Background:This study evaluated the addition of sorafenib to gemcitabine and cisplatin in biliary adenocarcinoma first-line therapy.Methods:Patients with advanced biliary adenocarcinomas received gemcitabine 1000 mg m−2 and cisplatin 25 mg m−2 on a 2 weeks on/1 week off cycle and sorafenib 400 mg twice daily. After the initial 16 patients were enrolled, the chemotherapy doses were amended in view of grade 3 and 4 hand–foot skin reaction and haematologic toxicity. Subsequently, 21 patients received gemcitabine 800 mg m−2, cisplatin 20 mg m−2 and sorafenib 400 mg. The primary end point was an improvement in 6-month progression-free survival (PFS6) from historical 57–77% (90% power, type I error of 10%). Pretreatment pERK, evaluated by immunostaining, was correlated with clinical outcome.Results:A total of 39 patients were accrued. The most common grade 3–4 toxicities noted in >10% of patients were fatigue, elevated liver function tests and haematologic toxicities including thromboemboli, hyponatraemia and hypophosphataemia. Six-month progression-free survival was 51% (95% confidence interval (CI) 34–66%). Median PFS and overall survival were 6.5 (95% CI: 3.5–8.3) and 14.4 months (95% CI: 11.6–19.2 months), respectively. No correlation was observed between pERK and outcomes.Conclusion:The addition of sorafenib to gemcitabine and cisplatin in biliary adenocarcinomas did not improve efficacy over historical data, and toxicity was increased.

Background and Aims IGF-IR is implicated in hepatic carcinogenesis. This and preliminary evidence of biological activity of anti-IGF-1R monoclonal antibody cixutumumab in phase I trials prompted this phase II study. Methods Patients with advanced HCC, Child-Pugh A-B8, received cixutumumab 6 mg/kg weekly, in a Simon two-stage design study, with the primary endpoints being 4-month PFS and RECIST-defined response rate. Tissue and circulating markers plus different HCC scoring systems were evaluated for correlation with PFS and OS. Results As a result of pre-specified futility criteria, only stage 1 was accrued: N= 24: median age 67.5 years (range 49–83), KPS 80% (70–90%), 20 males (83%), 9 stage III (37%)/15 stage IV (63%), 18 Child-Pugh A (75%), 11 HBV (46%) /10 HCV (42%)/11 alcoholic cirrhosis (46%)/2 NASH (8%), 11 (46%) diabetic. Median number of doses: 7 (range 1–140). Grade 3/4 toxicities > 10% included: diabetes, elevated liver function tests, hyponatremia, and lymphopenia. Four-month PFS was 30% (95% CI 13–48), and there were no objective responses. Median overall survival was 8 months (95%CI 5.8– 14). IGF-R1 staining did not correlate with outcome. Elevated IGFBP-1 correlated with improved PFS (1.2 [95%CI 1–1.4]; p 0.009) and OS (1.2 [95%CI 1.1–1.4]; p 0.003). Conclusions Cixutumumab monotherapy did not have clinically meaningful activity in this unselected HCC population. Grade 3–4 hyperglycemia occurred in 46% of patients. Elevated IGFBP-1 correlated with improved PFS and OS.

Deacylation of purified lipopolysaccharides (LPS)markedly reduces its toxicity toward mammals. However, the biological significance of LPS deacylation during infection of the mammalian host is uncertain, particularly because the ability of acyloxyacyl hydrolase, the leukocyte enzyme that deacylates purified LPS, to attack LPS residing in the bacterial cell envelope has not been established. We recently showed that the cellular and extracellular components of a rabbit sterile inflammatory exudate are capable of extensive and selective removal of secondary acyl chains from purified LPS. We now report that LPS as a constituent of the bacterial envelope is also subject to deacylation in the same inflammatory setting. Using Escherichia coli LCD25, a strain that exclusively incorporates radiolabeled acetate into fatty acids, we quantitated LPS deacylation as the loss of radiolabeled secondary (laurate and myristate) and primary fatty acids (3-hydroxymyristate) from the LPS backbone. Isolated mononuclear cells and neutrophils removed 50% and 20 -30%, respectively, of the secondary acyl chains of the LPS of ingested whole bacteria. When bacteria were killed extracellularly during incubation with ascitic fluid, no LPS deacylation occurred. In this setting, the addition of neutrophils had no effect, but addition of mononuclear cells resulted in removal of >40% of the secondary acyl chains by 20 h. Deacylation of LPS was always restricted to the secondary acyl chains. Thus, in an inflammatory exudate, primarily in mononuclear phagocytes, the LPS in whole bacteria undergoes substantial and selective acyloxyacyl hydrolase-like deacylation, both after phagocytosis of intact bacteria and after uptake of LPS shed from extracellularly killed bacteria. This study demonstrates for the first time that the destruction of Gram-negative bacteria by a mammalian host is not restricted to degradation of phospholipids, protein, and RNA, but also includes extensive deacylation of the envelope LPS.The prominent role ascribed to LPS 1 in evoking beneficial as well as harmful mammalian host responses to invading Gramnegative bacteria has prompted intense scrutiny of host recognition, detoxification, and elimination of this bacterial product. Underacylated and underphosphorylated biosynthetic precursors and chemically synthesized analogs of lipid A (the endotoxic part of LPS) possess greatly diminished endotoxic activity and can act as antagonists in human cell bioassays (1, 2). Mammalian enzyme systems capable of removing acyl and phosphate groups from lipid A may therefore play an important role in host defense against Gram-negative bacteria and their LPS. Thus far, only one mammalian enzyme, acyloxyacyl hydrolase, has been shown to deacylate LPS (3, 4).We recently showed that both the cells and extracellular fluid of a sterile inflammatory exudate actively deacylate purified LPS ex vivo in an acyloxyacyl hydrolase-like fashion (5). It has been much more difficult to analyze LPS breakdown products when the LPS is presented in intact bacteria...

Intraductal papillary mucinous neoplasms (IPMN) are being diagnosed with increasing frequency, necessitating an algorithm to help stratify patients into low- and high-risk groups, for follow-up versus more invasive evaluation. New evidence concerning their natural history and overall risk of malignancy has emerged since the 2006 International Association of Pancreatology consensus guidelines, prompting an update in 2012, that distinguishes radiologic 'worrisome features' from 'high-risk stigmata'. The aim of this article is to illustrate, with case examples, the variable imaging patterns of IPMN and how their radiologic features, such as cyst size and mural nodules, are interpreted in the context of the new 2012 guidelines. The 2012 and 2006 guidelines will be compared and discussed with reference to additional studies that have since been published. Despite these guidelines, lingering uncertainty remains about the natural history of IPMN, a source of unease to both radiologists and referring clinicians alike, mandating further refinement of clinical and radiologic parameters predictive of malignancy. Emerging data regarding the risk of extrapancreatic malignancy, as well as synchronous or metachronous pancreatic ductal adenocarcinoma remote in location from a branch duct IPMN are also reviewed. With the expanding research and evolving understanding of this clinicopathologic entity across the globe, radiologists will continue to play an important role in the management of patients with IPMN.

OBJECTIVE The purpose of this retrospective study was to measure interobserver agreement in the assessment of malignant imaging features of intraductal papillary mucinous neoplasms (IPMNs) on MDCT. MATERIALS AND METHODS Pancreatic protocol CT studies were reviewed for 84 patients with resected IPMNs. Maximal diameter of the dominant cyst, presence of a mural nodule, presence of a solid component, and diameters of the main pancreatic duct (MPD) and common bile duct (CBD) were measured by four radiologists independently. In each patient, the IPMN was classified into one of three types: main duct, branch duct, or mixed IPMN. Interobserver agreement of lesion features was examined using the intraclass correlation coefficient (ICC) for continuous features and Fleiss kappa for categorical features. RESULTS The final dataset included 55 branch duct IPMNs, nine main duct IPMNs, and 20 mixed IPMNs. Moderate agreement (κ = 0.458; 95% CI, 0.345–0.564) was observed in assigning branch duct, main duct, or mixed IPMN subtypes. Measurement agreement was substantial to excellent for dominant cyst (ICC = 0.852; 95% CI, 0.777–0.907), MPD (0.753, 0.655–0.837), and CBD (0.608, 0.463–0.724) but only fair to moderate for the detection of the presence of mural nodule (κ = 0.284, 0.125–0.432) or solid component (κ = 0.405, 0211–0.577). CONCLUSION Substantial to excellent interobserver agreement in the measurement of cyst diameter, MPD, and CBD support their use for characterizing malignant features of IPMN on MDCT. However, the subjective interpretation of the presence of solid components and mural nodules by individual radiologists was more variable.