Ceruloplasmin is the principal carrier of copper in human plasma. It is an abundant protein that participates in the acute phase reaction to stress, but its physiological function(s) is unknown. An ...antioxidant activity of ceruloplasmin has been described, but recent evidence suggests that the protein may also exhibit potent prooxidant activity and cause oxidative modification of low density lipoprotein (LDL). The pro-oxidant activity is highly dependent on the structure of the protein; removal of a single one of the seven integral copper atoms, or a specific proteolytic cleavage event, completely suppresses LDL oxidation. This newly described pro-oxidant activity may help to explain epidemiological studies indicating that ceruloplasmin is an independent risk factor for cardiovascular disease.
Cultured vascular smooth muscle cells (SMC) and endothelial cells (EC) stimulate low density lipoprotein (LDL) oxidation by
free radical-mediated, transition metal-dependent mechanisms. The ...physiological source(s) of metal ions is not known; however,
purified ceruloplasmin, a plasma protein containing 7 coppers, oxidizes LDL in vitro. We now show that ceruloplasmin also increases LDL oxidation by vascular cells. In metal ion-free medium, human ceruloplasmin
increased bovine aortic SMC- and EC-mediated LDL oxidation by up to 30- and 15-fold, respectively. The maximal response was
at 100â300 μg ceruloplasmin/ml, a level at or below the unevoked physiological plasma concentration. Oxidant activity was
dependent on protein structure as a specific proteolytic cleavage or removal of one of the seven ceruloplasmin copper atoms
inhibited activity. Three lines of evidence indicated a critical role for cellular superoxide (O 2 ) in ceruloplasmin-stimulated oxidation. First, the rate of production of O 2 by cells correlated with their rates of LDL oxidation. Second, superoxide dismutase effectively blocked ceruloplasmin-stimulated
oxidation by both cell types. Finally, O 2 production by SMC quantitatively accounted for the observed rate of LDL oxidation. To show this, the course of O 2 production by SMC was simulated by repeated addition of xanthine and xanthine oxidase to culture medium under cell-free conditions.
Neither ceruloplasmin nor O 2 alone increased LDL oxidation, but together they completely reconstituted the oxidation rate of ceruloplasmin-stimulated
SMC. These results are the first to show that ceruloplasmin stimulates EC- and SMC-mediated oxidation of LDL and that cell-derived
O 2 accounts quantitatively for metal-dependent, free radical-initiated oxidation of LDL by these cells.
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Background: In December 2011, the Metastatic Colorectal Cancer Liver Metastases Outcomes after Radioembolization (MORE) study retrospectively analyzed 606 patients with unresectable ...colorectal liver metastases treated with radioembolization using Y-90 resin microspheres. At a median follow-up of 8.6 months, 503 of these patients had died. Here, we summarize survival outcomes from extended follow-up of the remaining patients through September 1, 2016. Methods: Extended survival surveillance was abstracted from patient charts and public records. Survival time was compared for prognostic variables using Kaplan-Meier estimates. Results: Survival data were analyzed for 574 of 606 patients with median follow-up of 9.5 months (IQR 12.9 months). Patients received a median (range) of 2 (0 to 6) lines of chemotherapy. Additional death dates were obtained on 71 patients, and median survival was 10.0 months (95% CI 9.2-11.8) -versus 9.6 (95% CI 9.0-11.1) months originally reported. Data confirm ECOG PS, disease stage, extent of liver involvement, liver function, metachronous metastasis, and prior chemotherapy as predictors of post-radioembolization survival. Conclusions: Long-term follow-up confirms the originally reported prognostic factors for survival and that radioembolization offers a favorable survival benefit for patients with unresectable colorectal cancer liver metastases, even among those who already received 3 or more lines of chemotherapy. Table: see text
Purpose:
Monitoring of fibrinogen level is used to predict bleeding during lower extremity tissue plasminogen activator (tPA) infusions for peripheral arterial or venous thrombolysis. This practice ...is not fully addressed in the literature.
Materials and Methods:
We retrospectively reviewed fibrinogen levels and studied bleeding rate from charts of patients who underwent lower extremity tPA infusions at a single hospital from January 2010 to May 2012.
Results:
The rate of thrombolytic success did not correlate with fibrinogen level (P = .53). The rate of major bleeding was significantly higher for patients with a fibrinogen level at or below 150 mg/dL (P = .01). Patients whose tPA infusion was terminated within 46 hours had significantly lower rates of major bleeding (P = .01) and thrombolytic failure (P < .01). Periprocedural systolic blood pressure above 160 mm Hg was a risk factor for major bleeding (P = .02). There was no association between concomitant aspirin use (P = .90, .51) or hourly tPA dose (P = .71, .62) and thrombolytic success or major bleeding, respectively.
Conclusion:
Fibrinogen level ≤150 mg/dL is associated with increased risk of major bleeding during tPA infusions. We suggest serial fibrinogen measurement as a viable method to monitor bleeding risk during lower extremity tPA infusions.
The Metastatic colorectal cancer liver metastases Outcomes after RadioEmbolization (MORE) study was a retrospective analysis of 606 patients with unresectable colorectal liver metastases treated with ...radioembolization (RE) using
Y-labeled resin microspheres. The first analysis of this study was completed with a last patient follow-up of 77.7 months. We now provide an updated survival analysis through September 15, 2016, with a last patient follow-up of 125 months.
Y-RE was considered for patients with advanced liver-only or liver-dominant metastatic colorectal cancer which was deemed not suitable for surgery, ablation, or systemic therapy, and which had progressed or become refractory to at least one line of systemic therapy. All patients with a diagnosis of metastatic colorectal cancer who had received at least 1 RE treatment and 1 follow-up visit were included in the analysis. Patients were treated between July 2002 and December 2011 at one of 11 U.S. tertiary care centers. Data were collected at baseline, on the day of the first
Y-RE treatment (day 0), and at all subsequent visits or until death. Patient medical charts and/or public records were accessed to obtain dates of death.
Dates of death were obtained for 574 out of a total of 606 patients, and overall survival (OS) data analyzed. Updated median OS was 10.0 months (95% CI: 9.2-11.8 months) at a median follow-up of 9.5 months versus the originally reported median OS of 9.6 months (95% CI: 9.0-11.1 months) at a follow-up of 8.6 months in the first MORE analysis. Patients received a median (range) of 2 (0 to 6) lines of chemotherapy. Baseline characteristics and factors significantly associated with patient survival (P<0.01) are consistent with those reported in the first safety analysis of the MORE study. These factors include poor ECOG performance status, markers of advanced disease such as increased extent of tumor-to-target liver involvement, poor baseline liver function, pre-treatment anemia, lung shunt fraction, and number of lines of prior chemotherapy. Patient age did not significantly affect survival outcomes.
Long-term follow-up confirms that
Y-RE treatment offers favorable survival benefits for patients with unresectable metastatic colorectal cancer, even among patients who received 3 or more prior lines of chemotherapy. Our analysis also supports earlier reported prognostic factors for survival after
Y-RE. Overall, our updated analysis confirms that
Y-RE treatment provided a meaningful response and survival advantage for MORE patients across all ages and across diverse community and academic centers in the U.S.
Abstract
Polyarteritis nodosa (PAN) is a systemic, necrotizing vasculitis of small- and medium-sized arteries typically with multiorgan involvement. Most cases of PAN are idiopathic, although ...hepatitis B or C virus infections and hairy cell leukemia are important in the pathogenesis of some cases. PAN is characterized as segmental transmural inflammation of muscular arteries. Diagnosis is based on clinical suspicion, a negative immunofluorescence test for antineutrophil cytoplasmic antibodies, and whenever possible, biopsy conformation. Angiographic images may reveal microaneurysms affecting the renal, hepatic, or mesenteric vasculature. Aneurysmal formation and rupture are important complications that can be fatal. Treatment may warrant immunosuppression with steroids and cyclophosphamide. If left untreated, PAN can be fatal. To our knowledge, we report the second documented case of PAN-induced ruptured inferior pancreaticoduodenal artery aneurysm.
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