Comparison of multiple oncotype DX® from the same patient.

For women with breast cancer in whom multiple Oncotype DX® Recurrence Scores (RS) are obtained, RS concordance utilizing current NCCN recommendations has not been evaluated. Patients with two or more RS were identified. RS were stratified by NCCN guidelines and compared for concordance. Twenty-four patients were evaluated. RS concordance varied by tumor type: 100% in the same tumor, 91.7% in multiple ipsilateral tumors, 71.4% in contralateral tumors, and 66.7% in in-breast recurrent tumors. RS concordance for multiple assays in the same patient is not high enough to omit Oncotype DX® testing for each tumor.

Quantitative Measure of Intestinal Permeability Using Blue Food Coloring.

BACKGROUND: Loss of intestinal barrier integrity plays a fundamental role in the pathogenesis of various gastrointestinal diseases and is implicated in the onset of sepsis and multiple organ failure. An array of methods to assess different aspects of intestinal barrier function suffers from lack of sensitivity, prolonged periods of specimen collection, or high expense. We have developed a technique to measure the concentration of the food dye FD&C Blue #1 from blood and sought to assess its utility in measuring intestinal barrier function in humans. MATERIALS AND METHODS: Four healthy volunteers and 10 critically ill subjects in the intensive care unit were recruited in accordance with an institutional review board approved protocol. Subjects were given 0.5 mg/kg Blue #1 enterally as an aqueous solution of diluted food coloring. Five blood specimens were drawn per subject: 0 h (before dose), 1, 2, 4, and 8 h. After plasma isolation, organic extracts were analyzed by high-performance liquid chromatography/mass spectrometry detecting the presence of unmodified dye. RESULTS: We found no baseline detectable absorption in healthy volunteers. After including the subjects in the intensive care unit, we compared dye absorption in the six subjects who met criteria for septic shock with the eight who did not. Septic patients demonstrated significantly greater absorption of Blue #1 after 2 h. CONCLUSIONS: We have developed a novel, easy-to-use method to measure intestinal barrier integrity using a food grade dye detectable by mass spectrometry analysis of patient blood following oral administration.

Human hepatocyte transplantation corrects the inherited metabolic liver disorder arginase deficiency in mice.

The transplantation, engraftment, and expansion of primary hepatocytes have the potential to be an effective therapy for metabolic disorders of the liver including those of nitrogen metabolism. To date, such methods for the treatment of urea cycle disorders in murine models has only been minimally explored. Arginase deficiency, an inherited disorder of nitrogen metabolism that presents in the first two years of life, has the potential to be treated by such methods. To explore the potential of this approach, we mated the conditional arginase deficient mouse with a mouse model deficient in fumarylacetoacetate hydrolase (FAH) and with Rag2 and IL2-Rγ mutations to give a selective advantage to transplanted (normal) human hepatocytes. On day -1, a uroplasminogen-expressing adenoviral vector was administered intravenously followed the next day with the transplantation of 1 × 106 human hepatocytes (or vehicle alone) by intrasplenic injection. As the initial number of administered hepatocytes would be too low to prevent hepatotoxicity-induced mortality, NTBC cycling was performed to allow for hepatocyte expansion and repopulation. While all control mice died, all except one human hepatocyte transplanted mice survived. Four months after hepatocyte transplantation, 2 × 1011 genome copies of AAV-TBG-Cre recombinase was administered IV to disrupt endogenous hepatic arginase expression. While all control mice died within the first month, human hepatocyte transplanted mice did well. Ammonia and amino acids, analyzed in both groups before and after disruption of endogenous arginase expression, while well-controlled in the transplanted group, were markedly abnormal in the controls. Ammonium challenging further demonstrated the durability and functionality of the human repopulated liver. In conclusion, these studies demonstrate that human hepatocyte repopulation in the murine liver can result in effective treatment of arginase deficiency.

Noninvasive Imaging of Drug-Induced Liver Injury with 18F-DFA PET.

Drug-induced liver failure is a significant indication for a liver transplant, and unexpected liver toxicity is a major reason that otherwise effective therapies are removed from the market. Various methods exist for monitoring liver injury but are often inadequate to predict liver failure. New diagnostic tools are needed. Methods: We evaluate in a preclinical model whether 18F-2-deoxy-2-fluoroarabinose (18F-DFA), a PET radiotracer that measures the ribose salvage pathway, can be used to monitor acetaminophen-induced liver injury and failure. Mice treated with vehicle, 100, 300, or 500 mg/kg acetaminophen for 7 or 21 h were imaged with 18F-FDG and 18F-DFA PET. Hepatic radiotracer accumulation was correlated to survival and percentage of nonnecrotic tissue in the liver. Mice treated with acetaminophen and vehicle or N-acetylcysteine were imaged with 18F-DFA PET. 18F-DFA accumulation was evaluated in human hepatocytes engrafted into the mouse liver. Results: We show that hepatic 18F-DFA accumulation is 49%-52% lower in mice treated with high-dose acetaminophen than in mice treated with low-dose acetaminophen or vehicle. Under these same conditions, hepatic 18F-FDG accumulation was unaffected. At 21 h after acetaminophen treatment, hepatic 18F-DFA accumulation can distinguish mice that will succumb to the liver injury from those that will survive it (6.2 vs. 9.7 signal to background, respectively). Hepatic 18F-DFA accumulation in this model provides a tomographic representation of hepatocyte density in the liver, with a R2 between hepatic 18F-DFA accumulation and percentage of nonnecrotic tissue of 0.70. PET imaging with 18F-DFA can be used to distinguish effective from ineffective resolution of acetaminophen-induced liver injury with N-acetylcysteine (15.6 vs. 6.2 signal to background, respectively). Human hepatocytes, in culture or engrafted into a mouse liver, have levels of ribose salvage activity similar to those of mouse hepatocytes. Conclusion: Our findings suggest that PET imaging with 18F-DFA can be used to visualize and quantify drug-induced acute liver injury and may provide information on the progression from liver injury to hepatic failure.

Rescue Diverting Loop Ileostomy: An Alternative to Emergent Colectomy in the Setting of Severe Acute Refractory IBD-Colitis.

BACKGROUND: Severe acute refractory colitis has traditionally been an indication for emergent colectomy in IBD, yet under these circumstances patients are at elevated risk for complications because of their heightened inflammatory state, nutritional deficiencies, and immunocompromised state. OBJECTIVE: We hypothesized that rescue diverting loop ileostomy may be a viable alternative to emergent colectomy, providing the opportunity for colonic healing and patient optimization before more definitive surgery. DESIGN: This was a retrospective case series. SETTINGS: The study was conducted at a single academic center. PATIENTS: Patients with severe acute medically refractory IBD-related colitis were included. INTERVENTION: Rescue diverting loop ileostomy was the intervening procedure. MAIN OUTCOME MEASURES: The primary outcome was avoidance of urgent/emergent colectomy. The secondary outcome was efficacy, defined by 3 clinical aims: 1) reduced steroid dependence or opportunity for bridge to medical rescue, 2) improved nutritional status, and 3) ability to undergo an elective laparoscopic definitive procedure or ileostomy reversal with colon salvage. RESULTS: Among 33 patients, 14 had Crohn's disease and 19 had ulcerative colitis. Three patients required urgent/emergent colectomy, 2 with ulcerative colitis and 1 with Crohn's disease. Across both disease cohorts, >80% of patients achieved each clinical aim for efficacy: 88% reduced their steroid dependence or were able to bridge to medical rescue, 87% improved their nutritional status, and 82% underwent an elective laparoscopic definitive procedure or ileostomy reversal. A total of 4 patients (11.7%) experienced a postoperative complication following diversion, including 3 surgical site infections and 1 episode of acute kidney injury. LIMITATIONS: The study was limited by being a single-center, retrospective series. CONCLUSIONS: Rescue diverting loop ileostomy in the setting of severe, refractory IBD-colitis is a safe and effective alternative to emergent colectomy. This procedure has acceptably low complication rates and affords patients time for medical and nutritional optimization before definitive surgical intervention. See Video Abstract at http://links.lww.com/DCR/A520.

Pneumonia after liver transplantation.

PURPOSE OF REVIEW: Pneumonia occurs in 8-23% of patients after liver transplantation and contributes considerably to their morbidity and mortality. With the increasing acuity of liver transplantation patients in the current era, pneumonias, particularly ventilator-associated pneumonias, and multidrug-resistant pathogens, are of growing concern. RECENT FINDINGS: Postliver transplantation pneumonia cause varies with the timing of infection. In the early period (<1 month postliver transplantation), nosocomial pneumonias, including ventilator-associated pneumonias and multidrug-resistant species are most common. During the intermediate period (1-6 months postliver transplantation), opportunistic infections predominate as intensive immunosuppression persists. In the late period (>6 months postliver transplantation), community-acquired bacterial and viral pneumonias arise, as immunosuppression is reduced. Numerous risk factors have been implicated in postliver transplantation pneumonias. Prevention is aimed at reducing bacterial colonization, preventing aspiration events, and utilizing surveillance and targeted antibiotics. Novel studies have also shown reduced risk of infection with personalized immunosuppression regimens guided by an immune function assay. SUMMARY: The etiologic patterns, risk factors, and preventive measures for postliver transplantation pneumonia must be understood to minimize patient exposure to modifiable risks and optimize recipient status in the perioperative period. Prevention is multifaceted and may be enhanced by personalization of immune therapy based on predisposition to infection and graft rejection.

Optimizing the Management of Abnormal Liver Function Tests after Orthotopic Liver Transplant: A Systems-Based Analysis of Health Care Utilization.

Elevated liver function tests (eLFTs) are a major cause of unplanned readmissions (UR) after orthotopic liver transplantation. Diagnostic workup for eLFTs requires multiple invasive and noninvasive procedures, often done in the inpatient setting to expedite diagnosis, yet consequently resulting in increased costs. In this study, we evaluated eLFT readmissions at a single institution with respect to resource utilization. From 3/2013 to 12/2015, 388 patients underwent orthotopic liver transplantation, resulting in 463 UR totaling 5833 bed days; 87 (18.8%) UR and 929 (15.9%) bed days were for eLFTs. During eLFT-UR all patients underwent repeat laboratory testing, 75 (86.2%) liver ultrasound, 66 (75.8%) liver biopsy, and 17 (19.5%) endoscopic retrograde cholangiopancreatography. Discharge diagnoses were acute cellular rejection (40.2%), transaminitis not otherwise specified (17.2%), biliary complications (16.1%), recurrent hepatitis (11.5%), vascular complications (5.8%), viral hepatitis (5.8%), and steatohepatitis (3.5%). The greatest bed-day utilization was secondary to acute cellular rejection (60.8%) and biliary complications (13.7%). More than 35 per cent of eLFT-UR were due to transaminitis not otherwise specified, steatohepatitis, recurrent or viral hepatitis, none of which necessitate inpatient treatment. In addition, >25 per cent of eLFT-UR bed days were attributed to diagnostic workup. Identifying patients who can undergo expedited outpatient workup and require only outpatient management will result in significantly decreased readmissions, bed days, and hospital costs.