Callisia N. Clarke

CXC chemokines play a critical role in liver injury, recovery, and regeneration.

BACKGROUND Hepatic ischemia/reperfusion (I/R) injury is a principal consideration of trauma, resectional liver surgery, and transplantation. Despite improvements in supportive care, hepatic I/R injury continues to negatively impact patient outcomes because of significant tissue damage and organ dysfunction. CXC chemokines have been implicated as key mediators in the deleterious inflammatory cascade after hepatic I/R and also as important, beneficial regulators of liver recovery and regeneration. As such, their potential to mediate both beneficial and detrimental effects on hepatocytes makes them a key target for therapy. Herein, we provide a review of the inflammatory mechanisms of hepatic I/R injury, with a focus on the divergent functions of CXC chemokines in this response compared with other liver insults, and offer an explanation of this apparent paradox. DATA SOURCES MEDLINE and PubMed. CONCLUSIONS CXC chemokines are key mediators of both the inflammatory response to hepatic I/R as well as the recovery from this injury. Their contrasting functions in the regeneration of liver mass after an ischemic insult indicates that therapeutic manipulation of these mediator pathways should differ depending on the surgical milieu.

CXC chemokine receptor‐1 is expressed by hepatocytes and regulates liver recovery after hepatic ischemia/reperfusion injury

CXC chemokines mediate hepatic inflammation and injury following ischemia/reperfusion (I/R). More recently, signaling through CXC chemokine receptor‐2 (CXCR2) was shown to delay liver recovery and repair after I/R injury. The chemokine receptor CXCR1 shares ligands with CXCR2, yet nothing is known about its potential role in liver pathology. In the present study, we examined the role of CXCR1 in the injury and recovery responses to I/R using a murine model. CXCR1 expression was undetectable in livers of sham‐operated mice. However, after ischemia CXCR1 expression increased 24 hours after reperfusion and was maximal after 96 hours of reperfusion. CXCR1 expression was localized largely to hepatocytes. In order to assess the function of CXCR1, CXCR2−/− mice were treated with the CXCR1/CXCR2 antagonist, repertaxin. Prophylactic treatment with repertaxin had no effect on acute inflammation or liver injury. However, when repertaxin was administered 24 hours postreperfusion there was a significant increase in hepatocellular injury and a delay in recovery compared to control‐treated mice. CXCR1−/− mice also demonstrated delayed recovery and regeneration after I/R when compared to wild‐type mice. In vitro, hepatocytes from CXCR2−/− mice that were stimulated to express CXCR1 showed increased proliferation in response to ligand. Hepatocyte proliferation was decreased in CXCR1−/− mice in vivo. Conclusion: This is the first report to show that CXCR1 expression is induced in hepatocytes after injury. Furthermore, the data suggest that CXCR1 has divergent effects from CXCR2 and appears to facilitate repair and regenerative responses after I/R injury. (HEPATOLOGY 2011)

The peptidyl-prolyl isomerase, Pin1, facilitates NF-κB binding in hepatocytes and protects against hepatic ischemia/reperfusion injury

BACKGROUND/AIMS Our previous work suggested an important role for the peptidyl-prolyl isomerase, Pin1, in hepatic NF-kappaB activation and liver injury during ischemia/reperfusion (I/R). In this study, we sought to determine the function of Pin1 in the injury response to hepatic I/R. METHODS Wild-type and Pin1(-/-) mice were subjected to partial hepatic I/R. In addition, hepatocytes and Kupffer cells were isolated from these mice. RESULTS Pin1(-/-) mice had reduced hepatic NF-kappaB activation and more liver injury after I/R than wild-type mice. The increased injury was not a result of enhanced inflammation as Pin1(-/-) mice had the same level of proinflammatory cytokine production and less neutrophil accumulation in the liver. The reduced NF-kappaB activation was not a result of a defect in nuclear translocation of NF-kappaB. In fact, hepatic nuclear p65 protein expression was higher in Pin1(-/-) mice than wild-type mice. This suggests that Pin1 is important for NF-kappaB-DNA binding. This effect was specific to hepatocytes as isolated Kupffer cells from wild-type and Pin1(-/-) mice were identical in their activation of NF-kappaB and production of cytokines after stimulation. In contrast, hepatocytes stimulated with TNFalpha had greatly reduced NF-kappaB activation, reduced production of the CXC chemokine, MIP-2, and increased cell death. CONCLUSIONS These data suggest that Pin1 is a critical regulator of NF-kappaB activation in hepatocytes and its role in these cells appears to confer direct protective effects.

BRAF mutant colorectal cancer as a distinct subset of colorectal cancer: clinical characteristics, clinical behavior, and response to targeted therapies

Despite new and more effective cytotoxic chemotherapy, limitations to conventional agents have been reached in a subset of patients with advanced colorectal cancer (CRC). The identification of novel prognostic and predictive biomarkers to guide individualized treatment plans is critical to overcoming therapeutic resistance. Mutation of the BRAF proto-oncogene is linked to a variety of cancers and is increasingly being used as a prognostic tool and therapeutic target. This paper is a comprehensive review of the literature that summarizes the clinical, pathologic, and molecular features of BRAF mutated CRC that support the hypothesis that BRAF mutant cancers represent a distinct subset of CRC with its own clinical implications with regard to prognosis, treatments and emerging therapeutic strategies.

Hypobaric hypoxia exacerbates the neuroinflammatory response to traumatic brain injury.

OBJECTIVE To determine the inflammatory effects of time-dependent exposure to the hypobaric environment of simulated aeromedical evacuation following traumatic brain injury (TBI). METHODS Mice were subjected to a blunt TBI or sham injury. Righting reflex response (RRR) time was assessed as an indicator of neurologic recovery. Three or 24 h (Early and Delayed groups, respectively) after TBI, mice were exposed to hypobaric flight conditions (Fly) or ground-level control (No Fly) for 5 h. Arterial blood gas samples were obtained from all groups during simulated flight. Serum and cortical brain samples were analyzed for inflammatory cytokines after flight. Neuron specific enolase (NSE) was measured as a serum biomarker of TBI severity. RESULTS TBI resulted in prolonged RRR time compared with sham injury. After TBI alone, serum levels of interleukin-6 (IL-6) and keratinocyte-derived chemokine (KC) were increased by 6 h post-injury. Simulated flight significantly reduced arterial oxygen saturation levels in the Fly group. Post-injury altitude exposure increased cerebral levels of IL-6 and macrophage inflammatory protein-1α (MIP-1α), as well as serum NSE in the Early but not Delayed Flight group compared to ground-level controls. CONCLUSIONS The hypobaric environment of aeromedical evacuation results in significant hypoxia. Early, but not delayed, exposure to a hypobaric environment following TBI increases the neuroinflammatory response to injury and the severity of secondary brain injury. Optimization of the post-injury time to fly using serum cytokine and biomarker levels may reduce the potential secondary cerebral injury induced by aeromedical evacuation.

Equine-related injury: a retrospective analysis of outcomes over a 10-year period

BACKGROUND Morbidity and financial loss caused by equine-related injuries may be significant. The purposes of this study were to determine the patterns of equine-related injury and the impact on outcomes. METHODS A 10-year retrospective review of equine-related injuries was performed. Age, gender, mechanism, injury severity score, Glasgow Coma Score, length of stay, surgical interventions, and mortality were assessed. RESULTS Of 80 emergency department evaluations, 76 patients were admitted and form the basis of this study. The most frequent mechanism of injury was fall (68%), followed by crush injuries (15%), kicks (8%), and trampling (5%). Musculoskeletal injuries were most common (64%). Thirty-eight (50%) patients required surgical intervention. Thirty-seven (52%) patients were discharged home; 34% required outpatient physical therapy, and 14% required inpatient rehabilitation. The mortality rate was 7%. CONCLUSIONS Equine-related injuries resulted in significant morbidity; most victims required outpatient or inpatient rehabilitation. The use of preventive strategies may minimize mortality and reduce the financial impact of postinjury morbidity.

Embryonic Origin of Primary Colon Cancer Predicts Pathologic Response and Survival in Patients Undergoing Resection for Colon Cancer Liver Metastases

Background: The aim of this study was to determine the prognostic value of embryonic origin in patients undergoing resection after chemotherapy for colon cancer liver metastases (CCLM). Methods: We identified 725 patients with primary colon cancer and known RAS mutation status who underwent hepatic resection after preoperative chemotherapy for CCLM (1990 to 2015). Survival after resection of CCLM from midgut origin (n = 238) and hindgut origin (n = 487) was analyzed. Predictors of pathologic response and survival were determined. Prognostic value of embryonic origin was validated with a separate cohort of 252 patients with primary colon cancer who underwent resection of CCLM without preoperative chemotherapy. Results: Recurrence-free survival (RFS) and overall survival (OS) after hepatic resection were worse in patients with midgut origin tumors (RFS rate at 3 years: 15% vs 27%, P < 0.001; OS rate at 3 years: 46% vs 68%, P < 0.001). Independent factors associated with minor pathologic response were midgut embryonic origin [odds ratio (OR) 1.55, P = 0.010], absence of bevacizumab (OR 1.42, P = 0.034), and mutant RAS (OR 1.41, P = 0.043). Independent factors associated with worse OS were midgut embryonic origin [hazard ratio (HR) 2.04, P < 0.001], carcinoembryonic antigen value ≥5 ng/mL at hepatic resection (HR 1.46, P = 0.0021), synchronous CCLM (HR 1.45, P = 0.012), and mutant RAS (HR 1.43, P = 0.0040). In the validation cohort, patients with CCLM of midgut origin had a worse 3-year OS rate (55% vs 78%, P = 0.003). Conclusions: Compared with CCLM from hindgut origin, CCLM from midgut origin are associated with worse pathologic response to chemotherapy and worse survival after resection. This effect appears to be independent of RAS mutation status.

Oncologic progress for the treatment of parathyroid carcinoma is needed

Parathyroid carcinoma (PC) is rare but potentially lethal. No standardized staging system or treatment guidelines have been established. We aimed to determine whether management of PC and patient outcomes have changed at our institution over the past 35 years.

The Effect of Hepatic Ischemia Reperfusion Injury in a Murine Model of Nonalcoholic Steatohepatitis

BACKGROUND Nonalcoholic fatty liver disease (NAFLD) refers to an increasingly diagnosed condition involving triglyceride accumulation into hepatocytes resulting in a broad spectrum of liver injury. The progression of NAFLD, a relatively benign condition, to nonalcoholic steatohepatitis (NASH) involves the hepatic infiltration of inflammatory cells and subsequent hepatocellular injury. Ischemia/reperfusion (I/R) injury of the liver is a major complication of liver resection, hepatic trauma, and liver transplantation. To date, there have been no studies that have evaluated the effects of hepatic I/R on models of NASH. OBJECTIVE Evaluate the effects of hepatic I/R on a mouse model of NASH. METHODS A mouse model of progressive NASH was developed and evaluated using C57BL/6 mice fed a methionine choline deficient diet for 3, 6, 9, and 12 wk. Mice subsequently underwent 90 min of partial hepatic ischemia with reperfusion of 1, 4, and 8 h. Mice were sacrificed after the indicated periods, and blood and liver samples were taken for analysis. RESULTS Mice fed the MCD diet showed a rapid induction of hepatic steatosis, inflammation, and fibrosis by 3 wk that persisted over the 12-wk period of diet, as demonstrated by histologic examination, alanine aminotransferase (ALT), and liver content of myeloperoxidase (MPO). The response to I/R in livers with progressive NASH fed MCD diet for 3, 6, 9, and 12 wk showed marked neutrophil recruitment and hepatocyte necrosis. CONCLUSION These data suggest the inflammatory response from I/R is augmented in livers with NASH histopathology compared with normal liver.

Overall survival after resection of retroperitoneal sarcoma at academic cancer centers versus community cancer centers: An analysis of the National Cancer Data Base

Background Operative resection remains the definitive curative therapy for retroperitoneal sarcoma. Data published recently show a correlation between improved outcomes for complex oncologic operations and treatment at academic centers. For large retroperitoneal sarcomas, operative resection can be complex and require multidisciplinary care. We hypothesized that survival rates vary between type of treating center for patients undergoing resection for retroperitoneal sarcoma. Methods Patients with stage I to III nonmetastatic retroperitoneal sarcomas who underwent operative resection were identified from the National Cancer Database during the years 2004–2013. Treating centers were categorized as academic cancer centers or community cancer centers. Overall survival was analyzed by log‐rank test and graphed using Kaplan‐Meier method. Results A total of 2,762 patients were identified. A majority of patients (59.4%, n = 1,642) underwent resection at an academic cancer centers. Median age at diagnosis was 63 years old. Neoadjuvant radiotherapy was more common at academic cancer centers, while adjuvant radiotherapy was more common at community cancer centers. Improved overall survival was seen at academic cancer centers across all stages compared with community cancer centers (P = .014) but, after multivariable Cox regression analysis, was not a significant independent predictor of survival (hazard ratio = 0.91, 95% confidence interval, 0.79–1.04, P = .171). Academic cancer centers exhibited a greater rate of R0 resection (55.9% vs 47.0%, P < .001) and a lesser odds of positive margins (odds ratio 0.83, 95% confidence interval, 0.69–0.99, P = .044) after multivariable logistic regression. Conclusion Resection for retroperitoneal sarcoma performed at academic cancer centers was an independent predictor of margin‐negative resection but was not a statistically significant factor for survival. This observation suggests that site of care may contribute to some aspect of improved oncologic resection for retroperitoneal sarcoma.