2 KO and WT animals, and novel transgenic mice expressing a constitutively active Nrf2 mutant in hepatocytes (AlbCre+/caNrf2+) and their littermate controls underwent partial hepatic ischemia or sham surgery. The animals were sacrificed 6 hours after reperfusion and their serum and tissue collected for analysis. Results As compared to wild type animals after IR, Nrf2 KO mice had increased hepatocellular injury with increased serum ALT and AST, Suzuki score, apoptosis, an increased inflammatory infiltrate and enhanced inflammatory cytokine expression. On the other hand, AlbCre+/caNrf2+ that underwent IR had significantly reduced serum transaminases, less necrosis on histology, and a less pronounced inflammatory infiltrate and inflammatory cytokine expression as compared to the littermate controls. However, there were no differences in apoptosis. Conclusion Taken together, Nrf2 plays a critical role in our murine model of warm hepatic IRI, with Nrf2 deficiency exacerbating hepatic IRI and hepatocyte specific Nrf2 over-activation providing protection against warm hepatic IRI.

Hepatic ischemia/reperfusion injury (IRI) is an unavoidable consequence of liver transplantation that can lead to postoperative hepatic dysfunction. Myeloid cells that include Kupffer cells, monocytes, and neutrophils contribute to the inflammatory response and cellular injury observed during hepatic IRI. We hypothesize that overactivation of the nuclear erythroid 2 p45- related factor 2 (Nrf2)–antioxidant response element (ARE) pathway in myeloid cells leads to decreased cellular damage after hepatic IRI. We constructed transgenic mice with constitutively active nuclear erythroid 2 p45-related factor 2 (caNrf2) that over activates the Nrf2-ARE pathway in myeloid cells (lysozyme M cre recombinase [LysMcre]+/caNrf2−, n = 9), and their littermate controls lacking transgene expression (LysMcre+/caNrf2−, n = 11). The mice underwent either sham or partial hepatic ischemia surgery, with 60 minutes of ischemia followed by 6 hours of reperfusion. After IRI, LysMcre+/caN-rf2+ mice demonstrated significantly decreased serum alanine aminotransferase and decreased areas of necrosis. Immunohistochemistry and immunoblot of caspase 3 showed a significantly decreased cleaved to full-length caspase 3 ratio in LysMcre+/caNrf2+ animals. Lymphocyte antigen 6 complex locus G and CD68 staining demonstrated reduced inflammatory cell infiltration. LysMcre+/caNrf2+ animals also had significantly decreased gene expression of proinflammatory cytokines, including interleukin (IL) 1β, IL6, tumor necrosis factor α, chemokine (C-C motif) ligand 2, and chemokine (C-X-C motif) ligand 10, and significantly decreased levels of 8-isoprostanes. In our model, Nrf2 overactivation in myeloid cells leads to decreased hepatocellular damage, necrosis, apoptosis, inflammation, and oxidative stress. Pharmacologic targeting of the Nrf2-ARE pathway in myeloid cells may be a novel strategy to mitigate hepatic IRI.

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