Transplanting kidneys from hepatitis C virus (HCV) viremic donors into HCV-negative patients (HCV D-RNA-positive/R-negative) has evolved from experimental to “standard-of-care” at many centers. ...Nevertheless, most data derive from single centers and provide only short-term follow-up.
The Multicenter Study to Transplant Hepatitis C-Infected Kidneys (MYTHIC) study was a multicenter (7 sites) trial of HCV D-RNA-positive/R-negative kidney transplantation (KT) followed by 8 weeks of glecaprevir/pibrentasvir (G/P) initiated 2 to 5 days post-KT. Prespecified outcomes included probability of KT (vs. matched waitlist comparators) and 1-year safety outcomes, allograft function, and survival.
Among 63 enrolled patients, 1-year cumulative incidence of KT was approximately 3.5-fold greater for the MYTHIC cohort versus 2055 matched United Network for Organ Sharing (UNOS) comparators who did not opt-in to receive a kidney from an HCV-viremic donor (68% vs. 19%, P < 0.0001). Of 30 HCV D-RNA-positive/R-negative KT recipients, all achieved HCV cure. None developed clinically significant liver disease or HCV-related kidney injury. Furthermore, 1-year survival was 93% and 1-year graft function was excellent (median creatinine 1.17; interquartile range IQR: 1.02–1.38 mg/dl). There were 4 cases of cytomegalovirus (CMV) disease among 10 CMV-negative patients transplanted with a kidney from an HCV-viremic/CMV-positive donor.
The 1-year findings from this multicenter trial suggest that opting-in for HCV-viremic KT offers can increase probability of KT with excellent 1-year outcomes. Trial Registration: NCT03781726
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Abstract
We have previously identified that Neutrophil Extracellular Traps (NETs) are an important contributing factor to the metastatic process. However, the underlying molecular mechanisms by which ...NETs facilitate metastasis remain unclear. Using mass spectrometry, amongst 583 distinct proteins, we identified CEACAM1 (CC1) in isolated human NETs and we sought to determine whether CC1 has a role in NET-mediated cancer metastasis. The presence of CC1 on NETs was confirmed by immunofluorescence. In vitro static adhesion of human colon cancer HT29 cells to isolated purified human NETs was reduced by 50% using a function blocking antibody against human CC1, but not isotype control, an effect equal to NET degradation with DNAse. Adhesion of murine colon cancer MC38-CC1L cells to C57BL/6 mouse neutrophils stimulated to produce NETs with phorbol myristate acetate (PMA) was increased 3-fold compared to untreated neutrophils, an effect that was completely attenuated with DNAse. PMA stimulation of neutrophils isolated from Ceacam1−/− knockout (KO) mice did not increase adhesion to MC38-CC1L cells. Using a parallel plate flow chamber, a physiologically relevant adhesion model under the shear conditions encountered in liver sinusoids, we flowed Lewis lung carcinoma (C10) cancer cells over neutrophils isolated from C57BL/6 or Ceacam1−/− KO mice. PMA-induced NET formation in C57BL/6 mouse neutrophils increased cancer cell adhesion 5-fold, an effect again completely attenuated by DNAse or use of neutrophils from Ceacam1−/− KO mice. Using a transwell chamber, MC38-CC1L cancer cells exposed to NET-stimulated Ceacam1−/− KO neutrophils had a 50% decrease in migration, compared to those exposed to NETs from C57BL/6 neutrophils. In order to delineate the role of CC1 in NET-related in vivo adhesion of cancer cells to liver sinusoids, we performed a series of neutrophil depletion and re-infusion experiments. C57BL/6 mice, depleted of neutrophils with anti-GR1 24 hrs prior, were re-infused with neutrophils isolated from C57BL/6 or Ceacam1−/− KO mice. This was followed by injection of MC38-CFSE labelled cells and hepatic intravital microscopy was used to quantify in vivo cancer cell adhesion and migration. PMA-stimulated C57BL/6 neutrophils prior to re-infusion was associated with a two-fold increase in adhesion compared to PMA-stimulated Ceacam1−/− KO neutrophils, an effect that was completely attenuated using DNAse.
Our data support the notion that CEACAM1 is, at least in part, responsible for the increased cancer cell migration mediated by Neutrophil Extracellular Traps. We have thereby identified NET-associated CEACAM1 as a putative therapeutic target to prevent the metastatic progression of cancer cells.
Citation Format: Phil Vourtzoumis, Rashmi Seth, Roni Rayes, Sara Najmeh, Jonathan Cools-Lartigue, Betty Giannias, France Bourdeau, Nicole Beauchemin, Simon Rousseau, Richard Blumberg, Jonathan D. Spicer, Lorrenzo Edwin Ferri. The role of CEACAM1 in neutrophil extracellular Trap mediated cancer metastasis. abstract. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-078.
Winners of the Distinguished Scientific Awards for an Early Career Contribution to Psychology are profiled. The winners for 1997 are Seth C. Kalichman, Dare A. Baldwin, Mark S. Blumberg, Thomas N. ...Bradbury and Michael J. Tarr.
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