Citations

The Papanicolaou Society of Cytopathology has developed a set of guidelines for pancreatobiliary cytology including indications for endoscopic ultrasound guided fine‐needle aspiration biopsy, techniques of the endoscopic retrograde cholangiopancreatography, terminology and nomenclature of pancreatobiliary disease, ancillary testing, and postbiopsy management. All documents are based on the expertise of the authors, a review of the literature, discussions of the draft document at several national and international meetings over an 18‐month period and synthesis of online comments of the draft document on the Papanicolaou Society of Cytopathology website [www.papsociety.org]. This document presents the results of these discussions regarding the use of ancillary testing in the cytological diagnosis of biliary and pancreatic lesions. This document summarizes the current state of the art for techniques in acquiring cytology specimens from the biliary tree as well as solid and cystic lesions of the pancreas. Diagn. Cytopathol. 2014;42:333–337. © 2014 Wiley Periodicals, Inc.

Purpose Studies of diffuse large B-cell lymphoma (DLBCL) are typically evaluated by using a time-to-event approach with relapse, re-treatment, and death commonly used as the events. We evaluated the timing and type of events in newly diagnosed DLBCL and compared patient outcome with reference population data. Patients and Methods Patients with newly diagnosed DLBCL treated with immunochemotherapy were prospectively enrolled onto the University of Iowa/Mayo Clinic Specialized Program of Research Excellence Molecular Epidemiology Resource (MER) and the North Central Cancer Treatment Group NCCTG-N0489 clinical trial from 2002 to 2009. Patient outcomes were evaluated at diagnosis and in the subsets of patients achieving event-free status at 12 months (EFS12) and 24 months (EFS24) from diagnosis. Overall survival was compared with age- and sex-matched population data. Results were replicated in an external validation cohort from the Groupe d'Etude des Lymphomes de l'Adulte (GELA) Lymphome Non Hodgkinien 2003 (LNH2003) program and a registry based in Lyon, France. Results In all, 767 patients with newly diagnosed DLBCL who had a median age of 63 years were enrolled onto the MER and NCCTG studies. At a median follow-up of 60 months (range, 8 to 116 months), 299 patients had an event and 210 patients had died. Patients achieving EFS24 had an overall survival equivalent to that of the age- and sex-matched general population (standardized mortality ratio [SMR], 1.18; P = .25). This result was confirmed in 820 patients from the GELA study and registry in Lyon (SMR, 1.09; P = .71). Simulation studies showed that EFS24 has comparable power to continuous EFS when evaluating clinical trials in DLBCL. Conclusion Patients with DLBCL who achieve EFS24 have a subsequent overall survival equivalent to that of the age- and sex-matched general population. EFS24 will be useful in patient counseling and should be considered as an end point for future studies of newly diagnosed DLBCL.

Aims Citalopram ( CT ) and escitalopram ( S ‐ CT ) are among the most widely prescribed selective serotonin reuptake inhibitors used to treat major depressive disorder ( MDD ). We applied a genome‐wide association study to identify genetic factors that contribute to variation in plasma concentrations of CT or S ‐ CT and their metabolites in MDD patients treated with CT or S ‐ CT . Methods Our genome‐wide association study was performed using samples from 435 MDD patients. Linear mixed models were used to account for within‐subject correlations of longitudinal measures of plasma drug/metabolite concentrations (4 and 8 weeks after the initiation of drug therapy), and single‐nucleotide polymorphisms ( SNPs ) were modelled as additive allelic effects. Results Genome‐wide significant associations were observed for S ‐ CT concentration with SNPs in or near the CYP2C19 gene on chromosome 10 (rs1074145, P = 4.1 × 10 −9 ) and with S ‐didesmethylcitalopram concentration for SNPs near the CYP2D6 locus on chromosome 22 (rs1065852, P = 2.0 × 10 −16 ), supporting the important role of these cytochrome P450 ( CYP ) enzymes in biotransformation of citalopram. After adjustment for the effect of CYP2C19 functional alleles, the analyses also identified novel loci that will require future replication and functional validation. Conclusions In vitro and in vivo studies have suggested that the biotransformation of CT to monodesmethylcitalopram and didesmethylcitalopram is mediated by CYP isozymes. The results of our genome‐wide association study performed in MDD patients treated with CT or S ‐ CT have confirmed those observations but also identified novel genomic loci that might play a role in variation in plasma levels of CT or its metabolites during the treatment of MDD patients with these selective serotonin reuptake inhibitors.

AbstractObjectiveElevations in uric acid (UA) and the associated hyperuricaemia are commonly observed secondary to treatment with thiazide diuretics. We sought to identify novel single nucleotide polymorphisms (SNPs) associated with hydrochlorothiazide (HCTZ)‐induced elevations in UA and hyperuricaemia.MethodsA genome‐wide association study of HCTZ‐induced changes in UA was performed in Caucasian and African American participants from the pharmacogenomic evaluation of antihypertensive responses (PEAR) study who were treated with HCTZ monotherapy. Suggestive SNPs were replicated in Caucasians and African Americans from the PEAR study who were treated with HCTZ add‐on therapy. Replicated regions were followed up through expression and pathway analysis.ResultsFive unique gene regions were identified in African Americans (LUC7L2, ANKRD17/COX18, FTO, PADI4 and PARD3B), and one region was identified in Caucasians (GRIN3A). Increases in UA of up to 1.8 mg dL−1 were observed following HCTZ therapy in individuals homozygous for risk alleles, with heterozygotes displaying an intermediate phenotype. Several risk alleles were also associated with an increased risk of HCTZ‐induced clinical hyperuricaemia. A composite risk score, constructed in African Americans using the ‘top’ SNP from each gene region, was strongly associated with HCTZ‐induced UA elevations (P = 1.79 × 10−7) and explained 11% of the variability in UA response. Expression studies in RNA from whole blood revealed significant differences in expression of FTO by rs4784333 genotype. Pathway analysis showed putative connections between many of the genes identified through common microRNAs.ConclusionSeveral novel gene regions were associated with HCTZ‐induced UA elevations in African Americans (LUC7L2, COX18/ANKRD17, FTO, PADI4 and PARD3B), and one region was associated with these elevations in Caucasians (GRIN3A).

GH is an important regulator of body growth and composition as well as numerous other metabolic processes. In particular, liver plays a key role in the GH/IGF-I axis, because the majority of circulating “endocrine” IGF-I results from GH-stimulated liver IGF-I production. To develop a better understanding of the role of liver in the overall function of GH, we generated a strain of mice with liver-specific GH receptor (GHR) gene knockout (LiGHRKO mice). LiGHRKO mice had a 90% decrease in circulating IGF-I levels, a 300% increase in circulating GH, and significant changes in IGF binding protein (IGFBP)-1, IGFBP-2, IGFBP-3, IGFBP-5, and IGFBP-7. LiGHRKO mice were smaller than controls, with body length and body weight being significantly decreased in both sexes. Analysis of body composition over time revealed a pattern similar to those found in GH transgenic mice; that is, LiGHRKO mice had a higher percentage of body fat at early ages followed by lower percentage of body fat in adulthood. Local IGF-I mRNA levels were significantly increased in skeletal muscle and select adipose tissue depots. Grip strength was increased in LiGHRKO mice. Finally, circulating levels of leptin, resistin, and adiponectin were increased in LiGHRKO mice. In conclusion, LiGHRKO mice are smaller despite increased local mRNA expression of IGF-I in several tissues, suggesting that liver-derived IGF-I is indeed important for normal body growth. Furthermore, our data suggest that novel GH-dependent cross talk between liver and adipose is important for regulation of adipokines in vivo.

ObjectivesTo evaluate the oncologic safety of the submental flap regarding potential transposition of involved nodes to the reconstruction site and recognize the submental flap as an excellent option for oral cavity reconstruction.Study DesignCase series with chart review.SettingTertiary academic referral center.Subjects and MethodsAll patients undergoing reconstruction with submental flaps following the resection of primary and recurrent malignancies of the oral cavity between 2002 and 2012 were reviewed. Analysis included tumor location, staging, reconstructive details, postoperative course, and outcomes.ResultsFifty patients were identified having undergone submental flap reconstruction of defects following resection for oral cavity malignancies. No patient had identifiable clinical or radiographic level I nodal involvement preoperatively. Patients’ ages ranged from 35 to 88 years (mean, 70 years). American Joint Committee on Cancer staging of patients included stage II (n = 16, 32%), stage III (n = 10, 20%), and stage IVa disease (n = 28, 48%). All patients underwent a level 1A and 1B dissection with removal of the nodal basin and submandibular gland. The prevalence of occult lymph node metastasis involving level 1 was 10%. On follow‐up, there were no local recurrences associated with submental flap transposition to the oral cavity. One patient with multifocal oral disease had a tongue recurrence geographically separate from the submental flap reconstruction. There was 100% flap survival.ConclusionsThe submental flap provides a rapid and reliable option for oral cavity defect reconstruction. With appropriate management of the level 1 nodal compartment, oncologic outcomes are not compromised.

Easy M Our immune systems can produce a vastly diverse repertoire of antibody molecules that each recognize and bind to a specific foreign antigen via a hypervariable region. However, there are a few bacterial antigens—such as Protein A, Protein G, and Protein L—that instead bind to the antibody's conserved regions and can bind to a large number of different antibodies. These high-affinity broad-spectrum antibody-binding properties have been widely exploited both in the laboratory and in industry for purifying, immobilizing, and detecting antibodies. Grover et al. (p. 656 ) have now identified Protein M found on the surface of human mycoplasma, which displays even broader antibody-binding specificity. The crystal structure of Protein M revealed how Protein-M binding blocks the antibody's antigen binding site. This mechanism may be exploited by mycoplasma to escape the humoral immune response.

Loss of cystic fibrosis transmembrane conductance regulator (CFTR) function reduces chloride secretion and increases sodium uptake, but it is not clear why CFTR mutation also results in progressive lung inflammation and infection. We previously demonstrated that CFTR-silenced airway cells migrate more slowly during wound repair than CFTR-expressing controls. In addition, CFTR-deficient cells and mouse models have been reported to have altered sphingolipid levels. Here, we investigated the hypothesis that reduced migration in CFTR-deficient airway epithelial cells results from altered sphingolipid composition. We used cell lines derived from a human airway epithelial cell line (Calu-3) stably transfected with CFTR short hairpin RNA (CFTR-silenced) or nontargeting short hairpin RNA (controls). Cell migration was measured by electric cell substrate impedance sensing (ECIS). Lipid analyses, addition of exogenous glycosphingolipids, and immunoblotting were performed. We found that levels of the glycosphingolipid, GM1 ganglioside, were ∼60% lower in CFTR-silenced cells than in controls. CFTR-silenced cells exhibited reduced levels of activated β1-integrin, phosphorylated tyrosine 576 of focal adhesion kinase (pFAK), and phosphorylation of Crk-associated substrate (pCAS). Addition of GM1 (but not GM3) ganglioside to CFTR-silenced cells restored activated β1-integrin, pFAK, and pCAS to near control levels and partially restored (∼40%) cell migration. Our results suggest that decreased GM1 in CFTR-silenced cells depresses β1-integrin signaling, which contributes to the delayed wound repair observed in these cells. These findings have implications for the pathology of cystic fibrosis, where altered sphingolipid levels in airway epithelial cells could result in a diminished capacity for wound repair after injury.

Purpose To evaluate the feasibility of using three‐dimensional (3D) MR elastography (MRE) to determine the stiffness of the pancreas in healthy volunteers. Materials and Methods Twenty healthy volunteers underwent 1.5 Tesla MRE exams using an accelerated echo planar imaging (EPI) pulse sequence with low‐frequency vibrations (40 and 60 Hz). Stiffness was calculated with a 3D direct inversion algorithm. The mean shear stiffness in five pancreatic subregions (uncinate, head, neck, body, and tail) and the corresponding liver stiffness were calculated. The intrasubject coefficient of variation (CV) was calculated as a measure of the reproducibility for each volunteer. Results The mean shear stiffness (average of values obtained in different pancreatic subregions) was (1.15 ± 0.17) kPa at 40 Hz, and (2.09 ± 0.33) kPa at 60 Hz. The corresponding liver stiffness was higher than the pancreas stiffness at 40 Hz ([1.60 ± 0.21] kPa, mean pancreas‐to‐liver stiffness ratio: 0.72), but similar at 60Hz ([2.12 ± 0.23) kPa, mean ratio: 0.95). The mean intrasubject CV for each pancreatic subregion was lower at 40 Hz than 60 Hz ( P < 0.05 for all subregions, range: 11.9–15.7% at 40 Hz and 16.5–19.6% at 60 Hz). Conclusion The 3D pancreatic MRE can provide promising and reproducible stiffness measurements throughout the pancreas, with more consistent data acquired at 40 Hz. J. Magn. Reson. Imaging 2015;41:369–375. © 2013 Wiley Periodicals, Inc .