Prognosis and tumor biology of pancreatic cancer patients with isolated lung metastases: translational results from the German multicenter AIO-YMO-PAK-0515 study.

BACKGROUND: Pulmonary metastasis (M1-PUL) as first site of dissemination in pancreatic ductal adenocarcinoma (PDAC) is a rare event and may define a distinct biological subgroup. PATIENTS AND METHODS: Arbeitsgemeinschaft Internistische Onkologie-Young Medical Oncologists-Pankreas-0515 study (AIO-YMO-PAK-0515) was a retrospective German multicenter study investigating clinical and molecular characteristics of M1-PUL PDAC patients; 115 M1-PUL PDAC patients from 7 participating centers were included. Clinical characteristics and potential prognostic factors were defined within the M1-PUL cohort. Archival tumor samples were analyzed for Her2/neu, HNF1A and KRT81 expression. Additionally, messenger RNA (mRNA) expression analysis (using a 770-gene immune profiling panel) was carried out in the M1-PUL and in a control cohort (M1-ANY). RESULTS: Median overall survival in the entire M1-PUL cohort was 20 months; the most favorable prognosis (median survival: 28 months) was observed in the subgroup of 66 PDAC patients with metachronous lung metastases after previous curative-intent surgery. The number of metastatic lesions, uni- or bilateral lung involvement as well as metastasectomy were identified as potential prognostic factors. Her2/neu expression and PDAC subtyping (by HNF1A and KRT81) did not differ between the M1-PUL and the M1-ANY cohort. mRNA expression analysis revealed significant differentially expressed genes between both cohorts: CD63 and LAMP1 were among the top 20 differentially expressed genes and were identified as potential mediators of organotropism and favorable survival outcome of M1-PUL patients. CONCLUSION: M1-PUL represents a clinically favorable cohort in PDAC patients. Site of relapse might already be predetermined at the time of surgery and could potentially be predicted by gene expression profiling.

Pregnant women's use of e-cigarettes in the UK: a cross-sectional survey.

OBJECTIVE: To estimate prevalence of vaping in pregnancy. Compare characteristics and attitudes between exclusive smokers and vapers, and between exclusive vapers and dual users (smoke and vape). DESIGN: Cross-sectional survey. SETTING: Hospitals across England and Scotland. POPULATION: Pregnant women attending antenatal clinics in 2017. METHODS: Women at 8-24 weeks' gestation completed screening questions about their smoking and vaping. Current or recent ex-smokers and/or vapers completed a full detailed survey about vaping and smoking. MAIN OUTCOME MEASURES: The prevalence of vaping, characteristics and attitudes of women who vape and/or smoke. RESULTS: Of 3360 pregnant women who completed screening questions, 515 (15.3%, 95% CI 14.1-16.6) were exclusive smokers, 44 (1.3%, 95% CI 1.0-1.8) exclusive vapers and 118 (3.5%, 95% CI 2.9-4.2) dual users. In total, 867 (25.8%) women completed the full survey; compared with smokers (n = 434), vapers (n = 140) were more likely to hold higher educational qualifications (odds ratio [OR) 1.51, 95% CI 1.01-2.25). Compared with exclusive vapers (n = 33), dual users (n = 107) were younger (OR 0.91 95% CI 0.85-0.98) and less likely to hold high qualifications (OR 0.43, 95% CI 0.20-0.96). Compared with smokers, dual users were more likely to be planning to quit smoking (OR 2.27, 95% CI 1.24-4.18). Compared with smokers, vapers were more likely to think vaping was safer than smoking (78.6% versus 36.4%). CONCLUSIONS: One in 20 pregnant women report vaping, and most also smoke. Dual users are more motivated towards stopping smoking than smokers. Where women have tried but cannot stop smoking, clinicians could encourage them to consider vaping for smoking cessation. TWEETABLE EXTRACT: One in 20 women report vaping during pregnancy but of those that do vape, most also smoke, despite having intentions to quit.

Alternative type 2 diabetes screening tests may reduce the number of U.S. adults with undiagnosed diabetes.

AIM: To evaluate the U.S. population-level impact of two alternatives for initial type 2 diabetes screening [opportunistic random plasma glucose (RPG) > 6.7 mmol/l and a 1-h 50-g glucose challenge test (GCT) > 8.9 mmol/l] compared with American Diabetes Association (ADA)-recommended tests. METHODS: Using a sample (n = 1471) from the National Health and Nutrition Examination Survey (NHANES) 2013-2014 that represented 145 million U.S. adults at high risk for developing type 2 diabetes, we simulated a two-test screening process. We compared ADA-recommended screening tests [fasting plasma glucose (FPG), 2-h 75-g oral glucose tolerance test (OGTT), HbA1c ] vs. initial screening with opportunistic RPG or GCT (followed by FPG, OGTT or HbA1c ). After simulation, participants were entered into an individual-level Monte Carlo-based Markov lifetime outcomes model. Primary outcomes were representative number of U.S. adults correctly identified with type 2 diabetes, societal lifetime costs and quality-adjusted life years (QALYs). RESULTS: In NHANES 2013-2014, 100 individuals had undiagnosed diabetes [weighted estimate: 8.4 million, standard error (se): 1.1 million]. Among ADA-recommended screening tests, FPG followed by OGTT (FPG-OGTT) was most sensitive, identifying 35 individuals with undiagnosed diabetes (weighted estimate: 3.2 million, se: 0.9 million). Four alternative screening strategies performed superior to FPG-OGTT, with RPG followed by OGTT being the most sensitive overall, identifying 72 individuals with undiagnosed diabetes (weighted estimate: 6.1 million, se: 1.0 million). There was no increase in average lifetime costs and comparable QALYs. CONCLUSIONS: Initial screening using opportunistic RPG or a GCT may identify more U.S. adults with type 2 diabetes without increasing societal costs.

The utility of bone marrow sampling in the diagnosis and staging of lymphoma in South Africa.

INTRODUCTION: The bone marrow biopsy (BMB) is a diagnostic and staging tool in lymphoma that remains practically useful and relevant in resource-constrained settings, despite restricted applications in international staging guidelines, which favour less invasive nuclear medicine techniques. METHODS: Retrospective laboratory data review of BMBs in adult lymphoma patients from 2005 to 2010 to determine subtypes, rates of bone marrow involvement (BMI), human immunodeficiency virus (HIV) seroprevalence and CD4 counts, trephine length and additional findings. RESULTS: A total of 1215 BMBs reported in lymphoma included 759 newly diagnosed patients, with BMI in 43.6% of non-Hodgkin lymphoma (NHL) overall, 28.9% of high-grade B subtypes and 35.7% of Hodgkin lymphoma (HL). HIV seroprevalence was 38.8%, 53.0% and 33.9% in the 3 respective groups. There was a statistical association between BMI and HIV seropositivity in Burkitt lymphoma and HL, and BMI and CD4 count in HIV-related HL. Over 10% (n = 79) of new lymphoma cases were diagnosed by BMB with ancillary tests. Occasional histological discordance and transformation were reported in NHL. Focal/unilateral BMI was uncommon. Bilateral BMB and biopsy length exceeding 26 mm did not improve BMI detection. CONCLUSION: In the South African public sector, high HIV prevalence leads to a different lymphoma pathology profile from the developed world. High BMI rates are encountered. Here, and in similar resource-constrained settings, international lymphoma staging guidelines can be logistically challenging and unaffordable. BMB remains useful in the staging and diagnosis of lymphoma. Unilateral sampling with a processed trephine length of at least 26 mm is recommended.

Avascular necrosis in children with cerebral palsy after reconstructive hip surgery.

PURPOSE: Progressive hip displacement is one of the most common orthopaedic pathologies in children with cerebral palsy (CP). Reconstructive hip surgery has become the standard treatment of care. Reported avascular necrosis (AVN) rates for hip reconstructive surgery in these patients vary widely in the literature. The purpose of this study is to identify the frequency and associated risk factors of AVN for reconstructive hip procedures. METHODS: A retrospective analysis was performed of 70 cases of reconstructive hip surgery in 47 children with CP, between 2009 and 2013. All 70 cases involved varus derotation osteotomy (VDRO), with 60% having combined VDRO and pelvic osteotomies (PO), and 21% requiring open reductions. Mean age at time of surgery was 8.82 years and 90% of patients were Gross Motor Function Classification System (GMFCS) 4 and 5. Radiographic dysplasia parameters were analysed at selected intervals, to a minimum of one year post-operatively. Severity of AVN was classified by Kruczynski's method. Bivar- iate statistical analysis was conducted using Chi-square test and Student's t-test. RESULTS: There were 19 (27%) noted cases of AVN, all radio- graphically identifiable within the first post-operative year. The majority of AVN cases (63%) were mild to moderate in severity. Pre-operative migration percentage (MP) (p = 0.0009) and post-operative change in MP (p = 0.002) were the most significant predictors of AVN. Other risk factors were: GMFCS level (p = 0.031), post-operative change in NSA (p = 0.02) and concomitant adductor tenotomy (0.028). CONCLUSION: AVN was observed in 27% of patients. Severity of displacement correlates directly with AVN risk and we suggest that hip reconstruction, specifically VDRO, be performed early in the 'hip at risk' group to avoid this complication.

Impact of BRAF and RAS mutations on first-line efficacy of FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab: analysis of the FIRE-3 (AIO KRK-0306) study.

BACKGROUND: RAS and BRAF mutations have been identified as negative prognostic factors in metastatic colorectal cancer. Efficacy of 5-fluorouracil, leucovorin, irinotecan (FOLFIRI) plus bevacizumab in patients with RAS-mutant tumours needs to be further evaluated. Whether to treat patients with BRAF-mutant tumours with either bevacizumab or anti-epidermal growth factor receptor (EGFR) antibodies remains unclear. METHODS: Patients treated within the FIRE-3 trial were retrospectively tested for BRAF and RAS mutations using formalin fixated paraffin embedded (FFPE) tumour material applying pyrosequencing for KRAS and NRAS exon 2, 3 and 4 mutations as far as for BRAF mutations. Survival analysis was done using Kaplan-Meier estimation and differences were expressed using the log-rank test. Overall response rate (ORR) was compared using Fisher's exact test. Data from a central independent radiological response evaluation were used to calculate early tumour shrinkage (ETS) and depth of response (DpR). RESULTS: Overall, 188 patients with RAS-mutant tumours and 48 with BRAF-mutant tumours were identified. In BRAF-mutant patients, ORR was numerically higher in the cetuximab versus the bevacizumab arm (52% versus 40%), while comparable results were achieved for progression-free survival (PFS; hazard ratio [HR] = 0.84, p = 0.56) and overall survival (OS; HR 0.79, p = 0.45). RAS mutation was associated with a trend towards lower ORR (37% versus 50.5%, p = 0.11) and shorter PFS (7.4 versus 9.7 months; HR 1.25; p = 0.14) in patients receiving FOLFIRI plus cetuximab versus bevacizumab, but OS was comparable (19.1 versus 20.1 months; HR 1.05; p = 0.73), respectively. ETS identified subgroups sensitive to cetuximab-based treatment in both BRAF- (9/17) and RAS-mutant (18/48) patients and was associated with significantly longer OS. DpR was comparable between both treatment arms in RAS- and BRAF-mutant patients, respectively. CONCLUSIONS: In BRAF- and RAS-mutant patients, cetuximab- and bevacizumab-based treatment had comparable survival times. ETS represents an early parameter associated with the benefit from anti-EGFR, while this was not the case with vascular endothelial growth factor A blockade.

Glucose challenge test screening for prediabetes and early diabetes.

AIMS: To test the hypothesis that a 50-g oral glucose challenge test with 1-h glucose measurement would have superior performance compared with other opportunistic screening methods. METHODS: In this prospective study in a Veterans Health Administration primary care clinic, the following test performances, measured by area under receiver-operating characteristic curves, were compared: 50-g oral glucose challenge test; random glucose; and HbA1c level, using a 75-g oral glucose tolerance test as the 'gold standard'. RESULTS: The study population was comprised of 1535 people (mean age 56 years, BMI 30.3 kg/m2 , 94% men, 74% black). By oral glucose tolerance test criteria, diabetes was present in 10% and high-risk prediabetes was present in 22% of participants. The plasma glucose challenge test provided area under receiver-operating characteristic curves of 0.85 (95% CI 0.78-0.91) to detect diabetes and 0.76 (95% CI 0.72-0.80) to detect high-risk dysglycaemia (diabetes or high-risk prediabetes), while area under receiver-operating characteristic curves for the capillary glucose challenge test were 0.82 (95% CI 0.75-0.89) and 0.73 (95% CI 0.69-0.77) for diabetes and high-risk dysglycaemia, respectively. Random glucose performed less well [plasma: 0.76 (95% CI 0.69-0.82) and 0.66 (95% CI 0.62-0.71), respectively; capillary: 0.72 (95% CI 0.65-0.80) and 0.64 (95% CI 0.59-0.68), respectively], and HbA1c performed even less well [0.67 (95% CI 0.57-0.76) and 0.63 (95% CI 0.58-0.68), respectively]. The cost of identifying one case of high-risk dysglycaemia with a plasma glucose challenge test would be $42 from a Veterans Health Administration perspective, and $55 from a US Medicare perspective. CONCLUSIONS: Glucose challenge test screening, followed, if abnormal, by an oral glucose tolerance test, would be convenient and more accurate than other opportunistic tests. Use of glucose challenge test screening could improve management by permitting earlier therapy.

Evaluation of clinical coding data to determine causes of critical bleeding in patients receiving massive transfusion: a bi-national, multicentre, cross-sectional study.

OBJECTIVES: To evaluate the use of routinely collected data to determine the cause(s) of critical bleeding in patients who receive massive transfusion (MT). BACKGROUND: Routinely collected data are increasingly being used to describe and evaluate transfusion practice. MATERIALS/METHODS: Chart reviews were undertaken on 10 randomly selected MT patients at 48 hospitals across Australia and New Zealand to determine the cause(s) of critical bleeding. Diagnosis-related group (DRG) and International Classification of Diseases (ICD) codes were extracted separately and used to assign each patient a cause of critical bleeding. These were compared against chart review using percentage agreement and kappa statistics. RESULTS: A total of 427 MT patients were included with complete ICD and DRG data for 427 (100%) and 396 (93%), respectively. Good overall agreement was found between chart review and ICD codes (78·3%; κ = 0·74, 95% CI 0·70-0·79) and only fair overall agreement with DRG (51%; κ = 0·45, 95% CI 0·40-0·50). Both ICD and DRG were sensitive and accurate for classifying obstetric haemorrhage patients (98% sensitivity and κ > 0·94). However, compared with the ICD algorithm, DRGs were less sensitive and accurate in classifying bleeding as a result of gastrointestinal haemorrhage (74% vs 8%; κ = 0·75 vs 0·1), trauma (92% vs 62%; κ = 0·78 vs 0·67), cardiac (80% vs 57%; κ = 0·79 vs 0·60) and vascular surgery (64% vs 56%; κ = 0·69 vs 0·65). CONCLUSION: Algorithms using ICD codes can determine the cause of critical bleeding in patients requiring MT with good to excellent agreement with clinical history. DRG are less suitable to determine critical bleeding causes.

Giardia outbreak associated with a roadside spring in Rensselaer County, New York.

In September 2009, the Rensselaer County Department of Health investigated an increase in Giardia duodenalis cases. The epidemiological investigation identified that a source of the illness could be a roadside spring located in the eastern part of the county. Epidemiological and environmental health staff conducted a site visit to the roadside spring and found several concerns. Water samples were collected from the roadside spring and sent to the New York State Department of Health for analysis. The water sample results indicated the presence of empty Giardia cysts. Prevention methods occurred and the roadside spring was destroyed. A total of 36 laboratory-confirmed cases of Giardia were identified from this outbreak that included residents of New York State and Massachusetts.

Two C-C Family Chemokines, Eotaxin and RANTES, Are Novel Independent Plasma Biomarkers for Abdominal Aortic Aneurysm.

BACKGROUND: Inflammation of the aortic wall is recognised as a key pathogenesis of abdominal aortic aneurysm (AAA). This study was undertaken to determine whether inflammatory cytokines could be used as biomarkers for the presence of AAA. METHODS AND RESULTS: Tissue profiles of 27 inflammatory cytokine were examined in AAA (n=14) and nonaneurysmal (n=14) aortic tissues. Three cytokines, regulated upon activation normally T-cell expressed and secreted (RANTES), eotaxin, and macrophage inflammatory protein 1 beta (MIP-1b), had increased expression in AAA, particularly within the adventitial layer of the aortic wall. Basic fibroblast growth factor (bFGF) had reduced expression in all layers of the AAA wall. Examination of the circulating plasma profiles of AAA (n=442) and AAA-free controls (n=970) suggested a (risk factor adjusted) AAA-association with eotaxin, RANTES, and high sensitivity C-reactive protein (hsCRP). A plasma inflammatory cytokine score, calculated using these three markers, suggested a strong risk association with AAA (odds ratio, 4.8; 95% CI, 3.5-6.7; P<0.0001), independent of age, sex, history of ischemic heart disease, and smoking. CONCLUSIONS: Contrary to reports suggesting a distinct T helper 2-associated inflammatory profile in AAA, this current study suggests a more-generalized pattern of inflammation, albeit with some potentially distinct features, including elevated plasma eotaxin and decreased plasma RANTES. In combination with hsCRP, these markers may have potential utility as AAA biomarkers.

Disposition index identifies defective beta-cell function in cystic fibrosis subjects with normal glucose tolerance.

BACKGROUND: In non-cystic fibrosis (CF) subjects, the disposition index (DI) is a strong predictor of the development of type 2 diabetes. CF subjects are at high risk of diabetes. We hypothesized that DI would be reduced in CF patients with normal glucose tolerance (NGT), indicating ß-cell dysfunction, and DI would worsen with progression from CF with NGT to CF-related diabetes (CFRD). METHODS: This was a cross-sectional study in 39 CF patients and 21 healthy controls (Con) who underwent oral glucose tolerance test (OGTT). Insulin sensitivity was estimated as (1/fasting insulin) and insulin secretion as (∆insulin 0-30min/∆glucose 0-30min). DI was calculated as (insulin sensitivity)×(insulin secretion). RESULTS: Among CF subjects, 14 had NGT, 20 had prediabetes and 5 had CFRD. Among the controls, 14 had NGT and 7 had prediabetes. DI was significantly lower in CF-NGT compared to Con-NGT (p=0.0035). DI was also lower in CFRD compared to CF-NGT (p=0.025). There were no significant relationships in the CF groups between DI and age, BMI, percent body fat or FEV1. CONCLUSION: ß-Cell function as measured by DI is reduced in CF patients compared to non-CF controls-even in CF-NGT-and is decreased further in CF patients with diabetes. If DI proves to be a predictor of the development of CFRD in larger studies, then it could be used to identify CF patients who are at particularly high risk, allowing early interventions aimed to delay or prevent CFRD.

Evaluation of complications and feasibility of indwelling epidural catheter use for post-operative pain control in dogs in the home environment.

AIMS: The objective of this study was to describe the use of indwelling epidural catheters post-operatively in dogs in a home environment, and to report associated complications. METHODS: Dogs undergoing surgical procedures of the hind limb (n=83) were included in the study and were administered 0.05 or 0.10 mg/kg epidural morphine via an indwelling epidural catheter every 6 hours. Data compiled relating to catheter placement included time of placement, ease of placement and problems encountered, number of attempts of placement, and individual placing the catheter. A client questionnaire was provided to evaluate side effects, complications, pain, and ease of use of the epidural catheter system after discharge from the hospital and catheter removal at home. Side effects were compared between the dogs receiving 0.05 or 0.1 mg/kg epidural morphine. RESULTS: The most common patient complication was abnormal urination patterns (32/82, 39%); specifically dribbling urine where laying, emptying the entire bladder where laying, not urinating for extended periods of time, and taking a longer time to pass urine were reported. There were no significant differences in the number or types of side effects reported in either dosing group. The most common technical issues reported by owners were difficulty getting the needle into the injection port (10/81, 12%) and removing the adhesive covering keeping the epidural catheter system in place (19/78, 24%). There were no reports of inflammation or discharge at the catheter site in any of the dogs. Of the respondents surveyed, 76/79 (97%) found the epidural catheter system easy to use at home in the post-operative period. CONCLUSIONS: Indwelling epidural catheters are a feasible method of administration of post-operative analgesia in the immediate post-operative period in the home environment and were associated with only a few minor complications in this population.

Aging is associated with increased HbA1c levels, independently of glucose levels and insulin resistance, and also with decreased HbA1c diagnostic specificity.

AIM: To determine whether using HbA1c for screening and management could be confounded by age differences, whether age effects can be explained by unrecognized diabetes and prediabetes, insulin resistance or postprandial hyperglycaemia, and whether the effects of aging have an impact on diagnostic accuracy. METHODS: We conducted a cross-sectional analysis in adults without known diabetes in the Screening for Impaired Glucose Tolerance (SIGT) study 2005-2008 (n=1573) and the National Health and Nutrition Examination Survey (NHANES) 2005-2006 (n=1184). RESULTS: Both glucose intolerance and HbA(1c) levels increased with age. In univariate analyses including all subjects, HbA(1c) levels increased by 0.93 mmol/mol (0.085%) per 10 years of age in the SIGT study and by 1.03 mmol/mol (0.094%) per 10 years in the NHANES; in both datasets, the HbA(1c) increase was 0.87 mmol/mol (0.08%) per 10 years in subjects without diabetes, and 0.76 mmol/mol (0.07%) per 10 years in subjects with normal glucose tolerance, all P<0.001. In multivariate analyses of subjects with normal glucose tolerance, the relationship between age and HbA(1c) remained significant (P<0.001) after adjustment for covariates including race, BMI, waist circumference, sagittal abdominal diameter, triglyceride/HDL ratio, and fasting and 2-h plasma glucose and other glucose levels, as assessed by an oral glucose tolerance test. In both datasets, the HbA(1c) of an 80-year-old individual with normal glucose tolerance would be 3.82 mmol/mol (0.35%) greater than that of a 30-year-old with normal glucose tolerance, a difference that is clinically significant. Moreover, the specificity of HbA(1c) -based diagnostic criteria for prediabetes decreased substantially with increasing age (P<0.0001). CONCLUSIONS: In two large datasets, using different methods to measure HbA(1c), the association of age with higher HbA(1c) levels: was consistent and similar; was both statistically and clinically significant; was unexplained by features of aging; and reduced diagnostic specificity. Age should be taken into consideration when using HbA(1c) for the diagnosis and management of diabetes and prediabetes.

Postprandial total and HMW adiponectin following a high-fat meal in lean, obese and diabetic men.

BACKGROUND/OBJECTIVES: Recent work suggests that macronutrients are pro-inflammatory and promote oxidative stress. Reports of postprandial regulation of total adiponectin have been mixed, and there is limited information regarding postprandial changes in high molecular weight (HMW) adiponectin. The aim of this study was to assess the effect of a standardised high-fat meal on metabolic variables, adiponectin (total and HMW), and markers of inflammation and oxidative stress in: (i) lean, (ii) obese non-diabetic and (iii) men with type 2 diabetes mellitus (T2DM). SUBJECTS/METHODS: Male subjects: lean (n=10), obese (n=10) and T2DM (n=10) were studied for 6 h following both a high-fat meal and water control. Metabolic variables (glucose, insulin, triglycerides), inflammatory markers (interleukin-6 (IL6), tumour necrosis factor (TNF)α, high-sensitivity C-reactive protein (hsCRP), nuclear factor (NF)κB expression in peripheral blood mononuclear cells (p65)), indicators of oxidative stress (oxidised low density lipoprotein (oxLDL), protein carbonyl) and adiponectin (total and HMW) were measured. RESULTS: No significant changes in TNFα, p65, oxLDL or protein carbonyl concentrations were observed. Overall, postprandial IL6 decreased in subjects with T2DM but increased in lean subjects, whereas hsCRP decreased in the lean cohort and increased in obese subjects. There was no overall postprandial change in total or HMW adiponectin in any group. Total adiponectin concentrations changed over time following the water control, and the response was significantly different in lean subjects compared with subjects with T2DM (P=0.04). CONCLUSIONS: No consistent significant postprandial inflammation, oxidative stress or regulation of adiponectin was observed in this study. Findings from the water control suggest differential basal regulation of total adiponectin in T2DM compared with lean controls.

Investigation of outcomes following recombinant activated FVII use for refractory bleeding during abdominal aortic aneurysm repair.

OBJECTIVE: To evaluate the outcomes following recombinant activated factor VII (rFVIIa) use during abdominal aortic aneurysms (AAA) repair. DESIGN: AAA patients were selected from the Australian and New Zealand Haemostasis Registry (ANZHR) who received off-licence rFVIIa to control critical bleeding. METHODS: Patient characteristics and outcomes were compared between responders (bleeding stopped/attenuated) and non-responders (bleeding continued) to rFVIIa, stratified by aneurysm status (ruptured (r-AAA) vs. non-ruptured (nr-AAA)). Patients were also scored using POSSUM (Physiological and Operative Severity Score for the enUmeration of Mortality and morbidity) and Hardman Index mortality predictive models. RESULTS: In total, 77 AAA patients were included in the analysis. Approximately 73% (n = 56) of them had ruptured aneurysms and about 50% (n = 35/70 with known data) responded positively to rFVIIa. Eleven incidents of thromboembolic adverse events were reported in 9 patients (6 r-AAA and 3 nr-AAA). Responders in both ruptured and non-ruptured groups had significantly lower 28-day mortality than non-responders (r-AAA: 40% (10/25) vs. 92% (24/26); P < 0.001; nr-AAA: 30% (3/10) vs. 67% (6/9); P < 0.01). Mortality predictive models did not show any difference between overall observed and expected mortality in ANZHR patients. CONCLUSION: Patients who responded to rFVIIa had a lower mortality than those who did not respond to the treatment.

Syk-induced phosphatidylinositol-3-kinase activation in Epstein-Barr virus posttransplant lymphoproliferative disorder.

Posttransplant lymphoproliferative disorder (PTLD)-associated Epstein-Barr virus (EBV)+ B cell lymphomas are serious complications of solid organ and bone marrow transplantation. The EBV protein LMP2a, a B cell receptor (BCR) mimic, provides survival signals to virally infected cells through Syk tyrosine kinase. Therefore, we explored whether Syk inhibition is a viable therapeutic strategy for EBV-associated PTLD. We have shown that R406, the active metabolite of the Syk inhibitor fostamatinib, induces apoptosis and cell cycle arrest while decreasing downstream phosphatidylinositol-3'-kinase (PI3K)/Akt signaling in EBV+ B cell lymphoma PTLD lines in vitro. However, Syk inhibition did not inhibit or delay the in vivo growth of solid tumors established from EBV-infected B cell lines. Instead, we observed tumor growth in adjacent inguinal lymph nodes exclusively in fostamatinib-treated animals. In contrast, direct inhibition of PI3K/Akt significantly reduced tumor burden in a xenogeneic mouse model of PTLD without evidence of tumor growth in adjacent inguinal lymph nodes. Taken together, our data indicate that Syk activates PI3K/Akt signaling which is required for survival of EBV+ B cell lymphomas. PI3K/Akt signaling may be a promising therapeutic target for PTLD, and other EBV-associated malignancies.

Differential expression of microRNAs during allograft rejection.

MicrorRNA are small noncoding RNA molecules that regulate the posttranscriptional expression of target genes. In addition to being involved in many biologic processes, microRNAs are important regulators in innate and adaptive immune responses. Distinct sets of expressed microRNAs are found in different cell types and tissues and aberrant expression of microRNAs is associated with many disease states. MicroRNA expression was examined in a model of heterotopic heart transplantation by microarray analyses and a unique profile was detected in rejecting allogeneic transplants (BALB/c → C57BL/6) as compared to syngeneic transplants (C57BL/6 → C57BL/6). The microRNA miR-182 was significantly increased in rejecting cardiac allografts and in mononuclear cells that infiltrate the grafts. Forkhead box (FOX) proteins are a family of important transcription factors and FOXO1 is a target of miR-182. As miR-182 increases after transplant, there is a concomitant posttranscriptional decrease in FOXO1 expression in heart allografts that is localized to both the cardiomyocytes and CD3(+) T cells. The microRNA miR-182 is significantly increased in both peripheral blood mononuclear cells and plasma during graft rejection suggesting potential as a biomarker of graft status. Our results identify microRNAs that may regulate alloimmune responses and graft outcomes.

Interaction of the inflammasome genes CARD8 and NLRP3 in abdominal aortic aneurysms.

OBJECTIVE: Cholesterol crystals have been shown to cause inflammation, and ultimately atherosclerotic lesions through the activation of the NLRP3 inflammasome. As cholesterol crystals have also been found in the walls of patients with abdominal aortic aneurysms (AAA), it is possible that the NLRP3 inflammasome is involved in AAA and genetic variability within this protein complex could alter disease risk. The primary objective of this study was to assess whether there is genetic evidence for a role of the NLRP3 inflammasome in AAA by testing for association of AAA with functional single nucleotide polymorphisms (SNPs) in the CARD8 and NLRP3 genes. METHODS: AAA patients (n=1151) and controls (n=727) were genotyped for CARD8 SNP rs2043211 and NLRP3 SNP rs35829419 using TaqMan SNP assays. IL1-ß, C-reactive protein (CRP), and lipoprotein (a) [Lp(a)] were measured in the plasma of a subset of study participants. The Kruskal-Wallis Rank test was conducted to test for differences in mean concentration of IL1-ß, CRP and Lp(a). Logistic regression was used to test for interaction between CARD8 and NLRP3. RESULTS: Significantly higher mean concentration of plasma IL1-ß was observed in study participants who were homozygous for the common C allele of NLRP3 rs35829419 (p=0.010). Interaction between rs2043211 and rs35829419 was observed in this dataset (χ(2)=6.22; p=0.044), which strengthened when adjusted for age, gender, smoking, diabetes, hypertension, and dyslipidemia (χ(2)=14.75; p=0.012); and separately for NOD2 genotype (χ(2)=14.06; p=0.015). CONCLUSION: Our finding suggests genetic variability within the NLRP3 inflammasome may be important in the pathophysiology of AAA.

Akt phosphorylation on Thr308 but not on Ser473 correlates with Akt protein kinase activity in human non-small cell lung cancer.

BACKGROUND: The activity of the protein kinase Akt is frequently dysregulated in cancer and is an important factor in the growth and survival of tumour cells. Akt activation involves the phosphorylation of two residues: threonine 308 (Thr308) in the activation loop and serine 473 (Ser473) in the C-terminal hydrophobic motif. Phosphorylation of Ser473 has been extensively studied in tumour samples as a correlate for Akt activity, yet the phosphorylation of Thr308 or of downstream Akt substrates is rarely assessed. METHODS: The phosphorylation status of Thr308 and Ser473 was compared with that of three separate Akt substrates - PRAS40, TSC2 and TBC1D4 - in fresh frozen samples of early-stage human non-small cell lung cancer (NSCLC). RESULTS: Akt Thr308 phosphorylation correlated with the phosphorylation of each Akt substrate tested, whereas Akt Ser473 phosphorylation did not correlate with the phosphorylation of any of the substrates examined. CONCLUSION: The phosphorylation of Thr308 is a more reliable biomarker for the protein kinase activity of Akt in tumour samples than Ser473. Any evaluation of the link between Akt phosphorylation or activity in tumour samples and the prediction or prognosis of disease should, therefore, focus on measuring the phosphorylation of Akt on Thr308 and/or at least one downstream Akt substrate, rather than Akt Ser473 phosphorylation alone.