Volume 25 No. 2
Summer 2015
Gastroenterology Today In this issue Clinical Paper Case Reports BSG Posters
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Surgical Ops
CONTENTS
CONTENTS 5
EDITORS COMMENT
7
CLINCIAL PAPER Prospective Comprehensive Genomic Profiling
16
CASE REPORT A False Positive Meckel’s Scan
21
CASE REPORT An Unusual Case of Breathlessness
24
MEETING REPORT Coeliac Research Conference
29
NEWS
38
BSG POSTERS
45
COMPANY NEWS
COVER STORY As the use of endoscopes increase, so does the risk of infections linked to endoscope reprocessing. To combat this Getinge UK provides a comprehensive range of offerings for disinfection, sterilisation and infection control.
With our best in class offerings to support our AER’s such as the Getinge Academy with its unrivalled education package for users and managers, along with our comprehensive specialist team for consumables and IT. They can provide advice and solutions for all your issues utilising T-DOC, the most complete IT package for hospital management including Tracking & Tracing and a full range of detergents and endoscope accessories With Getinge UK and Lancer coming together utilising the best of both companies provides these advantages along with full customer support from the largest customer service team of its kind in the UK. Getinge UK ‘Fighting Contamination – Saving Lives’.
This issue edited by: A Poullis, Consultant Gastroenterologist, St George’s Hospital c/o Media Publishing Company Media House 48 High Street SWANLEY, Kent BR8 8BQ ADVERTISING & CIRCULATION: Media Publishing Company Media House, 48 High Street SWANLEY, Kent, BR8 8BQ Tel: 01322 660434 Fax: 01322 666539 E: MPCJournalss@aol.com www.MediaPublishingCompany.com PUBLISHING DATES: February, June and October. COPYRIGHT: Media Publishing Company Media House 48 High Street SWANLEY, Kent, BR8 8BQ PUBLISHERS STATEMENT: The views and opinions expressed in this issue are not necessarily those of the Publisher, the Editors or Media Publishing Company. Next Issue Autumn 2015 Subscription Information – Summer 2015 Gastroenterology Today is a tri-annual publication currently sent free of charge to all senior qualified Gastroenterologists in the United Kingdom. It is also available by subscription to other interested individuals and institutions. UK: Other medical staff - £18.00 inc. postage Non-medical Individuals - £24.00 inc. postage Institutions Libraries Commercial Organisations - £48.00 inc. postage Rest of the World: Individuals - £60.00 Air Mail Institutions Libraries Commercial Organisations - £72.00 inc. postage We are also able to process your subscriptions via most major credit cards. Please ask for details. Cheques should be made payable to MEDIA PUBLISHING. Designed in the UK by Hansell Design
GASTROENTEROLOGY TODAY - SUMMER 2015
Getinge’s mission statement of ‘Fighting Contamination – Saving Lives’, is fundamental in our design and manufacture of the range of Getinge’s AER’s. From the market leading ED Flow through to the ground breaking ED900 for smaller units such as ENT decontamination. Full accreditation and proved disinfection results across the country make us the Number 1 decontamination company in the UK for all endoscopes.
Gastroenterology Today
3
In moderately active ulcerative colitis:
RETURN TO EVERYDAY LIFE For: • FAST RELIEF FROM FLARES1 • EXTENSIVE MUCOSAL HEALING2 • EFFECTIVE MAINTENANCE OF REMISSION3
ASACOL 800MG MR TABLETS and help your patients return to everyday life. EFFICACY
TIMESCALE
RELIEVE
2 weeks1,4
At 4.8g/day, 73% of patients achieve symptom improvement* and 43% of patients achieve symptom resolution as early as 2 weeks1,4 * Symptom improvement = decrease of at least 1 point from baseline in the respective symptom score.
RESOLVE
Week 62
At 4.8g/day, 80% of patients achieve mucosal healing (endoscopy subscore 0 or 1) by week 62
www.assuresupport.co.uk Support programme for eligible patients prescribed Asacol.
RESUME
12 months3
When taken at 2.4g once daily, 4 out of 5 patients still remain in remission at 12 months3
Combined Abbreviated Prescribing Information: Asacol 400mg MR Tablet, Asacol 800mg MR Tablet, Asacol 250mg and 500mg Suppositories and Asacol Foam Enema Presentation: Asacol 400mg MR Tablets, PL 10947/0011; each modified release tablet contains 400mg mesalazine (5-aminosalicylic acid). Bottles of 120, £39.21. Bottles of 90, £29.41. Asacol 800mg MR Tablets, PL 10947/0012; each modified release tablet contains 800mg mesalazine (5-aminosalicylic acid). Bottles of 180, £117.62. Asacol 250mg Suppositories, PL 10947/0013, each containing 250mg mesalazine. Packs of 20, £4.82. Asacol 500mg Suppositories, PL 10947/0014, each containing 500mg mesalazine. Packs of 10, £4.82. Asacol Foam Enema, PL 10947/0015, 1g mesalazine per metered dose. Carton containing can of 14 metered doses, 14 disposable applicators and 14 disposable plastic bags, £26.72. Indications: Ulcerative colitis: Treatment of mild to moderate acute exacerbations. Maintenance of remission. Suppositories particularly appropriate for distal disease, Foam enema for distal colon disease only. 400mg Tablets, 800mg Tablets, Suppositories: Maintenance of remission. 400mg Tablets and 800mg Tablets only: Crohn’s ileo-colitis: Maintenance of remission. Dosage and administration: ADULTS: 400mg Tablets: Acute disease: 6 tablets a day, in divided doses, with concomitant corticosteroid therapy where clinically indicated. Maintenance therapy: 3 to 6 tablets a day, once daily or in divided doses. 800mg Tablets: Mild acute exacerbations of ulcerative colitis: 3 tablets a day in divided doses. Moderate acute exacerbations of ulcerative colitis: 6 tablets a day in divided doses. Maintenance of remission of ulcerative colitis: Up to 3 tablets a day, once daily or in divided doses. Maintenance of remission of Crohn’s ileocolitis: Up to 3 tablets a day in divided doses. Suppositories: 250mg: 3 to 6 a day, in divided doses, with the last dose at bedtime. 500mg: A maximum of 3 a day, in divided doses, with the last dose at bedtime. Foam Enema: 1 (disease of rectosigmoid region) or 2 (disease of descending colon) metered doses as single daily dose for 4-6 weeks. ELDERLY: The normal adult dosage may be used unless renal function is impaired. CHILDREN: 800mg Tablets: Not recommended. 400mg Tablets, Suppositories, Foam Enema: No dosage recommendation.
Contra-indications: A history of sensitivity to salicylates or renal sensitivity to sulfasalazine. Confirmed severe renal impairment (GFR <20ml/min). 400mg Tablets, Suppositories and Foam Enema only: Children under 2 years of age. 800mg Tablets only: Hypersensitivity to any of the ingredients. Severe hepatic impairment. Gastric or duodenal ulcer, haemorrhagic tendency. Precautions: Use in the elderly should be cautious and subject to patients having a normal renal function. Asacol should be used with extreme caution in patients with confirmed mild to moderate renal impairment. Concurrent use of nephrotoxic agents, eg NSAIDs and azathioprine may increase risk of renal reactions. Renal function should be monitored (with serum creatinine levels measured) prior to start of treatment, and periodically during treatment, taking into account individual history & risk factors. Mesalazine should be discontinued if renal function deteriorates. If dehydration develops, normal fluid & electrolyte balance should be restored as soon as possible. Serious blood dyscrasias (some with fatal outcome) have been very rarely reported with mesalazine. Haematological investigations including a complete blood count may be performed prior to therapy initiation, during therapy, and are required immediately if the patient develops unexplained bleeding, bruising, purpura, anaemia, fever or sore throat. Stop treatment if suspicion or evidence of blood dyscrasia. 400mg Tablets and 800mg Tablets: Lactulose or similar preparations which lower stool pH should not be concomitantly administered. 400mg tablets, Suppositories, Foam Enema: Only use during pregnancy if benefits outweigh the risk. Avoid during lactation unless essential. 800mg Tablets only: Mesalazine should be used with caution during pregnancy and lactation when the potential benefit outweighs the possible hazards in the opinion of the physician. If neonate develops suspected adverse reactions consideration should be given to discontinuation of breast-feeding or discontinuation of treatment of the mother. Discontinue treatment immediately if acute symptoms of intolerance occur including vomiting, abdominal pain or rash. Patients with the rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine because of the presence of lactose monohydrate. Standard
haematological indices (including the white cell count) should be monitored repeatedly in patients taking azathioprine, especially at the beginning of such combination therapy, whether or not mesalazine is prescribed. Undesirable Effects: Common: Nausea, diarrhoea, abdominal pain, headache. Rare reports of leucopenia, neutropenia, agranulocytosis, aplastic anaemia, thrombocytopenia, peripheral neuropathy, pancreatitis, abnormalities of hepatic function and hepatitis, myocarditis, pericarditis, alopecia, lupus erythematosus-like reactions and rash (inc. urticaria), drug fever, interstitial nephritis and nephrotic syndrome with oral mesalazine treatment, usually reversible on withdrawal. Renal failure has been reported. Suspect nephrotoxicity in patients developing renal dysfunction. Very rarely, mesalazine may be associated with exacerbation of the symptoms of colitis, Stevens Johnson syndrome & erythema multiforme. 400mg Tablets, Suppositories, Foam Enema: Rare reports of allergic and fibrotic lung reactions. 800mg Tablets only: Common: vomiting, arthralgia / myalgia. Rare reports of vertigo, bronchospasm, eosinophilic pneumonia, bullous skin reactions. Very rarely, interstitial pneumonitis. Suppositories, Foam Enema: Rarely, local irritation may occur after use of rectal dosage forms of mesalazine. Legal category: POM. Marketing Authorisation Holder: Warner Chilcott UK Ltd, Old Belfast Road, Millbrook, Larne, County Antrim, BT40 2SH, UK. Asacol is a trademark. Refer to Summary of Product Characteristics before prescribing. Date of preparation: March 2014. Job Bag Number: UK/AS/0095/04-13(1) References: 1. 2. 3. 4.
Orchard TR. et al. Aliment Pharmacol Ther 2011; 33(9): 1028-1035. Lichenstein GR. et al. Aliment Pharmacol Ther 2011; 33: 672-678. Hawthorne B. et al. Inflamm Bowel Dis 2012; 18(10): 1885-1893. Chadda S. Gastrointestinal Nursing 2013; 11(5): 33-37.
Adverse events should be reported. Reporting forms and information can be found at www.mhra.gov.uk/yellowcard Adverse events should also be reported to Warner Chilcott UK Ltd on 0800 0328701
(MESALAZINE) Job code: UK/AS/0004/01-15c – January 2015
Relieve, resolve, resume
EDITORS COMMENT
EDITORS COMMENT The last few months has seen dramatic changes with regards drug therapies for inflammatory bowel disease. In a short space of time we are seeing the arrival of a new 1st in class product, the introduction of generic biological agents and an extension to the indication for use of agents previously reasonably restricted for Crohn’s only being more widely utilised in ulcerative colitis. Now more than ever our patients need equality of access to these therapies. Now more than ever we need to see the N in NICE and NHS in action. The National Institute for Health and Care Excellence provides national advice and guidance to improve health (and social) care. Clinical commissioning groups (CCGs) are NHS organisations, set up by the Health and Social Care Act 2012, to organise the delivery of services in England. On the face of things CCGs should facilitate the implementation of NICE guidelines. The definition of facilitate is “to make an action easy or easier”. I am not sure how many gastroenterologists would describe their local CCGs as facilitators. Anecdotally CCGs delay implementation of NICE guidelines for as long as possible and largely for non-clinical reasons. Nationally CCGs seem to have widely differing levels of interaction with the Trusts they work with. This can lead to a proliferation of locally agreed pathways and protocols which seem to re-invent and potentially water down national guidelines. With the availability of cheaper generics a potential for shared reduction in costs “gainshare” has been proposed. Visionary CCGs and Trusts have split the cost savings enabling Trusts to re-invest in the IBD service - which will need more support to deliver the increasingly complicated drug regimens available. There is, however, a risk that these savings will be used to balance books as more Trusts struggle financially. Without this investment the implementation of National guidelines may be impacted and this will not lead to equality of access for our patients. Dr A Poullis St George’s Hospital London
GASTROENTEROLOGY TODAY - SUMMER 2015
“Now more than ever our patients need equality of access to these therapies. Now more than ever we need to see the N in NICE and NHS in action. The National Institute for Health and Care Excellence provides national advice and guidance to improve health (and social) care.”
Biological Revolution
5
An oral ulcerative colitis treatment that’s a step change, not a step up
Now that’s progress
When mesalazine doesn’t seem to be working, stepping up to immunosupressants might not be the only option. For those patients who could benefit from a simpler routine Salofalk Granules come in a convenient little sachet, only need to be taken once a day and even have a tasty vanilla flavour. Oh and if the inflammation is in the distal colon, the granules are pretty good at getting there too.1
Mesalazine, the Dr Falk way
Optimisation with Salofalk Granules for patients inadequately maintained on previous mesalazine resulted in:2
Prescribing Information (Please refer to full SPC before prescribing): Salofalk gastro-resistant prolonged-release granules Presentation: Stick-formed or round, greyish white gastro-resistant prolonged-release granules in sachets containing 500mg, 1000mg, 1.5g or 3g mesalazine per sachet. Indications: Treatment of acute episodes and the maintenance of remission of ulcerative colitis. Dosage: Adults: Once daily 1 sachet of 3g granules, 1 or 2 sachets of 1.5g granules or 3 sachets of 1000mg or 500mg granules (equivalent to 1.5 – 3.0g mesalazine daily) preferably to be taken in the morning, according to the individual clinical requirement. It is also possible to take the prescribed daily dose in three divided doses (1 sachet of 500mg granules three times daily or 1 sachet of 1000mg granules three times daily) if this is more convenient. Maintenance: 0.5g mesalazine three times daily (in the morning, at midday and in the evening) corresponding to a total dose of 1.5g mesalazine per day. For patients known to be at increased risk for relapse for medical reasons or due to difficulties to adhere to application of three daily doses the dosing schedule can be adapted to 3.0g mesalazine given as a single daily dose, preferably in the morning. Children: There is only limited documentation for an effect in children (age 6-18 years). Children 6 years of age and older: Active disease: To be determined individually, starting with 30-50mg/kg/day once daily preferably in the morning or in divided doses. Maximum dose: 75mg/kg/day. The total dose should not exceed the maximum adult dose. Maintenance treatment: To be determined individually, starting with 15-30mg/kg/day in divided doses. The total dose should not exceed the recommended adult dose. It is generally recommended that half the adult dose may be given to children up to a body weight of 40kg; and the normal adult dose to those above 40kg. Method of administration: The granules should be taken on the tongue and swallowed, without chewing, with plenty of liquid. Contra-indications: Hypersensitivity to salicylates or any of the excipients. Severe impairment of renal or hepatic function. Warnings/Precautions: Blood tests (differential blood count; liver function parameters such as ALT or AST; serum creatinine) and urinary status (dip sticks) should be determined
47% less routine hospital visits
60% less hospital visits due to UC flare-up
prior to and during treatment at the discretion of the treating physician. Caution is recommended in patients with impaired hepatic function. Should not be used in patients with impaired renal function. Mesalazineinduced renal toxicity should be considered if renal function deteriorates during treatment. Patients with pulmonary disease, in particular asthma, should be very carefully monitored. Patients with a history of adverse drug reactions to preparations containing sulphasalazine should be kept under close medical surveillance on commencement of treatment. Should Salofalk cause acute intolerance reactions such as abdominal cramps, acute abdominal pain, fever, severe headache and rash, therapy should be discontinued immediately. For patients with phenylketonuria - Salofalk granules contain aspartame as a sweetening agent equivalent to 0.56mg phenylalanine (500mg granules), 1.12mg phenylalanine (1000mg granules), 1.68mg phenylalanine (1.5g granules) and 3.36mg phenylalanine (3g granules). Salofalk granules contain sucrose: 0.02mg (500mg granules), 0.04mg (1000mg granules), 0.06mg (1.5g granules) and 0.12mg (3g granules). Interactions: Specific interaction studies have not been performed. Lactulose or similar preparations that lower stool pH: possible reduction of mesalazine release from granules due to decreased pH caused by bacterial metabolism of lactulose. In patients who are concomitantly treated with azathioprine, 6-mercaptopurine or thioguanine a possible increase in the myelosuppressive effects of azathioprine, 6-mercaptopurine or thioguanine should be taken into account. There is weak evidence that mesalazine might decrease the anticoagulant effect of warfarin. Use in pregnancy and lactation: There are no adequate data. Do not use during pregnancy unless the potential benefit outweighs the possible risks. Limited experience in the lactation period. Use during breast-feeding only if the potential benefit outweighs the possible risks; if the infant develops diarrhoea, breast-feeding should be discontinued. Undesirable effects: Headache, dizziness, peri- and myocarditis, abdominal pain, diarrhoea, flatulence, nausea, vomiting, aplastic anaemia, agranulocytosis, pancytopenia, neutropenia, leukopenia, thrombocytopenia, peripheral neuropathy, allergic and
44% less
GP visits due to UC flare-ups
50% less steroid courses used
fibrotic lung reactions (including dyspnoea, cough, bronchospasm, alveolitis, pulmonary eosinophilia, lung infiltration, pneumonitis), acute pancreatitis, impairment of renal function including acute and chronic interstitial nephritis and renal insufficiency, alopecia, myalgia, arthralgia, hypersensitivity reactions such as allergic exanthema, drug fever, lupus erythematosus syndrome, pancolitis, changes in hepatic function parameters, hepatitis, cholestatic hepatitis and oligospermia (reversible). Legal category: POM. Basic cost: Salofalk 500mg granules, pack size 100 sachets - £28.74; €41.55. Salofalk 1000mg granules, pack size 50 sachets – £28.74; €38.28. Salofalk 1.5g Granules, pack size 60 sachets - £48.85; €56.05. Salofalk 3g Granules pack size 60 sachets - £97.70; €129.07 (UKNHS price; IE - PtW). Product licence number: Salofalk 500mg granules – PL08637/0007; PA573/3/1. Salofalk 1000mg granules – PL08637/0008; PA573/3/2. Salofalk 1.5g granules PL08637/0016; PA573/3/7. Salofalk 3g granules PL08637/0025; PA573/3/6. Product licence holder: Dr Falk Pharma GmbH, Leinenweberstr.5, D-79108 Freiburg, Germany. Date of preparation: June 2014 Further information is available on request. Adverse events should be reported. Reporting forms and information can be found at http:// www.mhra.gov.uk/yellowcard (UK residents) or at http://www.hpra.ie/EN/Safety--Quality/Online-Forms.aspx (residents of the Republic of Ireland). Adverse events should also be reported to Dr Falk Pharma UK Ltd. References: 1. Leifeld L et al. Aliment Pharmacol Ther 2011; 34: 1115-22. 2. Prasher H et al. Poster P571 presented at the 8th ECCO congress, February 2013, Vienna, Austria. Date of preparation: March 2015
DrF 15/033
CLINICAL PAPER
PROSPECTIVE COMPREHENSIVE GENOMIC PROFILING OF ADVANCED GASTRIC CARCINOMA CASES REVEALS FREQUENT CLINICALLY RELEVANT GENOMIC ALTERATIONS AND NEW ROUTES FOR TARGETED THERAPIES Siraj M. Ali,a Eric M. Sanford,a Samuel J. Klempner,b Douglas A. Rubinson,c Kai Wang,a Norma A. Palma,a Juliann Chmielecki,a Roman Yelensky,a Gary A. Palmer,a Deborah Morosini,a Doron Lipson,a Daniel V. Catenacci,d Fadi Braiteh,e Rachel Erlich,a Philip J. Stephens,a Jeffrey S. Ross,a,f Sai-Hong Ignatius Ou,b Vincent A. Millera Foundation Medicine Inc., Cambridge, Massachusetts, USA; bChao Family Comprehensive Cancer Center, Division of Hematology-Oncology, Department of Medicine, University of California Irvine School of Medicine, Orange, California, USA; cDana-Farber Cancer Institute, Boston, Massachusetts, USA; dUniversity of Chicago, Chicago, Illinois, USA; eComprehensive Cancer Centersof Nevada, Las Vegas, Nevada, USA; f Department of Pathology and Laboratory Medicine, Albany Medical College, Albany, New York, USA Disclosures of potential conflicts of interest may be found at the end of this article. a
KeyWords. Gastric cancer • Sequencing • Targeted therapy • Mutation • Profiling • MET
Abstract
Implications for Practice
Background. Gastric cancer (GC) is a major global cancer burden
Despite description of many potentially clinically relevant genomic
and the second most common cause of global cancer-related deaths.
alterations in retrospective research studies, these alterations are not
The addition of anti-ERBB2 (HER2) targeted therapy to chemotherapy
regularly assessed in a comprehensive manner in clinical practice.
improves survival for ERBB2-amplified advanced GC patients; however,
This study demonstrates the feasibility of prospective comprehensive
the majority of GC patients do not harbor this alteration and thus cannot
genomic profiling (CGP) for advanced gastric carcinoma.
benefit from targeted therapy under current practice paradigms.
We demonstrated a high frequency of genomic alterations associated with potential benefit from targeted therapies. CGP in this setting
Materials and Methods. Prospective comprehensive genomic profiling of 116 predominantly locally advanced or metastatic (90.0%) gastric cancer cases was performed to identify genomic alterations (GAs) associated with a potential response to targeted therapies approved by the U.S. Food and Drug Administration or targeted therapy-based clinical trials. Results. Overall, 78% of GC cases harbored one clinically relevant GA or more,with the most frequent alterations being found in TP53 (50%), ARID1A (24%), KRAS (16%), CDH1 (15%), CDKN2A (14%), CCND1 (9.5%), ERBB2 (8.5%), PIK3CA (8.6%), MLL2 (6.9%), FGFR2
may inform therapeutic options beyond standard of care testing by identifying genomic alterations such as point mutations in the kinase domain of ERBB2 and MET amplification. Genotype-directed management is highlighted by the response of a MET-amplified gastric carcinoma patient to crizotinib.
Introduction Gastric cancer (GC) is the second most frequent cause of cancerrelated death worldwide [1]. The majority of patients present with
were detected in 20.6% of cases, primarily ERBB2, FGFR2, and MET
advanced disease, and the overall 5-year survival rate is <28%,
amplification,with ERBB2 alterations evenly split between amplifications
compared with <5% for patients presenting with metastatic disease
and base substitutions. Rare BRAF mutations (2.6%) were also
[2–4]. The clinical heterogeneity of GC is highlighted by significant
observed. One MET-amplified GC patient responded for 5 months to
worldwide geographic variations, differences in anatomic origin
crizotinib, a multitargeted ALK/ROS1/MET inhibitor.
(proximal vs. distal), risk factors including Helicobacter pylori infection and dietary patterns, and a poorly understood relationship to Asian
Conclusion. Comprehensive genomic profiling of GC identifies clinically
ethnicity [5–7]. Within the common intestinal histologic subtype, there
relevant GAs that suggest benefit from targeted therapy including MET-
are differences in ERBB2 amplification frequencies (proximal vs. distal)
amplified GC and ERBB2 base substitutions.
and association with H. pylori and progression from a metaplastic
The Oncologist 2015;20:1–9
background (distal vs. proximal, intestinal type) [8–10].
Correspondence: Siraj M.Ali, M.D., Ph.D., Foundation Medicine, Inc., 150 Second Street, Cambridge, Massachusetts, 02141, USA. Telephone: 617418-2241; E-Mail: Siraj@Foundationmedicine.com Received September 24, 2014; accepted for publication February 4, 2015. ©AlphaMed Press 1083-7159/2015/$20.00/0 http://dx.doi.org/10.1634/theoncologist.2014-0378
GASTROENTEROLOGY TODAY - SUMMER 2015
(6.0%), and MET (6.0%). Receptor tyrosine kinase genomic alterations
7
CLINICAL PAPER Efforts to identify predictive biomarkers to guide decision making
was performed with a custom bait set of 120-bp biotinylated DNA
for systemic therapy have yielded inconsistent results. To date, the
oligonucleotides (Integrated DNA Technology, Coralville, IA, http://www.
only validated predictive biomarker for targeted therapy is ERBB2
idtdna.com) covering 3,769 exons of 236 cancer-related genes and 47
amplification, which predicts benefit from the anti-ERBB2 (HER2)
introns of 19 genes frequently rearranged in cancer. The Illumina HiSeq
antibody trastuzumab in advanced disease [8, 11, 12].
2000 and Illumina HiSeq 2500 platforms were used to perform 49 × 49 paired-end sequencing. Sequence alignment, PCR duplicate-read
Systemic therapy for metastatic, relapsed, or refractory GC is largely
removal, and local alignment optimization were performed using Burrows-
based on empiric 5-fluoropyrimidine and platinum combinations, and
Wheeler aligner bwa-0.5.9 (SourceForge; Slashdot Media, San Francisco,
there are no definitive clinical predictors of response [13]. Although
CA, http://slashdotmedia.com), Picard 1.47 (Broad Institute, Cambridge,
trastuzumab offers improved survival for the 7%–34% of GC patients
MA, http://broadinstitute.github.io/picard/), SAM Tools samtools-0.1.12a
with ERBB2 amplification, there are no approved molecularly directed
(SourceForge; Slashdot Media), and GATK 1.0.4705 (Broad Institute).
therapies for the majority of patients [8, 14]. Although the recent approval of the anti-VEGFR2 antibody ramucirumab increases the GC
Variant calling was performed using custom tools. Base substitutions
armamentarium, there are no validated predictive biomarkers to identify
were called using a Bayesian methodology, and short insertions-deletions
patients who may derive benefit from anti-VEGFR targeted therapies
(indels) were called using local assembly. Somatic variants were
[13, 15].
annotated using COSMIC, and germline variants were removed using dbSNP. Rearrangements were called using chimeric read pairs clustered
Large-scale retrospective whole-genome sequencing analyses have
by genomic position. Copy number alterations (CNAs) were detected
highlighted recurrent genomic alterations in gastric cancer such
by fitting a statistical copy-number model to normalized coverage
as ARID1A, CDH1, RHOA, and FGFR2 [10, 16–18]. Prospective
and allele frequencies at all exons and ~3,500 genomewide single
comprehensive genomic profiling based on a clinical next-generation
nucleotide polymorphisms and accounting for stromal admixture. An
sequencing (NGS) assay in the course of clinical care can identify novel
extensive validation was performed for base substitutions, short indels,
and known clinically relevant genomic alterations (GAs) and increase
and CNAs. To validate CNA detection, seven tumor cell lines bearing 19
understanding of the underlying biology and immediately inform patient
focal gene amplifications (6–15 copies, 15 genes) and 9 homozygous
management options. In this study, we present a large series of primarily
gene deletions (6 genes) with their matched normal cell lines (thereby
relapsed and metastatic gastric carcinoma clinical specimens that
maintaining consistent genotypes) were pooled to create five ratios
underwent prospective comprehensive genomic profiling and highlight
ranging from low to high tumor content (20%–75%), creating a total test
therapeutic implications.
set of 210 CNAs.
Materials and Methods
High performance was achieved for both high-level amplifications (copy
Comprehensive genomic profiling using a clinical NGS-based assay
30%: sensitivity was 99% (91 of 92) with positive predictive value >99%
(FoundationOne) was performed in a Clinical Laboratory Improvements Amendment-certified, College of American Pathologists-accredited laboratory (Foundation Medicine, Cambridge, MA, http://www. foundationmedicine.com) using validated methods [19]. Clinical samples were sent in from both academic and community oncologists for genomic profiling in the context of clinical care, and patient outcomes in selected cases were obtained from the primary treating physician. With the exception of three samples received as extracted DNA, a pathologist reviewed hematoxylin and eosin-stained slides to confirm diagnosis of GC and to ensure adequate formalin-fixed, paraffin embedded (FFPE) GASTROENTEROLOGY TODAY - SUMMER 2015
8
specimen quality: sample volume >1mm3, nucleated cellularity >80% or >30,000 cells, and >20% tumor nuclei. When required, macrodissection was performed to enrich samples with <20% tumor nuclei. DNA was extracted from unstained FFPE specimens using the Promega Maxwell 16 Tissue LEV DNA kit (Promega, Madison, WI, http://
number ≥8) and homozygous deletions when tumor purity was as low as (127 of 127). Performance was reduced for lower CNAs (6–7 copies) and at lower sample purities (20%–30%), with overall sensitivity >80%. Cancer-related alterations were defined as those that are known sites of somatic mutation, truncations or homozygous deletions of known tumor suppressor genes, and amplifications of oncogenes and fusions of genes known to be rearranged in solid tumors. Clinically relevant GAs were defined as those that suggested potential response to targeted therapies approved in gastric carcinoma or in other tumor types or that suggested benefit from targeted therapy under development and being administered in the context of a clinical trial. The two-tailed Fisher’s exact test was used to determine statistical significance of all group comparisons. Local site permissions were used to study these samples.
Results
www.promega.com) and quantified using an Invitrogen PicoGreen fluorescence assay (Thermo Fisher Scientific, Waltham, MA, http://www.
Comprehensive genomic profiling was performed on 116 GC cases.
thermofisher.com). Library construction was performed with 50–200
The median patient age at time of testing was 62 years (range: 26–87
ng of DNA sheared by sonication (E210; Covaris, Woburn, MA, http://
years) (Table 1). Sixty-five (56%) specimens were from male patients.
covarisinc.com) to~100–400 base pairs before end repair, dA addition,
The stage distribution is shown in Table 1. Of the samples, 69% (n=80)
and ligation of indexed Illumina sequencing adaptors (Illumina, San
were from the primary GC and 31% (n=36) were from metastatic sites
Diego, CA, http://www.illumina.com). Prior to hybrid selection and
including ovary (n=7), peritoneum (n=4),omentum (n=3), colon (n=3),
sequencing, libraries were amplified with polymerase chain reaction
bone (n=3), pleural fluid (n=3), lymph node (n=3), ascites (n=2),
(PCR) for 10 cycles using KAPA HiFi (Kapa Biosystems, Wilmington,
esophagus (n=2), small intestine (n=2), mesentery (n=1), liver (n=1),
MA, http://www.kapabiosystems.com). Solution-based hybrid selection
pelvis (n=1), and soft tissue (n=1).
CLINICAL PAPER Ali, Sanford, Klempner et al.
3
Table 1. Clinicopathological and genomic characteristics of 116 gastric
had less frequent amplifications of cancer-related genes compared
cancer cases prospectively assayed by a comprehensive genomic
with cases with wildtype ARID1A. This finding was statistically
Table 1. Clinicopathological and genomic characteristics of 116 gastric cancer cases prospectively assayed by profiling assay a comprehensive genomic profiling assay Characteristic Patient age, average, years Sex, % Male Female Histology, n (%) Diffuse type Intestinal type Gastric carcinoma NOS Histologic grade, n (%) 1 2 3 Stage, n (%) I II III IV Site of tumor, n (%) Primary site Metastatic sitesa GA Total alterations Average per sample Clinically relevant GA Clinically relevant GA per sample
Result 59.5 44 56 24 (20.7) 12 (10.3) 80 (69.0) 2 (1.7) 24 (20.7) 90 (77.6) 4 (3.4) 7 (6.0) 21 (18.1) 84 (72.4) 80 (69) 36 (31) 501 4.3 201 1.8
a
Including ovary (n 5 7), peritoneum (n 5 4), omentum (n 5 3), colon (n 5 3), bone (n 5 3), pleural fluid (n 5 3), lymph node (n 5 3), ascites (n 5 2), esophagus (n 5 2), small intestine (n 5 2), mesentery (n 5 1), liver (n 5 1), pelvis (n 5 1), and soft tissue (n 5 1). Abbreviations: GA, genomic alteration; NOS, not otherwise specified.
KDR (VEGFR2) R275* and FLT4 (VEGFR3) S637R in all 116 GC cases, and neither alteration has been linked to benefit from ramucirumab
DISCUSSION
GASTROENTEROLOGY TODAY - SUMMER 2015
Overall, 501 cancer-related genomic alterations were identified in 116 cases, yielding an average of 4.32 alterations per 116 cases, yielding an average of 4.32 alterations per sample (Table sample (Table 1; Fig. 1). Of 501 GAs identified, 210 (41%) were 1; Fig. 1). Of 501 GAs identified, 210 (41%) were clinically relevant clinically relevant alterations, yielding an average of 1.8 alterations, yielding an average of 1.8 clinically relevant GAs per case clinically relevant GAs per case (Table 1). Moreover, 78% of (Table 1). Moreover, 78% of GC cases harbored at least 1 clinically GC cases harbored at least 1 clinically relevant variant relevant variant associated with targeted therapies approved by associated with targeted therapies approved by the U.S. Food the U.S. Food and Drug Administration (FDA) or mechanism-based and Drug Administration (FDA) or mechanism-based trials trials (Table 2).The most common clinically relevant GAs were KRAS, (Table 2).The most common clinically relevant GAs were KRAS, CDKN2A, CCND1, ERBB2, PIK3CA, MLL2, MET, PTEN, ATM, DNMT3A, CDKN2A, CCND1, ERBB2, PIK3CA, MLL2, MET, PTEN, ATM, NF1, NRAS, and MDM2 (Table 2).The most common GAs in the 116 DNMT3A, NF1, NRAS, and MDM2 (Table 2).The most common cases were TP53 (58 cases, 50%), ARID1A (28 cases, 24%), and GAs in the 116 cases were TP53 (58 cases, 50%), ARID1A (28 CDH1 (17 cases, 15%). cases, 24%), and CDH1 (17 cases, 15%). Twenty-eight cases (24%) harbored loss-of-function Twenty-eight cases (24%) harbored loss-of-function ARID1A ARID1A alterations (Fig. 2). ARID1A-altered samples harbored alterations (Fig. 2). ARID1A-altered samples harbored an increased an increased frequency of CREBBP variants (p , .0005), PIK3CA frequency of CREBBP variants (p<.0005), PIK3CA variants (p=.0017), variants (p 5 .0017), and MLL2 variants (p 5 .019) and were and MLL2 variants (p=.019) and were less likely to harbor TP53 less likely to harbor TP53 variants (p , .050). In this series, variants (p<.050). In this series, tumors with ARID1A alterations tumors with ARID1A alterations had less frequent amplifications of cancer-related genes compared with cases with wildtype ARID1A. This finding was statistically significant but was not replicated in an independent set of 192 gastric carcinomas Overall, 501 cancer-related genomic alterations were identified in
(data not shown). All other ARID1A findings remained significant with a type I error rate of ,.05 with a multiple hysignificant but was not replicated in an independent set of 192 gastric pothesis correction applied. carcinomas (data not shown). All other ARID1A findings remained Somatic CDH1 mutations were found in 6 of 24 (25%) diffuse significant with a type I error rate of <.05 with a multiple hypothesis GC cases compared with 11 of 92 (12%) nondiffuse GC cases correction applied. (p 5 .12). Matched normal tissue was not available to investigate germline CDH1 status. Enrichment of APC, CREBBP, and Somatic CDH1 mutations were found in 6 of 24 (25%) diffuse GC MLL2 alterations was observed in intestinal GC; 3 of 12 cases cases compared with 11 of 92 (12%) nondiffuse GC cases (p=.12). (25%) contained APC mutations compared with 3 of 104 cases Matched normal tissue was not available to investigate germline (2.9%) of nonintestinal GC (p 5 .014). APC variants were not obCDH1 status. Enrichment of APC, CREBBP, and MLL2 alterations served in any of the 24 diffuse GC cases. CREBBP was altered in 4 was observed in intestinal GC; 3 of 12 cases (25%) contained APC of 12 (33%) intestinal cases compared with 2 of 104 (1.9%) mutations compared with 3 of 104 cases (2.9%) of nonintestinal GC nonintestinal cases (p , .001), and MLL2 was altered in 4 of 12 (p=.014). APC variants were not observed in any of the 24 diffuse (33%) intestinal cases compared with 4 of 104 (3.8%) noninGC cases. CREBBP was altered in 4 of 12 (33%) intestinal cases testinal cases (p 5 .0038). compared with 2 of 104 (1.9%) nonintestinal cases (p<.001), and Alterations of genes involved in mismatch repair were MLL2 was altered in 4 of 12 (33%) intestinal cases compared with 4 observed in this series at a frequency of 2.6% for MLH1, 0.8% of 104 (3.8%) nonintestinal cases (p=.0038). for MSH2, and 0.8% for MSH6. Three of these five cases harboredof truncating alterations that arewere predicted toincause Alterations genes involved in mismatch repair observed loss of function, and no single case contained more than one this series at a frequency of 2.6% for MLH1, 0.8% for MSH2, and 0.8% alteration in this pathway. No information on microsatellite for MSH6. Three of these five cases harbored truncating alterations stability assessed by PCR was available. that are predicted to cause losstesting of function, and no single case Alterations tyrosine kinases (RTKs) were contained more thanin onereceptor alteration in this pathway. No information on harbored by 24 cases (20.6%). Tentesting samples (8.6%) harbored microsatellite stability assessed by PCR was available. ERBB2 alterations, 5 contained somatic base substitutions and 5 harbored (6–24were copies), with Alterations in receptor amplifications tyrosine kinases (RTKs) harbored by these events being mutually exclusive. ERBB2 base substitutions 24 cases (20.6%). Ten samples (8.6%) harbored ERBB2 alterations, in this seriessomatic consisted R678Q (two S310F (one case), 5 contained baseof substitutions andcases), 5 harbored amplifications L755S (one case), and V842I (one case). One case harbored (6–24 copies), with these events being mutually exclusive. ERBB2 both ERBB2 R678Q and MET amplification. CDH1 alteration base substitutions in this series consisted of R678Q (two cases), was (one not associated alteration incase). our GC sample S310F case), L755Swith (one ERBB2 case), and V842I (one One case (data not harbored bothshown). ERBB2 R678Q and MET amplification. CDH1 alteration Seven cases (6%) harbored MET amplifications (7–30 copies) was not associated with ERBB2 alteration in our GC sample (data not and seven cases (6%) had FGFR2 amplifications (12–32 copies) shown). (Table 2). One patient with MET-amplified gastric carcinoma Seven casescrizotinib (6%) harbored MET amplifications (7–30 copies) received and achieved disease control (Fig. 3).and seven One casesFGFR2-altered (6%) had FGFR2 amplifications (12–32 copies) (Table 2). case also harbored a coexisting ARID1A One patient with MET-amplified received crizotinib alteration. EGFR alterationsgastric were carcinoma detected in four cases (3.4%) and achieved of disease control (Fig. 3). one point mutation (F795V), consisting two amplifications, and one case with a deletion of exons 2–7 (EGFR viii). Rare RTK One FGFR2-altered case also harbored a coexisting ARID1A one case), alterations identified included FLT3 (amplification; alteration. EGFR alterations were detected in four cases (3.4%) KIT (D716N; one case), and FGFR3 (amplification; one case) consisting of two amplifications, one point mutation (F795V), (supplemental online Table 1). EGFR amplifications and wereone not case with a deletion of exons 2–7 (EGFR viii). Rare RTK alterations exclusive of other RTK alterations because they coexisted with identified FLT3 (amplification; (D716N; FGFR2 included amplification (one case) one andcase), bothKITMET and ERBB2 one case), and FGFR3 (amplification; one case) (supplemental amplifications (one case). No ROS1 alterations, including fuonline Table 1). detected. EGFR amplifications were not exclusive other sions, were Among clinically relevantofalterations in RTK alterations because they coexisted with FGFR2 amplification other kinases, BRAF alterations occurred at a frequency of 2.6%, (one and both METD594X and ERBB2 amplifications (one case). twocase) cases harbored and one case harbored G469VNo(supROS1 alterations, including fusions, were detected. Among clinically plemental online Table 1). Alterations in vascular endothelial relevant alterations in other kinases, BRAF alterations growth factor receptors 1–3 (VEGFR1–3) wereoccurred limited atto KDR a frequency 2.6%, and two cases harbored D594X one116 case (VEGFR2)ofR275* FLT4 (VEGFR3) S637Rand in all GC cases, harbored G469V (supplemental online Table 1). Alterations in and neither alteration has been linked to benefit vascular from raendothelial growth factor receptors 1–3 (VEGFR1–3) were limited to mucirumab [13, 15]. [13, 15].
The phase III ToGA trial demonstrated the power of molecular testing to prospectively identify a molecularly defined subgroup of patients who are likely to benefit from anti-ERBB2 (HER2)-directed therapy; the addition of trastuzumab to
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Figure 1. 1. Tile in in 116 consecutive gastric cancer cases. Figure Tileplot plotofofgenomic genomicalterations alterations 116 consecutive gastric cancer cases.
GASTROENTEROLOGY TODAY - SUMMER 2015
standard 5-fluorouracil/platinum chemotherapy led to a staPrior reports characterizing the genomic landscape of gastric Discussion tistically significant 2.5-month improvement in overall surcarcinoma have relied on banked, therapy-naive tissue from privival for ERBB2-amplified gastric cancer [8]. The methods of mary resections [10, 16–18, 25, 26]. Recent work from the Cancer The phase IIItesting, ToGA trial demonstrated the power of molecular testing to Prior reports the genomic gastric carcinoma molecular however, are also important, as demonstrated Genome Atlas characterizing has defined four groups landscape of gastric ofcarcinomas, by the negative results of the TyTAN In thatoftrial, thewho addition harboring for Epstein-Barr virusprimary (EBV), resections microprospectively identify a molecularly definedtrial. subgroup patients are likely each have relied on positivity banked, therapy-naive tissue from of lapatinib oral HER2 inhibitor) totherapy; paclitaxel did notoflead to satellite instability, multiple number to benefit from(an anti-ERBB2 (HER2)-directed the addition trastuzumab [10, 16–18, 25, 26].or Recent work copy from the Cancer amplifications Genome Atlas has significant improvement in progression-free survival or overall genomically stable or characterized by harboring chromosomal to standard 5-fluorouracil/platinum chemotherapy led to a statistically significant while defined four groups of gastric carcinomas, each positivity for survival (OS) when compared with single-agent paclitaxel as instability [27]. Characteristic single-gene alterations werecopy of- number 2.5-month improvement in overall survival for ERBB2-amplified gastric cancer [8]. Epstein-Barr virus (EBV), microsatellite instability, or multiple second-line treatment in EBRR2-amplified GC, as determined by ten but not perfectly associated with each group; EBV-positive The methods of molecular testing, however, are also important, as demonstrated amplifications while genomically stable or characterized by chromosomal fluorescence in situofhybridization alone [20]. of Subgroup gastric carcinomas often harbored PIK3CAalterations alterations, the by the negative results the TyTAN trial. In(FISH) that trial, the addition lapatinib instability [27]. Characteristic single-gene wereand often but not analysis indicated that ERBB2 amplification and immunohistogenomically stable group often harbored RHOA alterations (an oral HER2 inhibitor) to paclitaxel did not lead to significant improvement in perfectly associated with each group; EBV-positive gastric carcinomas chemistry (IHC)survival 31 derived a significant improvement [27].These groupsPIK3CA offer insight intoand common etiologies but do progression-free or overall survival (OS)6.4-month when compared with singleoften harbored alterations, the genomically stable group in overall survival. Similarly, early reporting from the LoGIC trial not currently direct therapeutic decision making. agent paclitaxel as second-line treatment in EBRR2-amplified GC, as determined often harbored RHOA alterations [27]. These groups offer insight into demonstrated OS improvements in Asian patients and those In contrast, the prospective series presented in this study by fluorescence in situ hybridization (FISH) alone [20]. Subgroup analysis common etiologies but do not currently direct therapeutic decision aged ,60 years but failed to demonstrate an association betreflects samples characteristic of clinical practice because the indicated that ERBB2 amplification and immunohistochemistry (IHC) 3+ derived making. ween OS and IHC score [21]. Neither of these trials included paseries is composed of cases from patients typically with ada significant 6.4-month improvement in overall survival. Similarly, early reporting tients with ERBB2 mutations. vanced gastric carcinoma. A high percentage of cases (78%) from the LoGIC trial demonstrated OS improvements in Asian patients and those In contrast, the prospective series presented in this study reflects samples In contrast, the phase III EXPAND and REAL3 trials in an harbor clinically relevant genomic alterations, including 1 in 5 aged <60 years but failed to demonstrate an association between OS and IHC characteristic of clinical practice because the series is composed of unselected gastric and esophageal cancer population failed to cases (20.6%) with alterations in RTKs, suggesting the utility of score [21]. Neither of these trials included patients with ERBB2 mutations. cases from patients typically with advanced gastric carcinoma. A high demonstrate improvement in outcomes with the addition of comprehensive genomic profiling to match patients with percentage of cases (78%) harbor clinically relevant genomic alterations, the EGFR-targeted therapies cetuximab or panitumumab to targeted therapies of specific potential benefit in clinical trials In contrast, the phase III EXPAND and REAL3 trials in an unselected gastric including 1 in 5 cases (20.6%) with alterations in RTKs, suggesting the chemotherapy [22, 23]. Retrospective analysis of this trial has (Table 2). For the common genomic alterations KRAS, ARID1A, and identified esophagealany cancer population failed tobiomarkers demonstrateto improvement of comprehensive genomic profiling to match patients with targeted not predictive response date [13]. in andutility TP53,their clinical relevance is best linked to possible benefit outcomes with the results additionhave of thealso EGFR-targeted therapies cetuximab therapies of specific in clinical trialsFDA (Table 2). For the Similar negative been observed in the phase or from clinical trials with potential targetedbenefit agents.The recent approval panitumumab chemotherapy [22, 23]. analysis of this common genomic alterations KRAS, ARID1A,for andmelanoma TP53, their clinical III GRANITE-1totrial of everolimus in Retrospective unselected advanced GC trial of trametinib as a MEK pathway inhibitor has has not identified anydata predictive response biomarkers date [13].and Similar resulted relevance is best linked to use possible benefit frominclinical with targeted patients, and few support empiric use oftotargeted in the anecdotal of trametinib othertrials tumors negative results also been observed agents. The recent FDA approval of trametinib a MEK pathway biologic agentshave in advanced GC [24]. in the phase III GRANITE-1 trial types and assessment in clinical trials for otheras indications [28]. inhibitor of everolimus in unselected advanced GC patients, and few data support empiric use of targeted and biologic agents in advanced GC [24].
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for melanoma has resulted in the anecdotal use of trametinib in other tumors types and assessment in clinical trials for otherThe indications [28].
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Table 2. Therapeutic implications ofsomatic recurrent somatic genomic alterations in 116 clinical gastric cancer cases analyzed by profiling Table 2. Therapeutic implications of recurrent genomic alterations in 116 clinical gastric cancer cases analyzed by prospective genomic prospective genomic profiling Gene
Type of alteration
Frequency (%)
Approved anticancer drugs
Novel targeted therapies under clinical investigation
TP53 ARID1A KRAS CDH1 CDKN2A CCND1 ERBB2 PIK3CA MLL2 FGFR2 MET PTEN ATM DNMT3A NF1 NRAS MDM2 BRAF
Sub/indel Sub/indel Sub Sub/indel Sub/indel Amp Amp, sub Amp, sub Sub Amp Amp Sub/indel Sub Sub Sub/indel Sub Amp Mut
50 24 16 15 14 9.5 8.6 8.6 6.9 6.0 6.0 5.2 4.3 4.3 4.3 4.3 4.3 2.5
None None None None None None Pertuzumab, trastuzumab, lapatanib Everolimus, temsirolimus None Pazopanib, ponatinib Crizotinib, cabozantinib Everolimus, temsirolimus None None None None None Vemurafenib; dabrafenib or trametinib
None None Trametinib None LEE011 LEE011, palbociclib Afatinib, neratinib BYL719, BKM120, None Dovitinib, AZD4547 Rilotumumab, AMG337 None Olaparib Decitabine, 5-azacitidine Trametinib, everolimus, temsirolimus Trametinib None MEK162, LGX818
Only representative examples of investigational compounds are shown because of space constraints. Abbreviations: Amp, amplifications; Indel, small insertions and/or deletions; Sub, base substitutions.
Figure 2. Lollipop plot graphically depicting the location of ARID1A genomic alterations in the 28 ARID1A-altered gastric cancer cases (one arrowhead per genomic alteration [GA] in this series, with some cases harboring several ARID1A GAs).
Figure 2. Lollipop plot graphically depicting the location of ARID1A genomic alterations in the 28 ARID1A-altered gastric cancer cases (one arrowhead per genomic alteration [GA] in this series, with some cases harboring several ARID1A GAs).
Similarly for TP53 and ARID1A, targeted therapies are in clinical
patient series but were mutually exclusive, consistent with observations in breast carcinoma [33]. Theconsistent low frequency in this our patient series but were mutually exclusive, with observations
remodeling. Aand recent development is remodeling. the paradigm suchchromatin kevetrin (NCT01664000), inhibitors of chromatin A of
of ERBB2 amplification 20% inseries breast(4.3%) carcinoma [33]. The low frequencyin in contrast this series with (4.3%)the of ERBB2
master trials, such the Novartis Signature Trial, multiple recent development is theas paradigm of master trials, such as with the Novartis
frequency in observed in previous studies observed is likely inisprevious due tostudies a amplification contrast with the 20% frequency
cancers ratherrather thanthan restrictionto a tumortype. design advanced cancers restriction to a tumor type.Such Suchaatrial trial design
previously fortested ERBB2 amplification and and were negative profiling weretested previously for ERBB2 amplification were negative for
agents and entry criteria Signature Trial, withgenomically multiple agentsdefined and genomically defined for entryadvanced criteria for
can accommodate the addition of future therapies to be decan accommodate the addition of future therapies to be developed, and veloped, and genomic profiling can provide the rationale for genomic profiling can provide the rationale for entering patients. entering patients. We identified five GC cases with ERBB2-activating base We identified five GC cases with ERBB2-activating base substitutions, which substitutions, which cannot be detected by IHC or FISH [29]. cannot be detected IHC or FISH The recentby description of[29]. somatic ERBB2 base substitutions in breast carcinoma and micropapillary urothelial carcinoma The suggests recent description of somatic ERBB2 base substitutions in breast that such alterations may also be oncogenic drivers in carcinoma and carcinoma suggests thatresponded such GC, and at micropapillary least one suchurothelial breast carcinoma patient has to anti-ERBB2 (HER2)-targeted [29–32]. Both ERBB2 alterations may also be oncogenic driverstherapy in GC, and at least one such breast amplifications and base substitutions were observed in our carcinoma patient has responded to anti-ERBB2 (HER2)-targeted therapy [29–32]. Both ERBB2 amplifications and base substitutions were observed in
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bias, is, cases submitted for genomic were isselection likely is due to athat selection bias, that is, cases submittedprofiling for genomic
for ERBB2, prompting a search for therapeutic alternatives [34]. Among ERBB2 base substitutions in this series, some have been functionally characterized as activating and sensitive to Among ERBB2 base substitutions in this series, some have been functionally lapatinib (S310F, V842I) or resistant to lapatinib (L755S) [30]. characterized as activating and sensitive to lapatinib (S310F, V842I) or The frequency of 4.3% was very similar to the frequency reresistant (L755S)confirming [30]. The frequency 4.3% was very ported to inlapatinib other series, that noof selection biassimilar was to the frequency reported in other series, confirming that no selection bias present because standard of care testing does not detect thesewas present because standard of care testing does not detectERBB2 these clinically clinically relevant alterations [34, 35]. Although R678Q relevant alterations Althoughor ERBB2 R678Qresistance was not found to be was not found to[34, be35]. activating to confer to antiERBB2 (HER2)-targeted therapy, it has been observed multiple activating or to confer resistance to anti-ERBB2 (HER2)-targeted therapy, in the context of cancer, which may indicate biologic ittimes has been observed multiple times in the context of cancer, which may ERBB2, prompting a search for therapeutic alternatives [34].
GASTROENTEROLOGY TODAY - SUMMER 2015
development, kevetrin (NCT01664000), and inhibitors of Similarly for TP53 andsuch ARID1A, targeted therapies are in clinical development,
indicate biologic significance.
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Figure 3. Response to crizotinib in a patient with MET-amplified gastric cancer identified by prospective comprehensive genomic
Figure 3. Response to crizotinib inFDG-avid a patient with MET-amplified gastric cancer identified by prospective comprehensive genomicinitiation. profiling. (A): Precrizotinib profiling. (A): Precrizotinib hepatic metastasis. (B–D): Ongoing response up to 5 months after crizotinib FDG-avid hepatic metastasis. (B–D): Ongoing response up to 5 months after crizotinib initiation.
GASTROENTEROLOGY TODAY - SUMMER 2015
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significance. Activating ERBB2 base substitutions appear to be sensitive to neratinib, suggesting a possible pathway to clinical neratinib, suggesting a possible pathway to clinical treatment, and treatment, and genomically selected basket trials of neratinib genomically selected basket trials of neratinib (NCT01953926) are (NCT01953926) are ongoing for ERBB2-altered tumors [30]. ongoing for ERBB2-altered tumors [30]. Previous studies have strongly associated ERBB2-amplified gastric carcinomas with intestinal type histology and proximal Previous studies have[8, strongly ERBB2-amplified gastric gastric location 12]. Allassociated five ERBB2-amplified GC cases in this carcinomas with intestinal type histology and proximal gastric location series had histology diagnosed as or at least suggestive of the [8, 12]. All five ERBB2-amplified GCapproximately cases in this series haddistributed histology intestinal subtype but were evenly diagnosed or at least suggestive of the intestinal subtype but were in site as of origin between the proximal and distal stomach (supapproximately distributed of originERBB2 between the proximal plementalevenly online Table 1).inInsite contrast, base substituand distal (supplemental In contrast, ERBB2of tions stomach were associated withonline signetTable ring1).features in three basefour substitutions were associated with signet features three of cases with histology available for ring review. Theindiffering histology these cases may differing clinicopathofour cases with of histology available forsuggest review. The differing histology of characteristics of ERBB2-amplified GCcharacteristics compared with theselogic cases may suggest differing clinicopathologic of ERBB2 base-substituted gastric carcinomas, but this awaits ERBB2-amplified GC compared with ERBB2 base-substituted gastricindependent confirmation in a largerconfirmation series. carcinomas, but this awaits independent in a larger Alterations in the FGFR family are well recognized as onseries. cogenic drivers [36, 37]. FGFR2 was amplified at 6% in this GC series, similar toa previous 38]. Limitedclinical Alterations in the FGFR family arestudy[18, well recognized as oncogenicstudies have shown that FGFR2-amplified breast carcinoma drivers [36, 37]. FGFR2 was amplified at 6% in this GC series, patients similar responded favorably dovitinib, a multikinase that to a previous study [18,38].to Limited clinical studies have inhibitor shown that inhibits FGFR family members [39]. For FGFR2-amplified GC, FGFR2-amplified breast carcinoma patients responded favorably to preclinical evidence suggests such tumors are sensitive to FGFRdovitinib, a multikinase inhibitor that inhibits FGFR family members targeted therapy, and molecularly stratified clinical trials are [39]. For FGFR2-amplified GC, preclinical evidence suggests such ongoing (NCT01719549) [40]. tumors are sensitive to FGFR targeted therapy, and molecularly Amplification of MET is a known driver of gastroesophstratified clinical trials are ongoing (NCT01719549) [40]. ageal and lung carcinomas and other tumor types [38, 41, 42]. We identified MET amplification (.6 copies) in 6% of GC Amplification of MET is a known driver of gastroesophageal and lung cases in this series. Based on the genomic profile, one of the carcinomas and other tumor types [38, 41, We identified METwith patients with MET amplification (1242]. copies) was treated amplification (>6 copies) in 6% of GC cases in this series. Based crizotinib and had regression of liver metastasis and disease on the genomic one of the 3). patients with METisamplification control forprofile, 5 months (Fig. This finding consistent with (12 copies)was treatedfor withphase crizotinib andfor hadcrizotinib regressioninofwhich liver two previous results I trials metastasis and disease control for 5 carcinoma months (Fig.patients 3). This finding advanced gastroesophageal with MET is consistent with previous for phase I trials crizotinib in amplifications (FISH results MET/CEN7P ratio of for .2.2) had partial whichresponse two advanced carcinoma patients with METof and gastroesophageal stable disease with time to progression amplifications (FISH MET/CEN7P ratio of >2.2) had partial response 3–4 months [41].The comprehensive genomic profiling assay
in this series used a process-matched normal control to quantitatively estimate the absolute copies of MET while a process-matched normal control to quantitatively estimate the controlling for ploidy. The threshold of six copies for the absolute copies of MET while controlling for ploidy. The threshold of six designation of MET amplification by FoundationOne in copies for the designation of MET amplification by FoundationOne in cases with a diploid genome can be translated as exceeding cases with a diploid can be a MET/CEP7 ratiogenome of 2.2 (Fig. 4). translated as exceeding a MET/ CEP7Notably, ratio of 2.2 (Fig. 4). the comprehensive genomic profiling assay used in this study (FoundationOne) provides quantitative estimates of Notably, the comprehensive genomic used estimates in this study copy number amplifications (Fig. profiling 4). Copyassay number (FoundationOne) provides quantitative estimates of copy number madebythegenomic profilingassayuseddo notdirectlytranslate amplifications (Fig.per 4). se Copy estimates made by the genomic to a FISH ratio but,number as shown by our patient response, profiling used relevant do not directly translate that to a FISH ratio per se of but, provideassay clinically information can guide use astargeted shown bytherapy our patient response, provide clinically relevantprofiling information (Fig. 3). Comprehensive genomic that can guide of targeted (Fig. 3).assessment Comprehensive genomic provides theuse advantage of therapy simultaneous of many profiling provides therelevant advantage ofnumber simultaneous assessment of many possible clinically copy amplifications including possible clinically relevant number amplifications including MET, FGFR2, and ERBB2copy while minimizing consumption of MET, the FGFR2, and [19]. ERBB2 minimizing consumption of the specimen specimen In while contrast, other forms of molecular testing are[19]. Inhypothesis contrast, other forms ofis, molecular testing hypothesis driven,that a“hotspot” exonare examines onlydriven,that specific is,exons a “hotspot” exon only is specific of genes interest of genes ofexamines interest and often exons combined withofFISH to and is often with FISH assay forand amplifications ERBB2 assay for combined amplifications (i.e.,to ERBB2 MET). A (i.e., focused and MET). Aoffers focused approach simplicity, offers conceptual but for approach conceptual but forsimplicity, those cases harthose cases harboring relevant genomic outside alterations boring relevant genomic alterations theoutside scopethe of scope such ofhotspot such hotspot testing, genomic profiling couldbe bedone done to to identify testing, genomic profiling could identify potential benefits of targeted therapy instead of expending both both time potential benefits of targeted therapy instead of expending and resources on hotspot mightthat not yield information time and resources on testing hotspotthat testing might not yieldtoinguide treatment. formation to guide treatment. In one of the largest screening studies for KRAS mutations Ininvolving one of theGC largest screening for KRAS involving samples from studies U.K., Japan, andmutations Singapore, KRAS GC samples were from U.K., Japan, KRAS mutations mutations found in 29and of Singapore, 710 GC samples (4.1%). The were found in 29 of 710 GC samples (4.1%). TheU.K. frequency of 4.0% KRAS frequencyof KRAS mutations was 5.8% among patients, mutations was 5.8%patients, among U.K. 4.0% Singapore among Japanese among Japanese andpatients, 1.5% among Chinese patients, patients. The of patients.and The1.5% role among of KRASSingapore mutation Chinese in GC is unknown, butrole in this KRAS mutation in GC is unknown, but in this mutations series, KRAS mutations were identified in series, 16% ofKRAS GC cases. The were in alterations 16% of GC cases. The most common alterations mostidentified common were G12V (3.4%) and G12D (2.5%), were G12V and G12D (2.5%), whichlikely are both transversions. which are(3.4%) both transversions. This most reflects a selection This likely reflects a selectionwith bias in this sample biasmost in this sample population, patients sent population, for genomicwith patients sent for genomic profilingand having poor KRAS prognosis and possible profiling having poor prognosis possible enrichment.
Activating ERBB2 base substitutions appear to be sensitive to
The comprehensive genomic profiling assay in this series used
and stable disease with time to progression of 3–4 months [41].
KRAS enrichment.
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Figure 4. Copy number alteration plots for several cases harboring receptor tyrosine kinase amplifications.
Figure 4. Copy number alteration plots for several cases harboring receptor tyrosine kinase amplifications.
profiling when options are limited [46]. In reporting these results,BRAF caveats foror directed are described included. in GC Neither V600E V600M germline alterationstesting previously Neither BRAF V600E or V600M alterations previously were observed in this series, but three nonBRAFV600 mutations were described in GC were observed in this series, but1).three found in this series [13, 48–50] (supplemental online Table nonBRAFV600 mutations found in this series [13, of 48–50] The BRAF alterations in thesewere series are variable activators BRAF. (supplemental online Table 1). The BRAF alterations in these series are variable activators of BRAF.were identified in this series. Interestingly, no alterations in VEGFR1–3 Interestingly, no alterations VEGFR1–3 Ramucirumab has been shown to in improve OS inwere GC inidentified second- in this series. Ramucirumab has been shown to improve OS in GC line treatment as a single agent or in combination with paclitaxel. in second-line treatment as a single agent or in combination Ramucirumab is a monoclonal antibody against VEGFR2, but, with paclitaxel. Ramucirumab is a monoclonal antibody against like other antiangiogenic therapies, there are no clear predictive VEGFR2, but, like other antiangiogenic therapies, there are no biomarkers [51, 52]. Current evidence is insufficient to examine clear predictive biomarkers [51, 52]. Current evidence is inwhether VEGFR1–3 alterations serve as biomarkers for ramucirumab. sufficient to examine whether VEGFR1–3 alterations serve as biomarkers for ramucirumab. Identifying clinically relevant alterations in the course of clinical care Identifying clinically relevant alterations in the course of of gastric carcinoma may drive clinical decisions making, which clinical care of gastric carcinoma may drive clinical decisions in turn will generate preliminary data on the efficacy of targeted making, which in turn will generate preliminary data on the therapies in gastric carcinoma and care of future patients and will efficacy of targeted therapies in gastric carcinoma and care of support future systematic investigation through clinical trials. At future patients and will support future systematic investigation present, most suggestion of benefit from targeted therapy gastric through clinical trials. At present, most suggestion of inbenefit carcinoma is guided by analogy to other tumor types. Such reasoning from targeted therapy in gastric carcinoma is guided by analogy highlights the limitations of thisreasoning approach,highlights for example, V600Eto other tumor types. Such the BRAF limitations mutant has not suggested benefit from of thiscolorectal approach,adenocarcinoma for example, BRAF V600E-mutant colorectal
results, caveats for directed germline testing are included.
vemurafenib monotherapy [53, 54].
www.TheOncologist.com
©AlphaMed Press 2015
GASTROENTEROLOGY TODAY - SUMMER 2015
Alterations in the tumor suppressors TP53 and ARID1A are common intumor gastric cancer. ARID1A encodes AT-rich inAlterations in the suppressors TP53 and ARID1A the are common teractive domain-containing protein 1A, a member in gastric cancer. ARID1A encodes the AT-rich interactive domain-of the SWI/SNF chromatin-remodeling complex. Inactivating altercontaining protein 1A, a member of the SWI/SNF chromatin-remodeling ations in ARID1A are frequent in ovarian clear carcinomas, complex. Inactivating alterations in ARID1A are frequentcell in ovarian clear neuroblastomas, and gastric carcinomas and loss of expression cell carcinomas, neuroblastomas, and gastric carcinomas and loss in other tumor with the tumor of expression in othertypes, tumor consistent types, consistent withhypothesized the hypothesized suppressor role of this protein [43, 44]. Alterations of ARID1A tumor suppressor role of this protein [43, 44]. Alterations of ARID1A in this series did not cluster around a hotspot (Fig. 2). The in this series did not cluster around a hotspot (Fig. 2). The statistically statistically significant enrichment of PIK3CA and the paucity of significant enrichment of PIK3CA and the paucity of TP53 alterations in TP53 alterations in the set of ARID1A-altered GCs are the set of ARID1A-altered GCs are consistent with previous findings in consistent with previous findings in gastric carcinoma [43, 45]. gastric carcinoma [43, 45]. In our series, ARID1A-altered cases were In our series, ARID1A-altered cases were also enriched for CREBBP also enriched for CREBBP and MLL2 alterations. and MLL2 alterations. Interestingly, our series identified somatic CDH1 mutation Interestingly, our series identified somatic CDH1 mutation rates (25% rates (25% diffuse, 12% nondiffuse) higher than previously diffuse, 12% nondiffuse) higher than previously reported (Fig. 5) [46]. reported (Fig. 5) [46]. The differences in alteration frequency The differences in alteration frequency may be related to the interrogation may be related to the interrogation of the entire coding seof the entire coding sequence of CDH1 in this assay compared with the quence of CDH1 in this assay compared with the limited limited hotspotassessment assessment of hotspot interrogation in prior in hotspot ofexon exon7–10 7–10 hotspot interrogation series [46, 47]. CDH1 somatic mutation has been correlated with the corprior series [46, 47]. CDH1 somatic mutation has been shortest survival in GC, and selection bias may underlie increased related with the shortest survival in GC, and selectionCDH1 bias mutation in thisincreased series because clinicians may rates be likely reach may rates underlie CDH1 mutation in tothis series for mutational when options limited In reporting these because profiling clinicians may be are likely to [46]. reach for mutational
13
CLINICAL PAPER 8
Clinical Genomic Profiling in Gastric Cancer
Figure 5. Lollipop plot graphically depicting the location of CDH1 genomic alterations (GAs) in the 17 CDH1-altered gastric cancer cases Figure 5. Lollipop plot graphically depicting the location of CDH1 genomic alterations (GAs) in the 17 CDH1-altered gastric cancer cases (one (one arrowhead per GA in this series). arrowhead per GA in this series). Abbreviation: TM, transmembrane. Abbreviation: TM, transmembrane. Because new approaches such as the combination of vemurafenib adenocarcinoma has not suggested benefit from vemurafenib and erlotinib confer some benefit to similar patients, as noted, monotherapy [53, 54]. Because new approaches such as the it is hoped that analogous approaches can also benefit gastric combination of vemurafenib and erlotinib confer some benefit carcinoma patients [54]. to similar patients, as noted, it is hoped that analogous approaches can also benefit gastric carcinoma patients [54].
Conclusion
CONCLUSION The high clinically relevant genomic alterations in The highfrequency frequencyofof clinically relevant genomic alterations in this patient reflective of routine clinicalclinical practicepractice is this patientpopulation population reflective of routine is encouraging in have a poor prognosis encouraging inaadisease diseasethat thatcontinues continuestoto have a poor prognosis with modern chemotherapy. The The clinically relevant alterations with modern chemotherapy. clinically relevant alterations identified byby this assay beyond those detected by standard of caseof identified this assay beyond those detected by standard can drive clinical trial participation and development case canincreased drive increased clinical trial participation and(e.g., deERBB2 base substitutions, MET amplifications) and clarify predictive velopment (e.g., ERBB2 base substitutions, MET amplifications) response and resistance biomarkers. and clarify predictive response and resistance biomarkers.
Acknowledgments A CKNOWLEDGMENTS GASTROENTEROLOGY TODAY - SUMMER 2015
14
We acknowledge important contributions from other researchWe that acknowledge important from other researchers that ers could not be citedcontributions due to space constraints. No external could notor begrant cited due to space Nothis external funding or funding support wasconstraints. involved in study. This work grant support was involved in this profiled study. This dedicated to theis is dedicated to the patients inwork thisisreport. G.A.P. patients profiled in this report. G.A.P. is currently currently affiliated with NantHealth, Culveraffiliated City, CA.with Nant Health, Culver City, CA.
AUTHOR CONTRIBUTIONS
Author Contributions
Conception/Design: Siraj M. Ali, Eric M. Sanford, Juliann Chmielecki, Vincent A. Miller
Conception/Design: Siraj M. Ali, Eric M. Sanford, Juliann Chmielecki, Vincent A. Miller R EFERENCES
Data analysis and interpretation: SirajM.Ali, KaiWang, Provision of study material or patients: DanielEricM.Sanford, V. Catenacci, Fadi Braiteh, SaiNorma A.Ignatius Palma, Ou JuliannChmielecki, Roman Yelensky, Gary A. Palmer, Hong Collection and/or assembly of data: Siraj M. Ali, Eric M. Sanford, Kai Wang, Doron Lipson, Daniel V. Catenacci, Jeffrey S. Ross, Sai-Hong Ignatius Ou Roman Yelensky, Doron Lipson, Daniel V. Catenacci, Fadi Braiteh, Philip J. Stephens, JeffreySiraj S. Ross Manuscriptwriting: M. Ali, Eric M. Sanford, Samuel J. Klempner, Data analysis and interpretation: Siraj M. Ali, Eric M. Sanford, Kai Wang, Norma Douglas A. Rubinson, Kai Wang, Norma A. Palma, Chmielecki, A. Palma, Juliann Chmielecki, Roman Yelensky, GaryJuliann A. Palmer, Doron Lipson, GaryDaniel A. Palmer, Deborah Morosini, Doron Lipson, Daniel V. Catenacci, Jeffrey S. Ross, Sai-Hong Ignatius OuV. Catenacci, Manuscript M. Ali, Eric M. Sanford, Samuel J. Klempner, Douglas Rachel Erlich,writing: Philip J.Siraj Stephens, Jeffrey S. Ross, Sai-Hong Ignatius Ou, A. Rubinson, Kai Wang, Norma A. Palma, Juliann Chmielecki, Gary A. Palmer, Vincent A. Miller Deborah Morosini, Doron Lipson, Daniel V. Catenacci, Rachel Erlich, Philip J. Stephens, Jeffrey S. Ross, Sai-Hong Ignatius Ou, Vincent A. Miller Final approval of manuscript: Siraj M. Ali, Juliann Chmielecki, Jeffrey S. Final approval of manuscript: Siraj M. Ali, Juliann Chmielecki, Jeffrey S. Ross, Ross, Vincent Miller Vincent A. A. Miller
DISCLOSURES Disclosures Siraj M. Ali: Foundation Medicine Inc. (E, OI); Eric M. Sanford:
Foundation Medicine Inc. (E, OI); Kai Wang: Foundation Medicine Inc.
Siraj M. Norma Ali: Foundation Inc. Medicine (E, OI); Eric (E, OI); A. Palma:Medicine Foundation Inc.M. (E,Sanford: OI); Juliann
Chmielecki: Foundation Inc.Wang: (E, OI);Foundation Roman Yelensky: Foundation Medicine Inc. Medicine (E, OI); Kai Medicine Foundation Medicine Inc. (E, IP); Gary A. Palmer: Foundation
Inc. (E, OI);Inc. Norma A. Deborah Palma: Foundation Medicine Inc. (E, OI); Inc. Medicine (E, OI); Morosini: Foundation Medicine
Juliann Foundation Medicine Inc. (E, OI); Chmielecki: Doron Lipson: Foundation Medicine Inc.(E,(E,OI); OI, Roman IP); Daniel V.
Catenacci:Foundation FoundationMedicine MedicineInc. Inc.(E, (C/A); Fadi Braiteh: Foundation Yelensky: IP); Gary A. Palmer: Medicine, Caris Life Sciences, Genomic Health, Molecular Health
Foundation Medicine (E, BMS, OI); Deborah Foundation (C/A); Amgen, Bayer,Inc. Pfizer, Celgene, Morosini: Insys, incyte, Caris Life
Medicine (E, OI);Health Doron(H); Lipson: MedicineMedicine Sciences,Inc. Genomic RachelFoundation Erlich: Foundation
Inc.(E, (E,OI, OI);IP); Philip J. Stephens: Foundation Medicine Inc. (E, OI); Inc. Daniel V. Catenacci: Foundation Medicine Inc.Jeffrey S. Ross: Foundation Medicine Inc. (RF, E, OI, IP); Vincent A. Miller: Foundation Medicine Inc. (E, OI). The other authors indicated no Genomic Molecular Health (C/A); Amgen, Bayer, Pfizer, financialHealth, relationships. (C/A); Fadi Braiteh: Foundation Medicine, Caris Life Sciences,
(C/A) Consulting/advisory relationship; Research (E) Employment; (ET)Health Expert BMS, Celgene, Insys, incyte, (RF) Caris Life funding; Sciences, Genomic
testimony; (H) Honoraria received; (OI) Ownership interests; (IP) Intellectual property rights/
(H); Rachel Erlich: Foundation Medicine inventor/patent holder; (SAB) Scientific advisory board Inc. (E, OI); Philip J. Stephens: Foundation Medicine Inc. (E, OI); Jeffrey S. Ross: Foundation Medicine Inc. (RF, E, OI, IP); Vincent A. Miller:
Foundation Medicine Inc. (E, OI). The other authors indicated no
financial relationships. Provision study material Fadi 1. Jemal A,ofBray F, Center MMoretpatients: al. GlobalDaniel cancer V. Catenacci, 5. Schwarz RE, Zagala-Nevarez K. Ethnic survival 7. Strong VE, Song KY, Park CH et al. Comparison statistics. CA CancerIgnatius J Clin 2011;61:69–90. differences after gastrectomy for gastric cancer are of disease-specific survival in the United States and Braiteh, Sai-Hong Ou better explained by factors specific for disease Korea after resection for early-stage node-negative 2. Bertuccio P, Chatenoud L, Levi F et al. Recent Collection and/orcancer: assembly of data: Siraj M. M. Sanford, Kai location and individual patient comorbidity. Eur J relationship; gastric carcinoma. J Surg Oncol (E) 2013;107:634–640. patterns in gastric A global overview. IntAli, J Eric (C/A) Consulting/advisory (RF) Research funding; Employment; Surg Oncol 2002;28:214–219. (ET) Expert testimony; (H) Honoraria received; (OI)Cutsem Ownership interests; (IP)A et al. Cancer Wang, 2009;125:666–673. Roman Yelensky, Doron Lipson, Daniel V. Catenacci, Fadi Braiteh, 8. Bang YJ, Van E, Feyereislova Intellectual rights/inventor/patent (SAB) Scientific advisory board 3. Takahashi T, Saikawa Kitagawa Y. Gastric 6. Strong VE, Song KY, Park CH et al.property Comparison Trastuzumabholder; in combination with chemotherapy Philip J. Stephens, Jeffrey Y, S. Ross cancer: Current status of diagnosis and treatment. of gastric cancer survival following R0 resection in versus chemotherapy alone for treatment of HER2Cancers (Basel) 2013;5:48–63. the United States and Korea using an internationpositive advanced gastric or gastro-oesophageal junc4. Siegel R, Naishadham D, Jemal A. Cancer ally validated nomogram. Ann Surg 2010;251: tion cancer (ToGA): A phase 3, open-label, randomised statistics, 2013. CA Cancer J Clin 2013;63:11–30. 640–646. controlled trial. Lancet 2010;376:687–697.
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27. Comprehensive molecular characterization of gastric adenocarcinoma. Nature 2014;513:202–209. 28. Infante JR, Fecher LA, Falchook GS et al. Safety, pharmacokinetic, pharmacodynamic, and efficacy data for the oral MEK inhibitor trametinib: A phase 1 dose-escalation trial. Lancet Oncol 2012;13:773–781. 29. Ross JS. Breast cancer biomarkers and HER2 testing after 10 years of anti-HER2 therapy. Drug News Perspect 2009;22:93–106. 30. Bose R, Kavuri SM, Searleman AC et al. Activating HER2 mutations in HER2 gene amplification negative breast cancer. Cancer Discov 2013;3:224–237. 31. Ross JS, Wang K, Sheehan CE et al. Relapsed classic E-cadherin (CDH1)-mutated invasive lobular breast cancer shows a high frequency of HER2 (ERBB2) gene mutations. Clin Cancer Res 2013;19:2668–2676. 32. Ali SM, Alpaugh RK, Downing SR et al. Response of an ERBB2-mutated inflammatory breast carcinoma to human epidermal growth factor receptor 2-targeted therapy. J Clin Oncol 2014;32:e88–e91. 33. Ross JS. Update on HER2 testing for breast and upper gastrointestinal tract cancers. Biomarkers Med 2011;5:307–318. 34. Lee J, Ou SH. Towards the goal of personalized medicine in gastric cancer—time to move beyond HER2 inhibition. Part II: Targeting gene mutations and gene amplifications and the angiogenesis pathway. Discov Med 2013;16:7–14. 35. Lee J, Ou SH. Towards the goal of personalized medicine in gastric cancer—time to move beyond HER2 inhibition. Part I: Targeting receptor tyrosine kinase gene amplification. Discov Med 2013;15:333–341. 36. Wu YM, Su F, Kalyana-Sundaram S et al. Identification of targetable FGFR gene fusions in diverse cancers. Cancer Discov 2013;3:636–647. 37. Singh D, Chan JM, Zoppoli P et al. Transforming fusions of FGFR and TACC genes in human glioblastoma. Science 2012;337:1231–1235. 38. Liu YJ, Shen D, Yin X et al. HER2, MET and FGFR2 oncogenic driver alterations define distinct molecular segments for targeted therapies in gastric carcinoma. Br J Cancer 2014;110:1169–1178. 39. André F, Bachelot T, Campone M et al. Targeting FGFR with dovitinib (TKI258): Preclinical and clinical data in breast cancer. Clin Cancer Res 2013;19:3693–3702. 40. Xie L, Su X, Zhang L et al. FGFR2 gene amplification in gastric cancer predicts sensitivity to the selective FGFR inhibitor AZD4547. Clin Cancer Res 2013;19:2572– 2583. 41. Lennerz JK, Kwak EL, Ackerman A et al. MET amplification identifies a small and aggressive subgroup of esophagogastric adenocarcinoma with evidence of responsiveness to crizotinib. J Clin Oncol 2011;29:4803–4810. 42. Sadiq AA, Salgia R. MET as a possible target for non-small-cell lung cancer. J Clin Oncol 2013;31:1089–1096. 43. Zang ZJ, Cutcutache I, Poon SL et al. Exome sequencing of gastric adenocarcinoma identifies recurrent somatic mutations in cell adhesion and chromatin remodeling genes. Nat Genet 2012;44:570–574. 44. Jones S, Wang TL, Shih IM et al. Frequent mutations of chromatin remodeling gene ARID1A in ovarian clear cell carcinoma. Science 2010;330:228–231. 45. Comprehensive molecular characterization of gastric adenocarcinoma. Nature 2014 (in press). 46. Corso G, Carvalho J, Marrelli D et al. Somatic mutations and deletions of the E-cadherin gene predict poor survival of patients with gastric cancer. J Clin Oncol 2013;31:868–875. 47. Oliveira C, Sousa S, Pinheiro H et al. Quantification of epigenetic and genetic 2nd hits in CDH1 during hereditary diffuse gastric cancer syndrome progression. Gastroenterology 2009;136:2137–2148. 48. Lee SH, Lee JW, Soung YH et al. BRAF and KRAS mutations in stomach cancer. Oncogene 2003;22:6942–6945. 49. Wu M, Semba S, Oue N et al. BRAF/K-ras mutation, microsatellite instability, and promoter hypermethylation of hMLH1/MGMT in human gastric carcinomas. Gastric Cancer 2004;7:246–253. 50. van Grieken NC, Aoyama T, Chambers PA et al. KRAS and BRAF mutations are rare and related to DNA mismatch repair deficiency in gastric cancer from the East and the West: Results from a large international multicentre study. Br J Cancer 2013;108:1495–1501. 51. Jubb AM, Oates AJ, Holden S et al. Predicting benefit from anti-angiogenic agents in malignancy. Nat Rev Cancer 2006;6:626–635. 52. Van Cutsem E, de Haas S, Kang YK et al. Bevacizumab in combination with chemotherapy as first-line therapy in advanced gastric cancer: A biomarker evaluation from the AVAGAST randomized phase III trial. J Clin Oncol 2012;30:2119–2127. 53. Prahallad A, Sun C, Huang S et al. Unresponsiveness of colon cancer to BRAF(V600E) inhibition through feedback activation of EGFR. Nature 2012;483:100–103. 54. Yaeger R, Cercek A, O’Reilly EM et al. Pilot trial of combined BRAF and EGFR inhibition in BRAFmutant metastatic colorectal cancer patients. Clin Cancer Res 2015;21:1313–1320.
15
CASE REPORT
A FALSE POSITIVE MECKEL’S SCAN IN A YOUNG WOMAN WITH IRON DEFICIENCY ANAEMIA K WM Abeysekera, B Bunsa, N Beharry*, A Poullis. Department of Gastroenterology and Radiology* St George’s Hospital, London
Case report
At review in clinic her abdominal symptoms had worsened slightly although there was still no change in bowel habit. A colonoscopy was arranged, this revealed macroscopically circumferential caecal ulceration involving the ileo-caecal valve, endoscopically thought to be consistent with Crohn’s disease with the terminal ileum appearing normal. The terminal ileum showed sparse superficial acute inflammation. Caecal biopsies showed ulceration with granulation tissue. Focal cryptitis and occasional crypt abscesses were present. Occasional loose non-necrotising granulomas and multinucleate giant
A 40 year old Indian woman who was referred initially to
cells were seen. Ziehl-Neelsen and fungi staining were negative as was
Haematology Clinic having been found to have thrombocytosis
immunostaining for cytomegalovirus. However, despite a negative acid-
with a platelet count consistently above 500x109/l and IDA
fast bacilli microscopy, Mycobacterium tuberculosis was isolated after
with a ferritin of 17 µg/l by her general practitioner. On further
16 days of incubation with the tuberculosis polymerase chain reaction
questioning she described a 3-year history of left iliac fossa
sent also returning positive for Mycobacterium tuberculosis. The patient
pain that was mild and never precipitated her to present to a
was referred to the TB team and was been commenced on quadruple
clinician previously. It had been relieved with non-steroidal anti-
therapy (Rifampicin, Pyrazinamide, Ethambutol, Isoniazid) for abdominal
inflammatories. She denied any history of vomiting, diarrhoea or
tuberculosis. At follow up her abdominal symptoms have all resolved.
constipation. She opened her bowels twice daily, with no report of per rectal bleeding. She also denied fevers, night sweats or a productive cough. There was initially no weight loss although during 2014 she lost 4kg. She denied a loss in appetite. Her periods were regular and she denied them ever being heavy. Her past medical history included autoimmune thyroiditis for which she took thyroxine replacement therapy. She also had had a superficial abdominal
Discussion Iron deficiency anaemia affects 800 million people worldwide and is a common problem that affects pre-menopausal women.1 IDA in this demographic is often attributed to menstruation and pregnancy. As a result, guidelines for investigation of premenopausal iron deficiency anaemia are not as meticulous as they
cyst removed at the age of 15 in India. Her only other medication included
are in the post-menopausal state when a greater focus is placed
the combined oral contraceptive pill. She had no family history of note
on detecting a neoplastic lesion due to the greater incidence of
including colorectal cancer. She had moved to the UK in 2010 and visited
colorectal cancer in women over the age of 50, with 95% of all
relatives in India annually. She worked as a nanny and was not vegetarian.
bowel cancers diagnosed after this age.2
Her clinical examination was entirely unremarkable. The British Society of Gastroenterology (BSG) published clear GASTROENTEROLOGY TODAY - SUMMER 2015
16
The Haematology team had tested her JAK-2 status, which was normal
guidelines on the management of IDA in 2011.3 As happened with
and performed a trephine bone marrow biopsy, which showed normo-
our patient, her coeliac serology was tested which was negative.
cellular marrow and no evidence of a primary haematological disorder.
Because she had vague abdominal pain she proceeded to have
Her IDA was treated with a Ferinject™ (ferric carboxymaltose) infusion
an oesophago-duodenoscopy, which was normal. Our patient had
following a failure to tolerate oral replacement.
initially been referred to Haematology for a thrombocytosis as well as IDA, so her JAK2 status and bone marrow were examined
In view of her normal haematology examination she was referred to the
to rule out essential thrombocythaemia. As this patient had no
gastroenterology clinic. The patient had a normal coeliac screen and
family history of colorectal carcinoma she did not proceed to
autoimmune screen. An oesophago-gastro duodenoscopy (OGD) was
colonoscopy, and she received appropriate iron replacement
performed which was macroscopically normal, with normal duodenal
therapy.
biopsies. As per BSG guidelines at this stage lower GI endoscopy was not carried out but given the mild lower abdominal pain a Meckel’s
It was in view of her ongoing non-specific lower abdominal pain and
scan was organized which identified a faint focus of tracer activity
IDA despite iron replacement that a Meckel’s scan was organised
demonstrated in the right side of the lower abdomen, and was felt to be
to rule out a Meckel’s diverticulum. Meckel’s scans are used to
suspicious of functioning ectopic gastric mucosa within the distal ileum
detect the ectopic gastric mucosa in patients with symptomatic
(Figure 1).
Meckel’s diverticulum. Utilising the physiological mimicry that exists
CASE REPORT
Figure 1. Images of Meckel’s scan performed. 99m Technetium production seen within stomach but also noted in right iliac fossa, initially thought to be consistent with a Meckel’s diverticulum. Increased contrast also seen bladder, related to renal excretion of contrast.
with ectopic gastric mucosa secreting chloride into the intestinal
Following the Meckel’s scan, the decision to perform colonoscopy
lumen, Technetium-99m (99m Tc) pertechnetate acts as an analogue
was taken. This identified caecal ulceration which whilst
of chloride. This allows the radiolabelled isotope to be secreted into
macroscopically looking like Crohn’s disease, cultures and PCR
the intestinal lumen, which is highlighted on a scan.
identified underlying abdominal TB. This has never previously been
4-6
documented as a cause of false positive Meckel’s scan result. It is hypothesised that was likely caused by the chronic inflammation
with a radiological report commenting that this could indeed be a
creating a localised hyperaemia. Abdominal TB needs to be
false positive result, reflecting underlying Crohn’s disease, given
considered within the differential of alternative causes for a false
the history of abdominal pain and IDA. Meckel’s scans have a
positive Meckel’s scan in any patient that has travelled from an area
specificity of 95% and sensitivity of 85% however this diminishes
of endemic TB.
after adolescence. 7 False positive Meckel’s scans have a wide differential. Any tissue containing ectopic gastric mucosa will be
This case also poses the question regarding colonoscopy in young
detected on scan. Focal small bowel pathology such as Crohn’s,
women and whether it should have been performed earlier, given
abdominal abscesses or intussusception can be highlighted. It is
that it elucidated the aetiology of this patient’s pathology through
hypothesised this is related to localized hyperaemia associated
cultures and PCR of the lesion. This is a controversial topic, not
with these conditions.
4-7
Other causes include neoplastic lesions
least because sinister diagnoses like colorectal carcinoma in pre-
e.g. colorectal carcinoma, leiomyosarcoma, ileal carcinoid
menopausal women are an elusive diagnosis and an emotional
and vascular malformations such as haemangiomas and A-V
topic.8 BSG guidelines highlight that dual upper and lower GI
malformation. As
99m
Tc pertechnetate is excreted renally, genito-
pathology, while uncommon, does occur in 1-10% of patients. 9-11
urinary false positive foci such as an extrarenal pelvis, horseshoe
Whilst recto-sigmoid colorectal carcinoma remains the commonest
kidneys, ureteric obstruction can be falsely identified as a positive
tumour 12, younger patients, especially those with ascending colon
result. Occasionally iatrogenic causes such as laxatives and
cancers, often present late.13
endoscopy can causes false positive results, again postulated to be due to hyperaemia caused by localized inflammation.7
GASTROENTEROLOGY TODAY - SUMMER 2015
Our patient had a positive scan within the terminal ileum/caecum,
>>> 17
CASE REPORT As is such, there is a growing voice of bi-directional endoscopic assessment in pre-menopausal women who present with IDA. Current BSG guidelines do not advocate colonoscopy in premenopausal women without a strong family history of colorectal carcinoma (two affected first-degree relatives or just one first degree relative affected before the age of 50 years 14) or colonic symptoms, neither of which this patient had. It should be noted that colonoscopy is not without its risk with an albeit low risk of perforation around 0.01%.15 It remains to be seen if other forms of colonic assessment are considered in future. CT colography is inappropriate in the pre-menopausal state due to high doses of radiation, whilst other alternatives such as capsule endoscopy may be considered, although sensitivities for detection of polyps >6mm vary anywhere from 63 – 89% and specificities ranging from 64-94%.16 It does however remain a cost effective and relatively risk free alternative option.17
References:
Summary
6. Swaniker F, Soldes O, Hirschl RB. The utility of technetium 99m pertechnetate scintigraphy in the evaluation of patients with Meckel’s diverticulum. J Pediatr Surg. May 1999;34(5):760-4; discussion 765
IDA assessment in pre-menopausal women who are negative with vague abdominal symptoms remains a controversial topic regarding bidirectional endoscopic assessment. In more ambiguous presentations like with our patient, a lower threshold for colonoscopy should be considered. Abdominal TB is a new recognised cause of a false positive Meckel’s scan and should be considered in any patient who is from, or has returned from, an area of endemic TB. ScheBo_GastroToday_Orange
1. World Health Organization/UNICEF/UNU. Iron Deficiency Anaemia: Assessment, Prevention, and Control. A Guide for Programme Managers. Geneva, Switzerland: World Health Organization; 2001 2. Data from Office of National Statistics, July 2013. 3. Goddard AF, James MW, McIntyre AS et al. Guidelines for the management of iron deficiency anaemia. Gut 2011;60:1309-1316 4. Emamian SA, Shalaby-Rana E, Majd M. The spectrum of heterotopic gastric mucosa in children detected by Tc- 99m pertechnetate scintigraphy. Clin Nucl Med. Jun 2001;26(6):529-35. 5. Omar AM, Al-Saee’d TA, Elgazzar A. Scintigraphic pattern of intestinal duplication on a Meckel’s diverticulum scan. Clin Nucl Med. Oct 1998;23(10):708-9.
7. Huynh, S., R. Amin, B. Barron, et al Nuclear imaging of Meckel’s Diverticulum: A pictorial essay of pitfalls. University of Texas Houston Medical School and Memorial Hermann - Texas Medical Center (TMC) 2007 8. Anonymous. Iron deficiency anaemia in a young woman: a plea for early investigation. MJA 2013;198:562-563 9. Rockey DC & Cello JP. Evaluation of the gastro-intestinal tract in patients with iron-deficiency anemia. N Engl J Med 1993;329:1691– 1695. 10. Cook, IJ, Pavli P, Riley JW, Goulston KJ & Dent OF. Gastrointestinal investigation of iron deficiency anaemia. BMJ 1986;292:1380–1382. 11. Zuckerman G & Benitez J. A prospective study of bidirectional endoscopy (colonoscopy and upper endoscopy) in the evaluation of patients with occult gastrointestinal bleeding. Am J Gastroenterol 1992;87:62–66 12. Abdulkareem, Fatimah Biade, et al. “Colorectal carcinoma in Lagos and Sagamu, Southwest Nigeria: a histopathological review.” World journal of gastroenterology: WJG 14.42 (2008): 6531. 13. Cappell, Mitchell S. “The pathophysiology, clinical presentation, and diagnosis of colon cancer and adenomatous polyps.” Medical Clinics of North America89.1 (2005): 1-42.
GASTROENTEROLOGY TODAY - SUMMER 2015
18
14. Cairns, Stuart R., et al. “Guidelines for colorectal cancer screening and surveillance in moderate and high risk groups (update from 2002).” Gut 59.5 (2010): 666-689. 15. Arora, Gaurav, et al. “Risk of perforation from a colonoscopy in adults: a large population-based study.” Gastrointestinal endoscopy 69.3 (2009): 654-664. 16. Riccioni, Maria Elena, et al. “Colon capsule endoscopy: Advantages, limitations and expectations. Which novelties?.” World journal of gastrointestinal endoscopy 4.4 (2012): 99. 17. Cook, C., et al. “National guidelines for capsule endoscopy: cost implications of non-compliance.” Gut 60.Suppl 1 (2011): A193-A194.
Prescribing Information (Please refer to the full Summary of Product Characteristics before prescribing).
Adverse events should be reported. Reporting forms and information can be found at www.mhra.gov.uk/yellowcard. Adverse events should also be reported to Shire Ltd on 01256 894000. UK/C-APROM/RES/15/0020 May 2015
Her way out... ...of chronic constipation
1
Reference: 1. National Institute for Health and Clinical Excellence. TA211 Constipation (women) – prucalopride: guidance. 15 December 2010. (http://guidance.nice. org.uk/TA211/Guidance/pdf/English).
CE AN ID HED LIS
RESOLOR® (prucalopride) Selective serotonin (5-HT4) receptor agonist, enterokinetic agent, available as 1 mg and 2 mg film-coated tablets for oral administration, once daily, with or without food, at any time of the day. INDICATION: Resolor is indicated for symptomatic treatment of chronic constipation in women in whom laxatives fail to provide adequate relief. DOSE: Women: 2 mg once daily. Older people (>65 years): Start with 1 mg once daily and increase to 2 mg once daily if necessary. Patients with severe renal impairment (GFR <30 ml/min/1.73m2): 1 mg once daily. Patients with severe hepatic impairment (Child-Pugh class C) start with 1 mg once daily which may be increased to 2 mg if required to improve efficacy and if the 1 mg dose is well tolerated. No dose adjustment required in patients with mild to moderate renal or hepatic impairment. Men: the safety and efficacy of Resolor has not been established in controlled clinical trials, therefore Resolor is not recommended for use in men until further data becomes available. Do not use in children and adolescents younger than 18 years. CONTRAINDICATIONS: Hypersensitivity to prucalopride or any of the excipients. Renal impairment requiring dialysis. Intestinal perforation or obstruction due to structural or functional disorder of the gut wall, obstructive ileus, severe inflammatory conditions of the intestinal tract, such as Crohn’s disease, and ulcerative colitis and toxic megacolon/megarectum. PRECAUTIONS: Caution should be exercised when prescribing Resolor to patients with severe hepatic impairment (Child-Pugh class C) due to limited data in patients with severe hepatic impairment. The safety and efficacy of Resolor for use in patients with severe and clinically unstable concomitant disease (e.g. cardiovascular or lung disease, neurological or psychiatric disorders, cancer or AIDS and other endocrine disorders) have not been established in controlled clinical trials. Caution should be exercised when prescribing Resolor to patients with these conditions especially when used in patients with a history of arrhythmias or ischaemic cardiovascular disease. In case of severe diarrhoea the efficacy of oral contraceptives may be reduced and an additional contraceptive method is recommended. Contains lactose monohydrate. Patients with galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption must not take Resolor. INTERACTIONS: Prucalopride has a low pharmacokinetic interaction potential. Studies in healthy subjects did not show a clinically relevant effect of prucalopride on the pharmacokinetics of warfarin, digoxin, alcohol, paroxetine or oral contraceptives. A 30% increase in plasma concentrations of erythromycin was found during prucalopride co-administration. The mechanism for this interaction was not clear. Ketoconazole increased the systemic exposure to prucalopride by 40%. This effect is too small to be clinically relevant. Therapeutic doses of probenecid, cimetidine, erythromycin and paroxetine did not affect the pharmacokinetics of prucalopride. PREGNANCY: Women of childbearing potential should use effective contraception during treatment with Resolor. Animal studies did not indicate harm. Experience of Resolor during human pregnancy is limited. Cases of spontaneous abortion have been observed in human clinical studies although, in the presence of other risk factors, the relationship to Resolor is unknown. Resolor is not recommended during pregnancy. LACTATION: Prucalopride is excreted in breast milk, however at therapeutic doses no effects are anticipated on the breastfed newborn/infant. In the absence of human data Resolor is not recommended during breastfeeding. EFFECTS ON ABILITY TO DRIVE AND USE MACHINES: No studies have been performed. Resolor has been associated with dizziness and fatigue, particularly on the first day of treatment, which may affect driving or using machines. SIDE EFFECTS: The most commonly reported side effects in Resolor clinical trials were headache and gastrointestinal symptoms (abdominal pain, nausea, diarrhoea) occurring in about 20% of patients each. These events occur mostly at the start of therapy and usually disappear within a few days whilst continuing Resolor. Other common adverse events in controlled trials included dizziness, vomiting, dyspepsia, rectal haemorrhage, flatulence, abnormal bowel sounds, pollakiuria and fatigue. Uncommon adverse events included anorexia, tremors, palpitations, fever and malaise. After the first day of treatment the most common adverse events were reported with similar frequency for Resolor and placebo except nausea and diarrhoea: these remained higher but the difference between Resolor and placebo was smaller (1 to 3%). Palpitations were reported in 0.7% of placebo patients, 1.0% of 1 mg Resolor patients and 0.7% of 2 mg Resolor patients. As with any new symptom, patients are advised to discuss new onset palpitations with their physician. PACK SIZE AND BASIC NHS PRICES: 28 tablets (4 blisters with 7 tablets) EU/1/09/581/001 (1 mg) £38.69, EU/1/09/581/002 (2 mg) £59.52. LEGAL CATEGORY: POM. MARKETING AUTHORISATION HOLDER: Shire Pharmaceuticals Ireland Limited, 5 Riverwalk, Citywest Business Campus, Dublin 24, Ireland. DATE OF PREPARATION: July 2014. Further information is available on request from: Shire plc, Unity Place, Hampshire International Business Park, Chineham, Basingstoke, Hampshire RG24 8EP.
NIC PU E GU B
Resolor® is indicated for symptomatic treatment of chronic constipation in women in whom laxatives fail to provide adequate relief. Please consult the Resolor® Summary of Product Characteristics before prescribing, particularly in relation to hypersensitivity to any of the constituents, renal impairment requiring dialysis, intestinal perforation or obstruction, obstructive ileus, severe inflammatory conditions of the intestinal tract, severe and clinically unstable concomitant diseases.
Helicobacter Test INFAI ® The most used 13C-urea breath test for the diagnosis of Hp-infection worldwide
• more than 4.5 million INFAI tests performed in Europe • approved for children from the ages of 3 to 11 • special INFAI test for patients with dyspepsia taking PPIs • cost-effective CliniPac Basic version for hospital use INFAI Institute for Biomedical Analysis & NMR Imaging, INFAI UK Ltd Innovation Centre, University Science Park, University Road, Heslington, YORK YO10 5DG, UK Phone +44 1904 435 228 - Fax +44 1904 435 229 - mail: info@infai.co.uk - Visit us at www.infai.com
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CASE REPORT
AN UNUSUAL CASE OF BREATHLESSNESS: HEPATIC HYDROTHORAX M Moore; S Chatu; A Saxena
varices and mild portal hypertensive gastropathy. A gastroenterology
Kings College Hospital, London, UK
hydrothorax.
Key Words: Chronic liver disease, pleural effusion, hepatic hydrothorax, refractory hydrothorax, cirrhosis
opinion was sought and evaluation led to a diagnosis of a right hepatic
Diuretics were commenced in addition to chest drain insertion The patient was started on dual diuretic therapy that included spironolactone 50mg and furosemide 40mg, which was up titrated every 3 days to a dose of 200mg and 120mg, respectively. Since the
Case: A 48 year old lady known to have compensated cirrhosis from alcohol misuse of Child Pugh grade B severity presented with a one week
patient remained well she was discharged with planned follow-up in the gastroenterology clinic. At follow-up there was no reoccurrence of her effusion and she is no longer on diuretic therapy.
history of worsening breathlessness rendering her dyspnoeic at rest.
Discussion and review of the literature
She did not report a cough, haemoptysis, fevers or chest pain and
This case demonstrates an atypical presentation of an uncommon
there was no history of primary cardio-respiratory disorders. There was
condition. Hepatic hydrothorax is another manifestation of
no history of lower limb swelling or abdominal distension.
extracellular fluid accumulation in patients with liver cirrhosis in addition to ascites. Due to the lack of large randomized-controlled
On examination she was breathless at rest. Her oxygen saturations
trials, the prevalence of hepatic hydrothorax has been estimated to
were 93% despite FiO2 of 60%. Her respiratory rate was 35 breaths per
be between 5-6%1. This has been based on an assortment of varying
minute, pulse rate 86 and blood pressure was 152/83 with no pyrexia.
frequencies being reported, such as autopsy and case reports9.
There were peripheral stigmata of chronic liver disease. Respiratory examination revealed reduced expansion of the right hemi-thorax,
Defining features include established liver cirrhosis from any cause in
with dull percussion note, reduced air-entry and reduced whispering
the context of a transudate pleural effusion > 500ml with no primary
pectoriloquy. The trachea was deviated to the left. Heart sounds were
cardiopulmonary disease2. Concurrent ascites has been reported in
normal; there was no ascites or lower limb oedema.
up to 84% of cases
3-4
, making this an altogether rarer presentation.
Our patient had a right pleural effusion which is in keeping with the Subsequent investigations included an arterial blood gas (ABG)
literature since this is the case in the majority of patients
3-4
.
revealing type 1 respiratory failure with a pH 7.47, PO2 9.31 and PCO2 There are several proposed mechanisms in the development of a hepatic hydrothorax. The pathogenesis is thought to be
eGFR >90 INR 1.52 and Bilirubin 170, ALP 121 AST 127 and gamma
the same as developing ascites. It has been suggested that
GT 98. A chest x-ray (figure 1) demonstrated a complete whiteout of
hypoalbumineamia, azygos vein hypertension and arterial splanchnic
the right lung consistent with a large right-sided pleural effusion with
dilatation all cumulatively contribute to fluid accumulation. Arterial
contralateral mediastinal shift.
splanchnic dilatation causes a fall in arterial blood volume, creating an accumulation of fluid4. Consequent activation of the renin-
An ultrasound (USS) of the thorax confirmed a massive pleural effusion
angiotensin-aldosterone system causes activation of sympathetic
(figure 1). Consequently, a 12F Seldinger chest drain was inserted
nervous system and vasopressin release4.
which drained 5 litres of fluid. Fluid analysis revealed a transudate with protein 3g/l; M,C&S, AFB stain and cytology were negative. The
These mechanisms do not explain the predilection to the right
pH was 7.5 making an empyema unlikely. Following drainage of the
lung, nor the absence of ascites. This has been attributed to
pleural effusion the patientâ&#x20AC;&#x2122;s breathlessness resolved.
diaphragmatic defects categorised into four morphologies. This includes small herniations, called pleuroperitoneal blebs, which
A repeat chest x-ray was performed (figure 2) demonstrating
create communications between the peritoneal and pleural cavities4.
effective drainage of the pleural effusion. Liver USS confirmed
The right hemi-diaphragm is not as muscular and robust as the
cirrhosis but there was no evidence of ascites, portal vein thrombosis
left; blebs are also more common on the right side4. Negative
or hepatocellular carcinoma. A CT chest was subsequently
intrathoracic pressure during inspiration causes a migration of fluid.
ordered excluding any underlying pulmonary pathology. An
Hydrothoraces occur when the pleural membranes exceed their
oesophagogastroduodenoscopy (OGD) demonstrated oesophageal
capacity to absorb the fluid creating the effusion5.
GASTROENTEROLOGY TODAY - SUMMER 2015
3.80 on supplemental oxygen with FiO2 of 60%.Laboratory results revealed a CRP of 8.6 (normal ranges in brackets). , WBC 12.24,
21
CASE REPORT
Figure 1.
Figure 2.
Initial management in this case was symptom control. The constrictive
to the rare nature of this condition there are few studies that have looked
nature of the pleural cavity means a small amount of fluid can cause
at transplantation for patients with hepatic hydrothorax, uncomplicated or
dramatic symptoms, unlike ascites where many litres of fluid may
complicated1. Despite this, the evidence shows that transplantation is the
accumulate. This patient drained an impressive 5 litres. Therapeutic
best therapeutic option for permanent resolution of hepatic hydrothorax,
thoracentesis is the most effective method for symptom relief4. Current
and has been associated with significant long-term survival rates7-8.
evidence shows that hydrothoraces tend to recur rapidly post drainage removal4. This, coupled with the infection risk associated with chest drains, meant other treatment options available were sought. As the pathophysiology behind a hydrothorax is the same as ascites, medical management is unchanged. Sodium restriction and excretion achieved by diet modification and diuretics is the mainstay of treatment. High doses of spironolactone and furosemide are effective means of diuresis, however in refractory hydrothorax; transjugular intrahepatic portosystemic shunt (TIPS) is an alternative3. Unfortunately patients with hepatic hydrothorax have limited survival with only favourable survival rates associated with those that have a liver transplant3. Hepatic hydrothoraces are a manifestation of end-stage liver disease, regardless of the primary pathology. The only definitive treatment for this is a liver transplant6. Due
Conclusion This case demonstrated a rare presentation of hepatic hydrothorax. It is important for any clinician on the medical-take to consider this manifestation in known or suspected patients with cirrhosis presenting with a unilateral pleural effusion. Early recognition and awareness, including involvement of the multidisciplinary team, can ensure prompt treatment and avoidance of unnecessary investigations.
Reference: 1. Hepatic hydrothorax Baikati K, le DL Jabbour II et al. Am J Ther 2014 Jan-Feb; 21(1): 43-51 2. Hepatic hydrothorax Krok KL, Cardenas A Semin Respir Crit Care Med 2012 Feb; 33(1): 3-10 3. Hepatic hydrothorax: Report of a series of 77 patients Porcel JM, Mas E, Rene JM et al Med Clin (Barc) 2013 Dec 7; 141 (11): 484-6
GASTROENTEROLOGY TODAY - SUMMER 2015
22
4. Hepatic hydrothorax Siddappa PK, Far P Trop Gastroenterol 2009 JulSep; 30 (3): 135-41 5. A fascinating presentation of hepatic hydrothorax Vinaya Gaduputi, Hassan Tariq, Kalyan Kannegantin World J Hepatol. 2013 Oct 27 ;5 (10): 589-91 6. Hepatic hydrothorax: the shower within. J Bronchology Interv Pulmonol 2014 Jan;(1): 88-9 doi: 10.1097/LBR.0000000000000030. 7. Liver transplantation in patients with hepatic hydrothorax. Xiol X, Tremosa G, Castellote J, Gornals J, Lama C, Lopez C, Figueras J. Transpl Int. 2005;18:672â&#x20AC;&#x201C;675 8. Transjugular intrahepatic portosystemic shunts and liver transplantation in patients with refractory hepatic hydrothorax. Jeffries MA, Kazanjian S, Wilson M, Punch J, Fontana RJ. Liver Transpl Surg 1998; 4: 416 9. Hepatic hydrothorax-pathophysiology, diagnosis and treatment-review of literature. Gur C, Ilan Y, Shibolet O. Liver Int. 2004;24:281â&#x20AC;&#x201C;284.
Tillotts Pharma firsts: GI health is our passion
Over 30 years of research and development in GI medicine Milestones Developed and launched the first 400mg modified-release mesalazine
Tillotts est. in the UK
1963
Developed and launched the first 800mg modified-release mesalazine
Launched online patient support programme
Obtained once-daily licence for 800mg dose
(Europe)
(UK)
2006
1987
2014
1st
1st
1985
2002
2008
2010
(UK)
(Europe)
(UK)
(UK)
Studied the utility of 4.8g/day1
Launched the first integrated care pathway for mild to moderate ulcerative colitis in the UK
1st
1st
The first 400mg pH-dependent mesalazine containing triethyl citrate
2015
Launched 400mg pH-dependent mesalazine containing triethyl citrate to align with Europe
(UK)
n Tillotts Pharma MR mesalazine is marketed in 47 countries2 n 2 million patient yearsâ&#x20AC;&#x2122; experience3 n Tillottsâ&#x20AC;&#x2122; pH-dependent mesalazine formulation is the most widely used around the world2,4 â&#x20AC;&#x201C; Tillotts 800mg MR mesalazine is the biggest selling 800mg MR mesalazine formulation in Europe5
Prescribing information and references can be found overfleaf.
For mild to moderate ulcerative colitis New triethyl citrate formulation
MEETING REPORT
References: 1. Schroeder KW et al. N Engl J Med 1987; 317(26):1629. 2. Data on file, Tillotts Pharma UK Limited. [Country data]. 3. Data on file, Tillotts Pharma AG. [Patient years – 2014]. 4. Data on file, Tillotts Pharma UK Limited. [Mesalazine sales]. 5. Data on file, Tillotts Pharma UK Limited. [Brand affiliates MAT data].
As a medical student, I learned about Coeliac Disease (CD), alongside cystic fibrosis, as diseases of failure to thrive in children. Today it is a genetically determined autoimmune condition characterized by small-intestinal mucosal injury and nutrient malabsorption. It is activated in genetically susceptible individuals by the dietary ingestion of proline- and glutamine-rich proteins that are found in wheat, rye, and barley and are widely termed “gluten”. The world seems to have woken up to the problems of sensitivity to wheat protein or gluten and from my personal perception is it not only a diagnosis made by healthcare professionals to explain malabsorption, but is also a fashion label of self-diagnosis used by individuals who truly find that there is something about wheat that does not agree with them or may be find that making themselves special fills a gap in their lives. The conference that I attended reported some outstanding science, which progresses the diagnosis, management and potentially the prevention of the condition. Professor Ludvig Sollid from the centre for Immune Regulation, Oslo, reviewed the rational behind novel therapies in CD. CD is a prevalent polygenic disorder caused by a harmful immune response to gluten – wheat protein (gliadin). The single most important genetic factor is the major histocompatibility complex (MHC) and the association with HLA DQ2.5, DQ2.2 and DQ8. If these are not present, then the risk of CD is low. These HLA molecules present gluten epitopes to CD4+ T cells. Gluten epitopes then are deamidated by the enzyme transglutaminase 2 (TG2) and CD patients have autoantibodies to this enzyme which are produced when there is consumption of wheat. There are a variety of peptides that CD patients should avoid. The genetic control is Tillotts: Octasa First Ad (PI strip) Supply as hi-res PDF Job no: 24007
probably in lymph nodes/Peyer’s patches. This offers a potentially interesting target for therapy e.g. modulating T cell effector function. There are a number of potentially preventative options such as grain modification so that the peptides are not recognized by relevant T cells, polymer binding to gluten, specific enzyme that will cleave gluten, epithelial barriers preventing contact and TG2 inhibitors. Treatment options suggested from the knowledge of the mechanism could involve modification of the immune response e.g. cytokine release. The promise for specific therapies for this immune response is there.
Dr Bob Anderson, Chief Scientific Officer of Immunosant, Cambridge, MA, USA presented on Bleed: 3 mm
therapy and diagnosis of CD using peptides recognized by gluten-reactive T cells. Since 2006, his focus has been on utilizing the most dominant peptides recognized by T-cell in CD using diagnostic blood tests (rather than jejunal biopsy) and to restore immune tolerance to gluten with adjuvant free ‘epitope specific’ immunotherapy. He reminded the audience that CD is a systemic Trim: 247 x 57 mm
Adverse events should be reported. Reporting forms and information can be found at www.mhra.gov.uk/yellowcard. Adverse events should also be reported to Tillotts Pharma UK Ltd. (address as above) Tel: 01522 813500.
COELIAC UK’S RESEARCH CONFERENCE, HELD AT ROYAL COLLEGE OF PHYSICIANS, MARCH 2015
Journal: Gastreonterology Today
UK/OC/0015/0215. Date of preparation: March 2015.
www.tillotts.com
GASTROENTEROLOGY TODAY - SUMMER 2015
OCTASA 400mg MR Tablets (mesalazine) and OCTASA 800mg MR Tablets (mesalazine) – Prescribing Information. Please consult the Summaries of Product Characteristics (SmPCs) for full prescribing information. Presentation: Modified Release tablets containing 400mg mesalazine or 800mg mesalazine. Indications: Ulcerative Colitis – Treatment of mild to moderate acute exacerbations. Maintenance of remission. Crohn’s ileocolitis – Maintenance of remission. Dosage and administration: 400mg tablets – Adults: Acute disease: Six tablets a day in divided doses, with concomitant steroid therapy where indicated. Maintenance therapy: Three to six tablets a day in divided doses. 800mg tablets – Adults: Mild Acute Disease: 3 tablets (2.4g) once daily or in divided doses. Moderate Acute Disease: 3 to 6 tablets (2.4g – 4.8g) daily. 2.4g may be taken once daily, higher doses should be taken in divided doses. Maintenance therapy: 2 to 3 tablets (1.6g to 2.4g) once daily or in divided doses. Not more than 3 tablets should be taken together. 400mg and 800mg tablets – Tablets must be swallowed whole. Elderly: Normal adult dose may be used unless renal function is impaired. Children: Limited documentation of efficacy. Dose to be determined individually. Generally recommended that half the adult dose may be given to children up to a body weight of 40 kg; and the normal adult dose to those above 40 kg. Contra-indications: Hypersensitivity to salicylates or any of the excipients, severe impairment of hepatic or renal function (GFR less than 20 ml/min), gastric or duodenal ulcer, haemorrhagic tendency. Warnings and Precautions: Blood tests (differential blood count; creatinine) and urinary status (dip sticks) should be determined prior to and during treatment, at discretion of treating physician. Follow-up tests are recommended 14 days after start of treatment, then a further two to three tests at intervals of 4 weeks. If findings are normal, carry out followup tests every 3 months. If additional symptoms occur, perform these tests immediately. Best avoided in patients with mild-moderate renal impairment; if necessary, use with extreme caution. Caution in patients with impaired hepatic function. If dehydration occurs, correct as soon as possible. Discontinue treatment if renal function deteriorates. Monitor patients with pulmonary disease, in particular asthma, very carefully. Discontinue immediately if acute intolerance reactions occur (e.g. abdominal cramps, acute abdominal pain, fever, severe headache and rash). Very rarely serious blood dyscrasia has been reported. Perform haematological investigations including a complete blood count especially if a patient develops signs and symptoms suggestive of blood dyscrasia during treatment, such as unexplained bleeding, haematoma, purpura, anaemia, persistent fever, or a sore throat. Stop treatment immediately if there is suspicion or evidence of blood dyscrasia and patients should seek immediate medical advice. Use with caution in the elderly subject to patients having normal renal function. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption, should not take this medicine. Interactions: Nephrotoxic agents (e.g. NSAIDs and azathioprine), digoxin, warfarin, azathioprine, 6-mercaptopurine or thioguanine. Pregnancy and lactation: Only to be used when the potential benefit outweighs the possible hazards. Adverse reactions: Rarely: Dizziness, headache myocarditis, pericarditis, abdominal pain, diarrhoea, flatulence, nausea, vomiting, bloating. Very rarely: Altered blood counts (aplastic anemia, granulocytosis, pancytopenia, neutropenia, leucopenia, thrombocytopenia), bone marrow depression, anaemia, peripheral neuropathy, vertigo, allergic and fibrotic lung reactions (including dyspnoea, cough, bronchospasm, alveolitis, pulmonary eosinophilia, lung infiltration, pneumonitis), eosinophilic pneumonia, pancreatitis, exacerbation of disease, changes in liver function parameters (increase in transaminases and cholestasis parameters), hepatitis, cholestatic hepatitis, hepatic function abnormal / abnormal liver function tests, alopecia, Stevens Johnson syndrome, erythema multiforme, bulbous skin reactions, urticaria, rash, myalgia, arthralgia, lupus-like syndrome with pericarditis and pleuropericarditis as prominent symptoms as well as rash and arthralgia, impairment of renal function including acute and chronic interstitial nephritis and renal insufficiency, renal failure, which may be reversible on withdrawal, nephrotic syndrome, hypersensitivity reactions such as allergic exanthema, drug fever, lupus erythematosus syndrome, pancolitis, oligospermia (reversible). Marketing Authorisation Numbers, Package Quantities and basic NHS price: 400mg – PL36633/0002; packs of 90 tablets (£19.50) and 120 tablets (£26.00).800mg – PL36633/0001; packs of 90 tablets (£47.50) and 180 tablets (£95.00). Legal category: POM. Marketing Authorisation Holder: Tillotts Pharma UK Ltd, The Larbourne Suite, The Stables, Wellingore Hall, Wellingore, Lincolnshire, LN5 0HX, UK. Octasa is a trademark. ©2010 Tillotts Pharma UK Ltd. Further Information is available from the Marketing Authorisation Holder. Date of preparation of API: September 2014.
disease triggered by gluten, but not a single entity gluten. The Enzyme-Linked ImmunoSpot (ELISPOT) assay is a widely used method for monitoring cellular immune responses in humans and has identified 2 dominant gliaden peptides after a 3 day oral gluten challenge and Nexvax2 is a therapeutic vaccine that combines three proprietary peptides that elicit an immune response in patients with coeliac disease who carry the immune recognition gene HLA-DQ2. In an approach similar to treatments for allergies to dander from cats and dust mites, Nexvax2 is designed to reprogram gluten-specific T cells triggered by the patient’s immune response to the protein. The goal is for Nexvax2, epitope specific immunotherapy for CD patients, delivered intradermally,
24 24007_Tillotts First Ad_Gastro Today_AW.indd 2
25/03/2015 09:43
MEETING REPORT to restore celiac patients’ immune tolerance to gluten, reduce
syndrome, with 30% improving on a GFD and the Low FODMAP Diet
inflammation in the nutrient-absorbing villi that line the small
(FODMAP=Fermentable Oligo-Di-Monosaccharides and Polyols)
intestine, return the intestine to a healthy state, and allow patients to
FODMAPs are carbohydrates (sugars) that are found in foods. Not
eat a normal diet. (It is noted that there are other immunotherapies
all carbohydrates are considered FODMAPs but spelt wheat is low in
in development by a variety of companies, but at the time of writing
FODMAPS. Apparently, there is wheat content in 30% of supermarket
none have successfully completed phase III studies.)
foods but that which is in bread, has been genetically selected and currently the search is on for synthetic hexaploid wheats where it may
Dr Daniel Adelman, Chief Medical Officer at Alvine Pharmaceuticals,
be possible to reduce or separate gliadin. It is interesting to note that
Inc. from San Francisco presented information on gluten degradation
sourdough breads, popular in Germany are safe for CD patients as
by ALV003, a novel drug candidate for CD. He reminded the
there is breakdown of the culprit peptides in the bakery process.
audience that at the moment the only treatment option for CD is a lifelong adherence to a gluten free diet (GFD), but this brings
He suggested a number of potential strategies to reduce the
with it many complications and limitations to normal life quality.
incidence of CD, including:
Villous height/crypt depth ratio is an important marker of success in management of CD and based on this outcome, it seems that
• Improvement of the GFD so that the health of individuals with
GFD may not be a totally adequate answer. A recent abstract in
persistent symptoms and villous atrophy despite adherence to
Gastroenterology tells us that ALV003 consists of 2 co-administrated
a GFD.
gluten-specific proteases, ALV001 and ALV002. ALV001 is a modified recombinant version of the proenzyme form of cysteine endoprotease, EP-B2, derived from barley. In vitro studies have shown that ALV001 proteolyzes gluten adjacent to glutamine residues, and ALV002, a modified recombinant version of prolyl endopeptidase from the bacterium Sphingomonas capsulate (SC-PEP), proteolyzes the peptide products of ALV001 digestion by cleaving adjacent to proline residues. Together these enzymes degrade gluten more rapidly and thoroughly than either enzyme
• Plant related strategies including the search for CD low immunogenic wheat varieties and silencing the expression of gluten gene families • Reduced use of gluten as a bread improver and improving processed foods to eliminate the highly CD immunogenic gliadin fraction • The use of alternative grains as CD patients can tolerate
alone. ALV003 proteolyzes various forms of gluten such as purified
uncontaminated gluten-free oats as none of the gluten epitopes
gliadin (as well as secalins and hordeins), uncooked gluten flour and
known from wheat, barley and rye occur in oats.
whole-wheat bread gluten, eliminating >90% of the immunoreactive epitopes in vitro. The treatment is envisaged as an adjunct to GFD. According to the paper in Gastroenterology, based on a phase 2 trial, the glutenase ALV003 appears to attenuate gluten-induced small intestinal mucosal injury in patients with CD in the context of an everyday gluten-free diet containing daily up to 2 g gluten. Dr Elena Verdu, Associate Professor, Department of Medicine, McMaster University, Canada discussed ‘What is elafin and does it
• It was concluded that the potential for these strategies depended on the cooperation of food breeders, the food industry and governments to better balance wheat with human health and food safety. Coeliac UK is committed to supporting research, and the conference gave an update of the future of the condition. There is now a clearer understanding of the causes of CD and the mechanisms
play a role in gluten related disorders?’
involved. As well at the traditional GFD, there are now potential
Elafin is an immunomodulatory serine protease inhibitor found in
potential to allow CD patients to access a normal diet, but none of
epithelial surfaces and has a potent inhibitory effect against various forms of pro-inflammatory elastases as well as proteinase-3. It that elafin might have a value as an adjunct to GFD in CD as elafin expression in the epithelium of CD patients is lower than in controls, and in an animal model, elafin has been found to decrease inflammation. The work at the moment is theoretical, but it was thought that work on elafin might lead to further knowledge about the
the therapies are approved for prescribing yet. These will function best in the context of specific and convenient diagnostics to identify CD by serological testing. As well as the preventative therapeutic measures, there are dietary approaches involving modification of wheat and use of non-wheat cereals that are devoid of gliadin. Martin Goldman
mechanisms of CD.
References
Dr Luud JWJ Gilissen, researcher at Wageningen University and
Coeliac UK Research Conference 2015, Abstract book.
research centre, The Netherlands told the audience about plant
Celiac disease: pathogenesis of a model immunogenetic disease. Martin F. Kagnoff The Journal of Clinical Investigation http://www.jci. org Volume 117 Number 1 January 2007 (open access)
and food technological approaches to reduce the incidence of CD. He said that about 2% of the population are ‘wheat sensitive’, which may not be surprising as there are about 30 proteins in identifiable proteins and hence there is also non coeliac wheat
Glutenase ALV003 Attenuates Gluten-Induced Mucosal Injury in Patients With Celiac Disease, Gastroenterology, June 2014 Volume 146, Issue 7, Pages 1649–1658
sensitivity. There is a correlation, she said, with irritable bowel
Immunosant and Alvine Pharmaceuticals websites.
wheat and changes in breeds have increased the number of
GASTROENTEROLOGY TODAY - SUMMER 2015
shows an abnormally low expression in IBD patients. It was thought
immunotherapeutic and enzyme active agents which have the
25
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NEWS Dutch scientists build colon cancer progression model Utrecht, April 30,2015 - Scientists from
determine which mutations are essential for
contribution to cancer development. Drost
cancer development and survival. Those
and colleagues showed that mutating these
mutations could be targeted for therapeutic
four genes is sufficient to convert a healthy
intervention. However, until now no good
intestinal cell into an invasive tumor cell. The
human model systems to study such
model published in Nature can be used to
mutations exist.
study processes involved in colon cancer
the Hubrecht Institute and the University
development and for cancer drug discovery.
Medical Center Utrecht (UMC Utrecht)
Organoids
have developed a cell culture model of
The recent development of the organoid
human colon cancer progression. This
technology by the research group of Hans
model mimics the situation in patients
Clevers allows the culturing of healthy
more closely than any other colon cancer
human tissues under laboratory conditions.
model so far. It enables researchers to
Organoids functionally recapitulate the organ
study processes involved in colon cancer
of origin and are genetically stable. Utilizing
development and find new cancer drugs.
this technology, the Clevers lab has now
The work by Clevers and colleagues is
successfully engineered a colon cancer
published online in Nature this week.
progression model in organoids from human
Reference Drost J, Van Jaarsveld RH, Ponsioen B, Zimberlin C, Van Boxtel R, Buijs A, et al. Sequential cancer mutations in cultured human
small intestine and colon.
Genomic Profiling of Gastric Cancer Identifies DrugTargetable Mutations
and deadly forms of cancer. Like all cancers,
Genome editing
Durham, NC – The majority of gastric
it arises through an accumulation of DNA
Jarno Drost, researcher in Hans Clevers’
cancers harbor genomic alterations (GAs)
changes (mutations) in the cell’s genome
research group, and his colleagues utilized
associated with potential benefit from
(the genetic information in a cell). In
the genome editing system CRISPR/Cas9
targeted therapies, according to a new
contrast to healthy cells, many colon cancer
to introduce specific mutations in four of
study published in The Oncologist on April
cells have very unstable genomes and
the most commonly altered genes in colon
16, 2015. These findings suggest a role for
generally contain hundreds to thousands
cancer (KRAS, APC, TP53 and SMAD4) and
genotype-directed management of locally
of mutations. This makes it difficult to
performed an in-depth analysis on their
advanced and metastatic gastric cancer.
Colon cancer is one of the most common
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NEWS To date, the ERBB2 amplification is the only GA
The research team performed comprehensive
alterations in receptor tyrosine kinase (RTK)
in advanced gastric cancer associated with a
genomic profiling on 116 gastric cancer
signaling pathways. In the current series,
survival benefit in response to targeted therapy.
specimens harvested from patients with
1 in 5 gastric cancer cases (20.6%) harbored
However, because most patients with gastric
primarily (90.0%) locally advanced or metastatic
alterations in RTKs such as ERBB2, FGFR2,
cancer do not harbor this rare alteration, most
disease. Thus, the tumor samples were
and MET.
cannot benefit from targeted therapy under
characteristic of gastric carcinomas seen in
current practice guidelines.
clinical practice, where the majority of patients
To identify additional opportunities for targeted therapy, a team of researchers led by Siraj M. Ali, MD, PhD, at Foundation Medicine, Inc., in Cambridge, MA, conducted comprehensive genomic profiling of patients with locally advanced or metastatic gastric cancer. The goal was to identify clinically relevant GAs, defined as alterations that are currently targetable with therapies approved in gastric cancer or other tumor types, or with therapies currently under development and administered in clinical trials.
present with advanced disease. The genomic profiling assay detected 501 alterations in 116 samples. Of these, 201 alterations (41%) were clinically relevant, yielding 1.8 drug-targetable GAs per case. In total, 78% of all gastric cancer samples harbored at least 1 clinically relevant GA associated with approved or investigational targeted therapies. The most common clinically relevant GAs were KRAS (16%), CDKN2A (14%), CCND1 (9.5%), ERBB2 (8.6%), and PIK3CA (8.6%).
genomic profiling may be used as a tool for identifying appropriate therapy. One patient with MET-amplified gastric cancer was treated with crizotinib, an inhibitor of c-MET and ALK RTKs currently approved for the treatment of non-small cell lung cancer. Following crizotinib initiation, the patient had regression of a liver metastasis and disease control for 5 months. “The high frequency of clinically relevant GAs in a population reflective of routine clinical practice highlights potential therapeutic avenues in a disease with historically low responses to
Other common alterations that are currently
current therapies and overall poor survival,”
of comprehensive genomic profiling to match
not associated with approved or investigational
said Samuel Klempner, MD, a member of the
patients to targeted therapies of specific
targeted therapies included TP53 (50%), ARIDIA
research team. “The patient response to MET
potential benefit in clinical trials,” Dr. Ali said.
(24%), and CDHI (15%).
inhibition encapsulates the genotype-directed
“Our study demonstrates the potential utility
approach and underscores the need for
“This is encouraging in a disease that continues to have a poor prognosis with modern
Many current and emerging targeted therapies
molecularly directed clinical trials to confirm
chemotherapy.”
used in other tumor types are directed to known
observations such as seen in our study.”
Faecal Immunochemical Tests (FIT) A FIT Assay for Suspected Colorectal Cancer (CRC)
GASTROENTEROLOGY TODAY - SUMMER 2015
30
According to the study authors, comprehensive
Faecal Immunochemical Tests (FIT) offer significant advantages over traditional guaiac based occult blood tests. ■ Quantitative results for consistent measurement ■ Identification of high risk patients for immediate therapy ■ Low f-Hb <10µg/g faeces has a high negative predictive value (NPV) of: □ 100% for cancer □ 94.65% for High Risk Adenoma (HRA) □ 93.50% for Low Risk Adenoma (LRA) □ 94.00% for Inflammatory Bowel Disease
Patient presents at GP with abdominal symptons Patients triaged based on risk factors SUSPECTED COLORECTAL CANCER FAECAL IMMUNOCHEMICAL TEST for Hb NEGATIVE
PJ McDonald et al: Colorectal disease 2013 Mar:15(3):151-9 DOI:10.1111/codi12087
Many studies have now demonstrated the clinical value of quantitative FIT tests in both symptomatic as well as screening applications. To find out about better treatment algorithms for your patients, please come and see our solutions and discuss your testing needs at: ■ ACB - Focus, Cardiff, 8-11th June, Stand 19 ■ DDF - Excel London, 22-25th June, Stand 95 Or find out more at: www.alphalabs.co.uk/FIT Gastro-Today_FIT+DDF_May15.indd 1
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A first-in-class treatment to improve the multiple symptoms of moderate-to-severe Irritable Bowel Syndrome with Constipation (IBS-C)2–6
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PRESCRIBING INFORMATION (Please consult the Summary of Product Characteristics (SmPC) before prescribing.) Constella®t 290 micrograms hard capsules Linaclotide Active Ingredient: contains 290 micrograms of linaclotide. Indication: Constella is indicated for the symptomatic treatment of moderate to severe irritable bowel syndrome with constipation (IBS-C) in adults. Dosage and Administration: The recommended dose is one capsule (290 micrograms) once daily. The capsule should be taken 30 minutes before a meal. Physicians should periodically assess the need for continued treatment. Consult SmPC for further information. Contraindications, Warnings, etc: Contraindications: Hypersensitivity to linaclotide or to any of the excipients or known or suspected mechanical gastrointestinal obstruction. Precautions: Use once a diagnosis of moderate to severe IBS-C is established. Should prolonged (more than 1 week) or severe diarrhoea occur, medical advice should be sought and temporary discontinuation of linaclotide until diarrhoea episode is resolved may be considered. Exercise caution in patients prone to a disturbance of water or electrolyte balance such as elderly, patients with CV diseases, diabetes, hypertension; and electrolyte
control should be considered. Not recommended in patients with chronic inflammatory conditions of the intestinal tract, such as Crohn’s disease and ulcerative colitis. Elderly: Special attention should be given to these patients and the treatment benefi t-risk ratio should be carefully and periodically assessed. Children: Not recommended. Interactions: The efficacy of medicinal products absorbed in the intestinal tract with a narrow therapeutic index such as levothyroxine and oral contraceptives may be reduced. The use of additional contraceptives is recommended. Pregnancy and lactation: It is preferable to avoid the use during pregnancy. Use during breast-feeding is not recommended. Animal studies indicate that there is no effect on male or female fertility. Ability to drive and use machines: None known. Adverse Effects: Very common: diarrhoea. Common: abdominal pain, flatulence, abdominal distension, dizziness. Consult SmPC in relation to other side effects. Legal Category: POM. Marketing Authorisation Number(s): EU/1/12/801/002. NHS Cost: (excluding VAT) £37.56 – Carton containing HDPE bottle containing 28 capsules. Marketing Authorisation Holder: Almirall S.A., Ronda General Mitre, 151, 08022 Barcelona, Spain, Further information is available from Almirall Limited, 1 The Square, Stockley Park, Uxbridge, Middlesex,
UB11 1TD, UK. Tel: (0)207 160 2500. Fax: (0)208 7563 888. Email: almirall@professionalinformation.co.uk Date of Revision: 12/2012 Item code: UKLIN1411 References: 1. National Institute of Health and Clinical Excellence. Clinical Guideline 61, February 2015. Available at: www.nice.org.uk/guidance/cg61 Last accessed: April 2015. 2. Rao S, et al. Am J Gastroenterol 2012;107:1714– 24. 3. Castro J, et al.Gastroenterology 2013;145(6):1334–46. 4. Chey WD, et al. Am J Gastroenterol 2012;107:1702–12. 5. Quigley EM, et al. Aliment Pharmacol Ther 2013;37(1):49–61. 6. Constella® Summary of Product Characteristics. United Kingdom: Almirall Ltd.
Adverse events should be reported. Reporting forms and information can be found at www.mhra.gov.uk/yellowcard. Adverse events should also be reported to Almirall Ltd.
NEWS In addition to driving increased clinical trial
provoke new ways to treat inflammatory
the intestine, which is often linked to the
participation, identifying clinically relevant GAs
bowel disease -- including Crohn’s disease
development and progression of diseases
in patients with gastric cancer may shape
and ulcerative colitis -- whose origins have
like inflammatory bowel disease, HIV, viral
future drug development and research on
been mysterious and treatment difficult.
hepatitis, cardiovascular disease, obesity, diabetes and cancer. Therapeutic strategies
biomarkers of resistance and therapeutic response.
Weill Cornell Investigators Discover a New Pathway that Prevents Chronic Inflammation in the Gut
The investigators studied T cells -- critical
to promote and boost the activity of this
components of the adaptive immune system
education pathway may be beneficial
-- which have the capacity to recognize,
in treating patients with these chronic
eliminate and remember foreign microbes
inflammatory disorders, the investigators say.
that invade our bodies. T cells are named after the thymus, an organ where they
“In many chronic human diseases, the
develop and are taught not to attack normal
immune system attacks bacteria in the
human tissues and organs, leaving them
intestine that are normally beneficial. Although
free to target and eradicate disease-causing
we do not yet know whether this is a cause
Investigators Show How Immune Cells
foreign invaders. One question that had
or consequence of these complex diseases,
are “Educated” Not to Attack Beneficial
puzzled scientists until now is how these
experimental evidence suggests that this
Bacteria
cells learn to ignore beneficial bacteria in the
inflammatory process contributes to disease
intestine that are also foreign, but not harmful.
progression,” says senior author Dr. Gregory
New York (April 23, 2015) -- An international
F. Sonnenberg, an assistant professor of
research team led by Weill Cornell Medical
In the study, the research team discovered
microbiology and immunology in medicine
College investigators has discovered an
that once they leave the thymus, T cells are
and a member of the Jill Roberts Institute for
answer to why the human immune system
again educated in the gastrointestinal tract,
Research in Inflammatory Bowel Disease at
ignores roughly 100 trillion beneficial
or gut, to leave beneficial bacteria alone. This
Weill Cornell. “Our study demonstrates that
bacteria that populate the gastrointestinal
dual education strategy is vital to supporting
there may be an efficient way to eliminate pro-
tract. The findings, published April 23 in
healthy immune function, the investigators
inflammatory T cells in the intestine that attack
the journal Science, advance investigators’
say. Disruption in the pathway that facilitates
beneficial bacteria. This would not only help
understanding of how humans maintain
this education, they add, causes the immune
our patients with inflammatory bowel disease,
a healthy gastrointestinal tract, and may
system to attack beneficial bacteria in
but also might give us clues about how to
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NEWS treat other chronic inflammatory diseases
tract, using ILCs, they are further educated
France; and Charles O. Elson from the
caused by abnormal T cell responses, such
not to attack beneficial bacteria.”
University of Alabama at Birmingham.
Using mice to test their findings, the
Research in Dr. Sonnenberg’s laboratory
In earlier research, Dr. Sonnenberg and his
researchers discovered that ILCs destroy T
is supported by the National Institutes
team identified that a recently discovered
cells with the potential to attack beneficial
of Health (DP5OD012116), the NIAID
member of the innate immune system
bacteria, and that impairing ILC function led
Mucosal Immunology Studies Team (MIST),
-- innate lymphoid cells (ILCs) -- critically
to severe intestinal inflammation. Then, with
Scholar Award in Mucosal Immunity and
regulate immune cell interactions with
the help of researchers at Children’s Hospital
the Institute for Translational Medicine and
bacteria. These ILCs, and other cells of the
in Philadelphia, the team looked at intestinal
Therapeutics, Transdisciplinary Program in
immune system, are found in the intestine,
biopsies of pediatric patients diagnosed with
Translational Medicine and Therapeutics
which is constantly exposed to and colonized
Crohn’s disease, one of the major forms of
(UL1-RR024134 from the U.S. National
by beneficial bacteria. “There is a physical
inflammatory bowel disease.
Center for Research Resources). Other
as allergic and autoimmune disorders.”
investigator support includes a research
separation between the immune system and most beneficial bacteria,” Dr. Sonnenberg
“We found ILCs in intestinal biopsies from
fellowship from the Crohn’s, and Colitis
says.
pediatric patients diagnosed with Crohn’s
Foundation of America (CCFA, #297365), a
disease, but they were not functioning
Cancer Research Institute Student Training
The researchers had previously found that
properly because, in many cases, they were
and Research in Tumor immunology (STaRT)
ILCs reinforce a physical barrier between
lacking MHCII machinery, so T cells were
grant, a Wellcome Trust Research Career
the immune system and intestinal beneficial
not educated to ignore beneficial bacteria,”
Development Fellowship, and the National
bacteria, but in this study, they uncovered a
Dr. Sonnenberg says. “In fact, we found the
Institutes of Health (DK071176).
new key role for these cells -- that they act like
loss of MHCII correlated with an increase in
the cells in the thymus that educate T cells.
pro-inflammatory cells from matched biopsies
Weill Cornell Medical College
of children with Crohn’s disease. That tells us
Weill Cornell Medical College, Cornell
In a process that developed over evolution,
that this education process may be impaired
University’s medical school located in New
bits of human tissues and organs are
in patients with inflammatory bowel disease,
York City, is committed to excellence in
introduced to T cells in the thymus so they
and that restoring adequate levels of MHCII
research, teaching, patient care and the
“know” what not to attack after leaving
might help to eliminate pro-inflammatory
advancement of the art and science of
the organ. Specialized cells in the thymus
T cells and reduce chronic intestinal
medicine, locally, nationally and globally.
teach T cells this behavior by interacting
inflammation.”
Physicians and scientists of Weill Cornell Medical College are engaged in cutting-
with a molecule known as the Major Histocompatibility Complex class II (MHCII).
Dr. Sonnenberg says there are likely many
edge research from bench to bedside
Any T cells with the potential to attack the
causes of inflammatory bowel disease, and
aimed at unlocking mysteries of the human
human body and organs and cause auto-
other pathways that help control T cells in
body in health and sickness and toward
immunity are destroyed before they can
the gut. “But our work shows a previously
developing new treatments and prevention
leave the thymus. However, T cells with the
unrecognized pathway whereby ILCs educate
strategies. In its commitment to global health
potential to attack beneficial bacteria are
our immune system not to attack beneficial
and education, Weill Cornell has a strong
not educated or eliminated in the thymus. It
bacteria,” he says.
presence in places such as Qatar, Tanzania, Haiti, Brazil, Austria and Turkey. Through the
was therefore unclear what stopped these T Dr. Sonnenberg, his laboratory and the Jill
historic Weill Cornell Medical College in Qatar,
intestine.
Roberts Institute for Research in IBD are
the Medical College is the first in the U.S. to
now exploring how scientists can utilize this
offer its M.D. degree overseas. Weill Cornell
The scientists found a similar process
knowledge and design novel therapeutic
is the birthplace of many medical advances
happening directly within the GI tract, an
strategies to boost MHCII on ILCs and limit
-- including the development of the Pap test
organ that contains the majority of the body’s
chronic intestinal inflammation.
for cervical cancer, the synthesis of penicillin, the first successful embryo-biopsy pregnancy
total immune system. Co-authors include Thomas C. Fung from
and birth in the U.S., the first clinical trial of
“Due to the similarities of what we know
Weill Cornell Medical College; Terri M. Laufer
gene therapy for Parkinson’s disease, and
happens in the thymus, we have called
from the University of Pennsylvania; Samuel
most recently, the world’s first successful use
this new process ‘intestinal selection,’”
H. Masur, Judith R. Kelsen and Robert N.
of deep brain stimulation to treat a minimally
says first author Dr. Matthew R. Hepworth,
Baldassano from Children’s Hospital of
conscious brain-injured patient. Weill Cornell
a postdoctoral associate in medicine who
Philadelphia; Fiona M. McConnell and David
Medical College is affiliated with NewYork-
works in Dr. Sonnenberg’s laboratory. “ILCs
R. Withers from University of Birmingham,
Presbyterian Hospital, where its faculty
also interact with T cells through MHCII
United Kingdom; Juan Dubrot, Stephanie
provides comprehensive patient care at
machinery to educate T cells in the intestine.
Hugues and Walter Reith from the University
NewYork-Presbyterian Hospital/Weill Cornell
of Geneva Medical School in Switzerland;
Medical Center. The Medical College is also
“In the thymus, T cells are educated not to
Michael A. Farrar from the University of
affiliated with Houston Methodist. For more
attack our organs,” he adds, “and in the GI
Minnesota; Gerard Eberl from Institut Pasteur,
information, visit weill.cornell.edu.
GASTROENTEROLOGY TODAY - SUMMER 2015
cells from attacking beneficial bacteria in the
33
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GASTROENTEROLOGY TODAY - SUMMER 2015
To find out more about how ENDOCUFF VISION can increase the success of your colonoscopies, visit www.endocuff.com. Alternatively speak to your local Norgine representative for further information.
Reference: 1. Patel K, Misra R, Suzuki N, et al. Single Centre Pilot Evaluating the use of Endocuff-Vision in Screening. UEG; 2014:2 (Supplement 1). *ENDOCUFF VISION can be used with all the major endoscope makes, including Fujinon, Olympus and Pentax.
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Norgine and the sail logo are registered trademarks of the Norgine group of companies. ENDOCUFF VISION is a registered trademark of Arc Medical Design Limited. Date of preparation: April 2015.
NEWS First UK online assessment for Coeliac Disease launched to find the undiagnosed half a million Coeliac UK, the national Charity for
A dedicated website,
Key symptoms caused by coeliac disease
www.isitcoeliacdisease.org.uk will host
include: frequent bouts of diarrhoea,
the new assessment questionnaire and
stomach pain and cramping, regular
provide detailed information about coeliac
mouth ulcers, ongoing fatigue, lots of gas
disease and outline the campaign activities.
and bloating, nausea and vomiting, and unexplained anaemia.
Based on National Institute for Health and Care Excellence (NICE) guidelines, the new
One in 100 people in the UK has coeliac
people with coeliac disease, will launch
online assessment will give people more
disease, with the prevalence rising to one
the UK’s first online assessment to help
confidence to seek further medical advice
in ten for close family members. However,
fast track diagnosis among the half
from their GP. Upon completion of the
current statistics show only 24% of those
a million people in the UK living with
assessment, they will receive an email with
with the condition are diagnosed, leaving
undiagnosed coeliac disease.
the results which will indicate whether their
an estimated half a million people in the UK
symptoms are potentially linked to coeliac
undiagnosed.
The online assessment tool is a key
disease.
initiative of the Charity’s new campaign, ‘is
The ‘is it coeliac disease?’ campaign will
it coeliac disease?’, which is launching in
Coeliac disease is a serious autoimmune
also target healthcare professionals to
Coeliac UK’s Awareness Week (11-17 May)
disease where the body’s immune system
refresh their knowledge of the condition
and backed by the Charity’s new patron,
damages the lining of the small bowel when
and its symptoms, and will be promoted
actress Caroline Quentin.
gluten, a protein found in wheat, barley
through radio and digital advertisements,
and rye, is eaten. There is no cure and no
social media activity and information in GP
The two year campaign will highlight the
medication; the only treatment is a strict
surgeries.
most common symptoms of coeliac disease
gluten-free diet for life. Left untreated,
and prompt people experiencing these
coeliac disease can lead to a number of
Outreach events will also take place
symptoms to ask themselves, ‘is it coeliac
complications including osteoporosis and in
across the country over the next two years
disease?’.
rare cases even small bowel cancer.
providing more information for the general
The UBT using [13C] urea remains the best test to diagnose H pylori infection, has a high accuracy and is easy to perform2
For the reliable and quick in vivo diagnosis for the gastro-duodenal presence of Helicobacter pylori.
Precise 98.3%3 and non-invasive Easy to use
When to use Pylobactell 13 C-Urea Breath Test (UBT)
Peptic Ulcer Disease Test to confirm before treating and to confirm eradication 6-8 weeks after commencement of treatment1
Highly sensitive and specific to Helicobacter pylori Results within 48
(working)
hours
Legal Category: POM. NHS Price £20.75. Marketing Authorisation Number: EU/1/98/064/001. Marketing Authorisation Holder: Torbet Laboratories Ltd. Information about this product, including adverse reactions, precautions, contra-indications and method of use can be found at www.cambridge-healthcare.co.uk/laboratory Adverse events should be reported. Reporting forms and information can be found at www.mhra.gov.uk/yellowcard. Adverse events should also be reported to Torbet Laboratories Ltd Prescribers are recommended to consult the summary of product characteristics before prescribing.
1 2 3
NICE Guidelines: Dyspepsia and gastro-oesophageal reflux disease: Guidelines [CG184] Published date: September 2014 Gisbert JP, Pajares JM.: 13C-urea breath test in the diagnosis of Helicobacter pylori infection—a critical review. Aliment Pharmacol Ther 2004;20:1001–17 ¹³C-urea breath test – a reliable diagnostic technique for assessment of eradication. Gut 1996: 39 (suppl 3): A37.
Torbet Laboratories Ltd., Unit 1 Chestnut Drive, Wymondham, Norfolk, NR18 9SB. Tel: 01953 607856 Fax. 01953 713649 E-mail: customerservices@torbetlaboratories.co.uk
2PYL12/1501b
GASTROENTEROLOGY TODAY - SUMMER 2015
Uninvestigated Dyspepsia Offer H pylori ‘test and treat’ to patients with dyspepsia1
can be performed at home or under the supervision of healthcare staff
35
NEWS public to ask questions and gain advice
As well as help reduce the unacceptable
from experts. Further details of these events
length of time to gain a diagnosis which is
can be found at:
currently, on average, 13 years.”
Sarah Sleet continued:
members to also be tested.
www.isitcoeliacdisease.org.uk. Caroline Quentin, who is close to
“Awareness of coeliac disease has
Sarah Sleet, chief executive of Coeliac UK,
completing her own diagnosis journey after
increased greatly in recent years with the
said:
an initial positive blood test two years ago
Charity’s Helpline supporting hundreds of
and more recently a genetic test, said:
callers seeking a diagnosis. Yet, around
“With half a million people living with
“Coeliac UK’s campaign to reach the half a
500,000 people in the UK are still suffering
undiagnosed coeliac disease we must
million people still undiagnosed with coeliac
unnecessarily. Please check your symptoms
take radical action to turn around this
disease really resonates with me because I
through our online assessment tool, and if
horrendous situation. We hope that
struggled for years with constant stomach
you think you may have coeliac disease,
giving people direct access to an online
pains, vomiting and total exhaustion.”
go to your doctor and ask for a blood test
assessment tool will put those who
but don’t stop eating gluten until you are
are suffering with the symptoms of
A confirmed medical diagnosis of coeliac
tested otherwise critical follow up tests will
undiagnosed coeliac disease on a pathway
disease enables people to receive
not work,”
to diagnosis and avoid potentially life
appropriate follow-up care and support, as
threatening long term health complications.
well as providing evidence for close family
Ms Sleet said.
CALL FOR PAPERS Have you written articles of a clinical nature that you would like published? Have you written a case report you would like published?
GASTROENTEROLOGY TODAY - SUMMER 2015
36
Have you attended an interesting meeting that you would like to share with your colleagues? If so, please submit the details to: info@mediapublishingcompany.com for editorial consideration.
LASTING REMISSION
1
• Maintenance of clinical and endoscopic remission for 12 months.1 • Well documented safety and tolerability.1
LOW PILL BURDEN ONCE-DAILY
2
3
A simple step to lasting remission Mezavant XL Safety Information. Mezavant XL is indicated for the induction of clinical and endoscopic remission in patients with mild to moderate ulcerative colitis and for the maintenance of remission. It is recommended that all patients have an evaluation of renal function prior to initiation of therapy and at least twice a year, whilst on treatment. Please consult the Mezavant XL Summary of Product Characteristics before prescribing. Mezavant XL (mesalazine) Prescribing Information (Please refer to full Summary of Product Characteristics [SmPC] before prescribing). Presentation: Mesalazine provided as 1200mg gastro-resistant, prolonged release tablets. Uses: For the induction of clinical and endoscopic remission in patients with mild to moderate, active ulcerative colitis. For maintenance of remission. Dosage and administration: Oral. Tablets to be taken once daily. Tablets must not be crushed or chewed and should be taken with food. Adults/Elderly: For induction of remission: 2.4 to 4.8g (two to four tablets) should be taken once daily. The highest dose of 4.8g/day is recommended for patients not responding to lower doses of mesalazine. When using the highest dose (4.8g/day), the effect of the treatment should be evaluated at 8 weeks. For maintenance of remission: 2.4g (two tablets) should be taken once daily. Children: Not recommended. Contraindications: History of hypersensitivity to salicylates (including mesalazine) or any of the excipients of Mezavant XL. Severe renal impairment (GFR <30ml/min/1.73m2) and/or severe hepatic impairment. Special Warnings and Precautions: Use with caution in patients with confirmed mild to moderate renal impairment. All patients should have an evaluation of renal function prior to initiation of therapy and at least twice a year. If there is suspicion of blood dyscrasia, treatment should be terminated. If acute intolerance syndrome is suspected, prompt withdrawal of mesalazine is required. Caution should be used in prescribing to patients with hepatic impairment, patients with chronic lung function impairment, especially asthma (due to risk of hypersensitivity reactions), patients allergic to sulfasalazine, or patients with conditions predisposing to myoor pericarditis. Organic or functional obstruction in the upper gastrointestinal tract may delay onset of action. See SPC for full details on warning and precautions.
Mesalazine has been associated with an acute intolerance syndrome that may be difficult to distinguish from a flare of inflammatory bowel disease. Interactions: Caution is recommended with concomitant use of known nephrotoxic agents including non-steroidal anti-inflammatory drugs (NSAIDS). Mesalazine inhibits thiopurine methyltransferase and caution is recommended for concurrent use of mesalazine with azathioprine or 6-mercaptopurine. Administration with coumarin type anticoagulants could result in decreased anticoagulant activity. Pregnancy and Lactation: Only use during pregnancy when clearly indicated, using caution with high doses. Caution should be exercised if using mesalazine whilst breastfeeding. Undesirable Effects: Common: flatulence, nausea, headache, hypertension, abdominal distension, abdominal pain, diarrhoea, dyspepsia, vomiting, liver function test abnormal, pruritus, rash, arthralgia, back pain, asthenia, colitis, fatigue and pyrexia . Uncommon: thrombocytopenia, dizziness, somnolence, tremor, ear pain, tachycardia, hypotension, pharyngolaryngeal pain, pancreatitis, rectal polyp, acne, alopecia, urticaria,and myalgia. Rare: agranulocytosis, face oedema, renal failure. Incidence unknown: myocarditis, pericarditis, hypersensitivity pneumonitis (including interstitial pneumonitis, allergic alveolitis, eosinophilic pneumonitis), hepatitis, interstitial nephritis, aplastic anaemia, leukopenia, neutropenia, pancytopenia, neuropathy, bronchospasm, cholelithiasis, angioedema, systemic-lupus erythematosuslike syndrome and nephrotic syndrome, hypersensitivity, anaphylactic shock, Stevens-Johnson syndrome, Drug rash with eosinophilia and systemic symptoms (DRESS). Overdose: Conventional therapy for salicylate toxicity may be of benefit. Hypoglycaemia, fluid and electrolyte imbalance should be corrected and adequate renal function maintained. Basic NHS price: £62.44 (60 tablet pack).
Legal category: POM. Marketing Authorisation number: PL 08081/0040. Marketing Authorisation holder: Shire Pharmaceuticals Contracts Limited, Hampshire International Business Park, Chineham, Basingstoke, Hampshire, RG24 8EP, UK. Date of revision: January 2015. Further information is available from: Shire Pharmaceuticals Limited, Hampshire International Business Park, Chineham, Basingstoke, Hampshire, RG24 8EP, UK. MEZAVANT is a trademark of Shire LLC in the UK. MMX® is a registered trademark of Cosmo Technologies Ltd., Wicklow, Ireland. MMX Multi Matrix System® is a registered trademark of Cosmo S.p.A., Milan, Italy.
Adverse events should be reported. Reporting forms and information can be found at www.mhra.gov.uk/ yellowcard. Adverse events should also be reported to Shire Pharmaceuticals Ltd on 01256 894000 or at globalpharmacovigilance@shire.com. References: 1. Kamm MA, Lichtenstein GR, Sandborn WJ, Schreiber S, Lees, K, Bennett K, et al. Randomised trial of once- or twice-daily MMX mesalazine for maintenance of remission in ulcerative colitis. Gut 2008; 57: 893-902. 2. Iacucci M, de Silva S, Ghosh S. Mesalazine in inflammatory bowel disease: A trendy topic once again? Can J Gastroenterol 2010; 24(2): 127-133. 3. Mezavant XL Summary of Product Characteristics. Shire Pharmaceuticals Limited. Date of preparation: May 2015. UK/CPROM/MEZ/14/0006b(1).
POSTERS
A model to assess the cost of flar
Ash Bassi1, Keith Tolley2, Gw
Gastroenterology Department, Whiston Hospital, Prescot, Merseyside; 2Tolley Health Eco
1
Background
• Taking a conservative approach, costs for surgery and post-surgical management, e.g. stoma care, were excluded as inclusion would have skewed the data and significantly increased average flare cost estimates.
• Disease flares of active ulcerative colitis (UC) can result in substantial cost implications to the NHS, affecting both primary and secondary care.1 • In secondary care, flares of active UC are associated with a 2-fold increase in costs for non-hospitalised cases and more than 20-fold increase for hospitalised cases, compared with the maintenance phase.1
Total population
Second inves
Admit to hospital direct or via A&E
Second inves
£27
Decision point Outcome Pathway terminates
100,000
Prevalence of UC per 100,000
2408
Estimated proportion of patients on Asacol
Asacol dose was doubled to 4.8 g/day for 6 weeks;5,13, induction dose followed by 80 mg, then 3 doses of 40
a
39.5%9
Estimated number of patients on Asacol in cohort
95
Table 3. Calculating the average cost of fl
Results Pathway via which flare is managed
Costs of remission and flare • The estimated annual cost to manage a patient with UC in remission was £955 (base case; Table 2).
• For secondary care inpatient management, the estimated cost was £3,488 (Figure 1). • If a biologic/ciclosporin was needed, the estimated cost rose to £4,272 (Figure 1). All costs were inclusive of clinical investigations and treatment reviews. • Applying the default values for proportions of patients to each of the 3 pathways produced an estimated average cost of flare of £984 in the UC cohort (Table 3).
Estimated cost per flare
Primary care
• The additional estimated cost to control a flare in primary care was £175 and for secondary care outpatient management was £578 (Figure 1).
• Within the model, the baseline UC patient cohort was assumed to be maintained on Asacol at a maximum dose of 2.4 g/day, given as 800 mg MR tablets. This is the maximum daily dose recommended for maintenance of remission and provides an upper estimate of the drug costs.5
GASTROENTEROLOGY TODAY - SUMMER 2015
38
Outpa ent review
£66
Table 1. The model population in the adherence analysis.
Costs of UC in remission (base case)
Mode (defa
£175
Secondary care (outpatient)
£578
Secondary care (inpatient)a
£3,880
Estimated average cost of a flare
£
Crude average of controlled and severe flare
a
• In sensitivity analysis the proporti each route were varied to reflect characteristics across localities (T
Adherence analysis Table 2. Annual costs of ulcerative colitis in remission (base case). Annual drug costs
Costs associated with flare • Illustrative care pathways were mapped, assuming that patients with a flare of active disease would either be treated and managed in primary care, or as an outpatient, or admitted to hospital.
Pa ent has UC flare
• Using a cohort approach, costs associated with an increase in flare in patients who are non-adherent to Asacol were estimated for a population of 100,000 people (Table 1).
• A market forces factor of 1.08 (the UK average) was applied to account for cost differences between healthcare providers due to geographical location.3,4
• Annual management costs for patients in remission were estimated assuming one secondary care consultation per year,2 colonic surveillance every 5 years6 and routine monitoring tests per year, such as full blood count, liver function and renal function tests.7
£48
Costs associated with non-adherence
• The model forms the basis for estimating the average cost of flare in a model cohort, which allows for sensitivity analyses and adapting the model to local patient populations.
• Drug costs were calculated using the British National Formulary (BNF) and healthcare management costs were based on published unit costs.
Prima inves
• The default values provide an illustrative example of a model population.
• A decision tree model was developed in Excel to estimate the direct healthcare costs of flares of varying clinical severity.
• Treatment and management strategies were based on best practice guidelines, published data sources and expert opinion.2
Primary care review
• To calculate an estimated average cost of flare, default values for proportions of patients were assigned to each treatment pathway, based on clinical experience.2
• This model was then used to estimate costs associated with increased flares, which may result from non-adherence to Asacol® (mesalazine).
Methods
A
Average cost of flare
• While the costs associated with treatment and management of UC in secondary care are well-documented, estimates of the cost of flare across the spectrum of care pathways are lacking. • A cost analysis was performed to estimate the healthcare costs associated with managing a flare by modelling resource use across alternative pathways in primary and secondary care.
Figure 1. Estimated costs associated with
Asacol 2.4 g/day (800 mg MR tablets)5
Management costs £715.52
Secondary care consultation unit cost10 Endoscopy10 Monitoring tests
Market forces factor applied
a
7
£111.52a £123.43a £5.00
Annual costs in remission
£955 per patient
• The estimated annual cost of flar patients adherent to Asacol and £ adherent (Figure 2A).
• A potential annual cost saving of could be achieved if 5–15% of the adherent (Figure 2B).
POSTERS
PTU-066
re in ulcerative colitis to the NHS
wen Wiseman3, Sarah Shaw4
onomics Ltd, Buxton; 3Medical Affairs, Warner Chilcott (UK) Ltd; 4Policy Matters LLP, Surrey
dary care ga ons
6.23
dary care ga ons
71.17
£126.56
Asacol, 4.8 g/day (800 mg tabs)a
£82.33
GP consultation11
£43.00
Prednisolone (14.7% of patients)b
£0.93
Monitoring tests7
£5.00
Alendronate (70% of patients on steroids)b
£0.30
Asacol, 4.8 g/day (800 mg tabs)a
£82.33
Sigmoidoscopy with biopsy (14% of patients)1,10
Prednisolone (75% of patients)b
£4.73
Monitoring tests7
£5.00
Alendronate (70% of patients on steroids)b
£1.51
Tests associated with azathioprine use (25% of patients using it)2,5,7
£10.00
Not controlled, referral to outpa ent Controlled
Secondary care treatment review £512.20
Uncontrolled, admit to hospital
Add ciclosporin/biologic
Severe flare
Investigations
Azathioprine (25% of patients)
Controlled
Secondary care treatment review £3,216.51
Drug costs
Secondary care (outpatient)
8.00
B Controlled
Primary care treatment review
Controlled
£784.60 Uncontrolled, consider surgery (not costed)
Secondary care (inpatient)
ary care ga ons
Primary care
h flare in ulcerative colitis: A. Illustrative primary and secondary care pathways for treatment and management of flare; B. break down of costs. Treatment review & resource use
£51.23f
GP consultation11
£43.00
£175 per flare Consultant gastroenterologist initial consultation10
£195.97f
Multidisciplinary gastroenterology follow up consultation10
£220.87f
Asacol, 4.8 g/day (800 mg tabs)a
£82.33
Sigmoidoscopy with biopsy (70% of patients)1,10
Prednisolone (74% of patients)b
£4.66
Monitoring tests7
£5.00
Alendronate (70% of patients on steroids)b
£1.49
Tests associated with azathioprine use (25% of patients using it)5,7,12
£10.00
Azathioprine (25% of patients)c
£6.79
IV hydrocortisone (80% of patients)d
£12.24
£256.17f
Multidisciplinary gastroenterology follow up consultation10
£220.87f
Hospital stay10,12
£2,888.13f
Severe flare – additional drug costs Infliximab (14% of patients)e Adalimumab (2% of patients)
e
Ciclosporin (23% of patients)e,g
Secondary care (outpatient)
£578 per flare
£6.79
c
Primary care
£708.99 £60.85 £14.76
Secondary care (inpatient, controlled)
£3,488 per flare Secondary care (inpatient, severe flare)
£4,272 per flare
,14,15 b Prednisolone (30 mg/day, with a tapering dose) and alendronate (10 mg/day) for 6 weeks;2,5,12,16 cAzathioprine (125 mg/day) for 12 weeks;2,5,12 dIntravenous hydrocortisone (100 mg, three times daily) for 5 days;5,12,17 eInfliximab (3 doses of 312.5 mg),5,12,18,19 adalimumab (160 mg mg),5,12,18 and ciclosporin (250 mg/day for 7 days)5,12,17,19 were prescribed for severe flare; fMarket forces factor applied; gUnlicensed indication
flare. Proportion of patients managed via this pathway (illustrative examples)
el population ault values)2
Increased management in primary care
Reduced management in primary care
10.0%
20.0%
5.0%
76.5%
71.5%
79.0%
13.5%
8.5%
16.0%
£984
£778
£1,086
tion of patients managed via t differences in patient population Table 3).
£1,156–£3,468 per 100,000 people ese non-adherent patients became
• A decision tree model was developed to estimate the cost of treating a flare of active UC via illustrative primary or secondary care pathways.
A Adherent patients
Non-adherent patients
% patients adherent
50%20
Number of adherent patients
47
% patients non-adherent
50%20
Number of non-adherent patients
47
11%21
% non-adherent patients experiencing flare
61%21
Estimated number of flares
5.17
Estimated number of flares
28.67
Average cost of flare
£984
Average cost of a flare
£984
% adherent patients experiencing flare
Cost of flares in patients adherent to Asacol
Cost of flares in patients non-adherent to Asacol
£5,086
£28,204
• The findings support the argument for focusing services towards prompt detection and early management of flares,22 to help avoid A&E attendances, unplanned hospital admissions and other costly secondary care resource use. – In the base case, the estimated annual cost to manage a patient with UC in remission was £955. – Depending on the severity of the episode, costs to manage a single flare ranged from £175 to £4,272 with an average of £984. – A potential annual cost saving of £1,156–£3,468 per 100,000 people could be achieved if 5–15% of non-adherent patients became adherent. • While further investigation is required to assess real-world validity, this cost model represents a valuable tool for exploring resource utilisation in UC flare management.
Adherence intervention
B % of non-adherent patients who become adherent
5%
15%
Number of patients who become adherent
2.4
7.1
Estimated reduction in number of flares
1.18
3.53
Estimated reduction in cost of flares
£1,156
£3,468
Acknowledgements This model was developed by Policy Matters LLP and Tolley Health Economics Ltd, sponsored by Warner Chilcott UK Ltd. Editorial support was provided by Acumen Healthcare Communications Ltd, funded by Warner Chilcott UK Ltd. Citation: Bassi A et al. A model to assess the cost of flare in ulcerative colitis to the NHS. British Society of Gastroenterology Annual Meeting, 16–19 June 2014, Manchester, Poster PTU-066.
References: 1. Bassi A et al. Gut 2004;53:1471-8; 2. Bassi A. Expert opinion to Warner Chilcott. 2013; 3. Monitor. A guide to the Market Forces Factor. 2013; 4. Monitor. Annex 6A: Market Forces Factor payment values 2014-15. www.monitor.gov.uk/nt [Last accessed April 2014]; 5. Joint Formulary Committee 2013. British National Formulary (online). www.medicinescomplete.com [Last accessed September 2013]; 6. National Institute for Health and Care Excellence. CG118: Colonoscopic Surveillance for Prevention of Colorectal Cancer in People with Ulcerative Colitis, Crohn’s Disease or Adenomas. 2011; 7. National Clinical Guideline Centre. Ulcerative colitis clinical guideline. Appendix K: Costs of drugs used in the treatment of ulcerative colitis. 2013; 8. National Institute for Health and Care Excellence. CG166: Ulcerative colitis: Management in adults, children and young people. 2013; 9. Warner Chilcott. Data on file. IMS Health: Market share UK/AS/0185/08-13. 2013; 10. Department of Health. Payment by results in the NHS: Tariff information spreadsheet 2013-14 Version 6. www.gov.uk [Last accessed April 2014]; 11. Curtis L (ed). PSSRU unit costs of health and social care. 2012; 12. Royal College of Physicians. Report of the results for the national clinical audit of adult inflammatory bowel disease inpatient care in the UK. Round 3. 2012; 13. Hanauer SB et al. Am J Gastroenterol 2005;100:2478-85; 14. Hanauer SB et al. Can J Gastroenterol 2007;21: 827-34; 15. Sandborn WJ et al. Gastroenterology 2009;137:1934-43; 16. Royal College of Physicians. The inaugural national report of the results for the primary care questionnaire responses. Part of the UK inflammatory bowel disease audit 3rd round. 2012; 17. NHS map of medicine healthguides. Severe ulcerative colitis and toxic megacolon. http://healthguides.mapofmedicine.com [Last accessed April 2014]; 18. Royal College of Physicians. National clinical audit of biological therapies: UK Inflammatory Bowel Disease (IBD) audit. Adult national report. 2013; 19. National Institute for Health and Care Excellence. NICE TA163 infliximab for acute exacerbations of ulcerative colitis. 2008; 20. Cegedim Strategic Data (CSD). Patient Retention Analysis. 2012; 21. Kane S et al. Am J Med 2003;114:39-43; 22. IBD Standards Group. Standards for the healthcare of people who have Inflammatory Bowel Disease (IBD): 2013 Update. 2013.
GASTROENTEROLOGY TODAY - SUMMER 2015
re per 100,000 people was £5,086 for £28,204 for those who were non-
Conclusion
Figure 2. Estimated annual costs associated with non-adherence to Asacol per 100,000 people: A. Cost of flare for adherent vs non-adherent patients; B. Potential cost savings if a proportion of non-adherent patients become adherent.
39
POSTERS
Investigations, cance non-two week
INTRODUCTION
• The aim was to significantly reduce cancerrelated mortality by shortening the time between presentation, diagnosis and treatment. • Since its initiation, very little data has indicated improved survival outcomes for patients diagnosed with cancer via this pathway. • Our aim was to evaluate the efficacy of the two week rule service and compare the cancer pickup rate with cost.
Primary reason for referral in both patient groups
40 Percentage of patients (%)
• In 2000, the UK government introduced the two week rule (TWR) referral initiative. This was to ensure all patients with symptoms potentially indicating a diagnosis of cancer were seen by a relevant specialist within two weeks of referral by their GP.
33.7
35 30
26.9
25 20
17.3
15.7
15 10 5
TWR
19.2
9.6
10.1
14.6 7.7
6.7
Non TWR
14.6 7.7
7.7 4.5
3.8 0
0
Reason for referral
The majority of TWR referrals were vomiting, weight loss and anaemia respectively. The bulk of non-TWR referrals was abdominal pain.
60% 50% 40% TWR Non-TWR
30% 20% 10%
METHOD
GASTROENTEROLOGY TODAY - SUMMER 2015
40
• All patients presenting to gastroenterology under Two Week Rule (TWR) and standard non-Two Week Rule (non-TWR) pathway were collected over a set 6 week period. • These patients were prospectively followed up for a 3 month period from date of referral. This was done covertly by the investigators to avoid influencing decision making by the clinic physicians. • Data recorded included number of clinic visits, number and type of radiological and endoscopic investigations undertaken, end diagnosis and cancer diagnosis. • Crude costs per patient were calculated using the hospital’s unit costing database.
0%
1 Radiological Investigation (%)
2 Radiological Investigations (%)
A similar percentage of patients in both groups underwent radiological investigation (TWR: 53.9%, non-TWR: 50.6%). More TWR patients underwent second imaging than non-TWR (9.6% vs 6.7%).
CONCL
• In our sample of patients, those referred under the investigation with no significant increase in cancer pic
• Of concern, a large proportion of this group did not h
• We suggest alternative referral pathways to be cons patients.
POSTERS
er diagnoses and cost: A prospective study of two week rule versus k rule gastroenterology referrals at a district general hospital A. Shalabi, C. Alexakis, S. Moodie
Department of Gastroenterology, Epsom General Hospital
RESULTS AND DISCUSSION Gender of patients presenting to clinic
Percentage of patients undergoing an endoscopic procedure 100%
64%
70%
80%
51.9%
60%
48.1%
50%
60%
36%
Male
40%
Female
30% 20%
40%
20%
10% 0%
0%
TWR
TWR
Non-TWR
There were 52 TWR patients (mean age 72.5) and 89 non-TWR patients (mean age 57.9) (p=0.0001). Female gender represented 51.9% of TWR patients and 64% of non-TWR patients.
Non-TWR
76.9% of TWR patients had an endoscopic procedure compared to 62.9% of non-TWR patients (p=0.09). Mean cost per patient
25% 20%
TWR
15%
TWR
Non-TWR 10% Non-TWR
5%
0%
Patients with cancer diagnosis
Patients with no diagnosis
7.7% of TWR patients and 3.4% of non-TWR patients had an end diagnosis of cancer, although this difference did not reach statistical significance. 23.1% and 19.1% of patients had no clear diagnosis at 3 months in the TWR and non-TWR respectively.
£0
sidered in a bid to improve cancer diagnosis in high risk
£300
£400
£500
£600
£700
£800
REFERENCES •
Flashman K, O’Leary DP, Senapati A, Thompson MR. The Department of Health’s ‘‘two week standard’’ for bowel cancer: is it working? Gut 2004;53: 387-391.
•
Thorne K, Hutchings HA, Elwyn G. The Two-Week Rule for NHS Gastrointestinal Cancer Referrals: A Systematic Review of Diagnostic Effectiveness. The Open Colorectal Cancer Journal 2009;2: 27-33.
GASTROENTEROLOGY TODAY - SUMMER 2015
have a formal diagnosis by after 3 months of follow up.
£200
The mean cost of investigations and follow-up was significantly higher in the TWR cohort (£754.10 vs £613.10, p=0.04).
LUSION
e TWR pathway underwent a higher burden of invasive ck up, despite being significantly more costly.
£100
41
POSTERS
SELF PROVIDED GUIDED MEDICAL HISTO
Chloe van Someren 1, Niall van Someren 2Andrew Millar 1Gwen Edwards 1 1Gastroenterology, North Middlesex University Hospital, 2Gastroenterology, Chase Farm H
AIMS
METHODS
Increased:
We have developed a large during history taking. A comp question depending on the pr questionnaires to be develope phrased in plain English, bu medical terminology. The his presentation to the clinician. P touch screen, and checked the process were recorded from trialed in a hepatitis assessmen voluntary and secure system pr
1) Clinical Efficiency Reduced costs on establishing the history will speed healthcare allowing larger numbers of patients to be assessed 2) Patient Experience More acceptable methodology for asking sensitive questions 3) Patient Safety A more comprehensive medical history will protect patients and via an integration engine could feed directly into existing databases and electronic patient records
INTRODUCTION A number of studies have demonstrated the benefits of touch screen history taking in the primary care setting (Main, Quintela et al. 2004)
GASTROENTEROLOGY TODAY - SUMMER 2015
42
This project aims to evaluate the set up of a self directed automated clinic using of a new innovative touch screen program (Pre-DocTM) designed by NHS professionals to establish key parts of a patientâ&#x20AC;&#x2122;s history. The screen layout is designed to be clear and intuitive and the answers to questions are delivered in an annotated form for rapid reading. We wish to establish whether this technology will provide better clinical information than traditional history taking or paper forms and whether its use can improve clinical efficiency and the patient experience of healthcare.
REFERENCES
Main, D. S., J. Quintela, R. Araya-Guerra, S. Holcomb and W. D. Pace (2004). "Exploring patient reactions to pen-tablet computers: a report from Ca
POSTERS
ORY IS FAST, COMPLETE AND ACCURATE
Hospital, London, United Kingdom
database of questions that could be asked puterised algorithm selects the next relevant revious answer. A designer interface allows ed and adjusted readily. The questions are ut the program translates the answers into story is then available in PDF format for Patients self completed their history using a e results before printing. Comments about the patients and clinical staff. The system was nt clinic. Patients are fully informed about this rior to use.
443 patients used the touch screen. 12 did not complete their history because of language problems (8) or indifference (3). The average time to complete was 14.7 minutes (range 7-21 minutes). 7 patients were identified who were at high risk of hepatitis infection, and a monospot test was offered and accepted in all of these and further serological tests undertaken. 180 patients with known positive serology completed their history for use in a new patient hepatitis outpatients clinic.
CONCLUSION Patients found the touch screen easy to use, and were able to complete their history in the waiting area prior to consultation. They were universally happy to keep a printout of their history. The clinicians were able to spend more time discussing risks and treatment options, and were able to ask supplementary questions rather than repeatedly obtaining basic data. Printouts of the PDF were retained in the notes as part of the medical record. This technology has shown great potential in allowing more new patients to be seen, increasing efficiency in carrying out regular reviews, gathering better clinical information and reducing patient distress when asking sensitive questions. Perceived benefits are â&#x20AC;&#x201C; more rapid and thorough clinical assessment; semi-automated follow up; health screening; and patient surveys. There are applications for this technology in many fields of medical practice.
GASTROENTEROLOGY TODAY - SUMMER 2015
aReNet." Ann Fam Med 2(5): 421-424.
RESULTS
43
POSTERS
Dried blood Spot Testing for Hepatitis B and C in the Chinese Community living in Northern Ireland
The Liver Unit Royal Victoria Hospital
Annelies.McCurley1, Seana Murray1, Neil McDougall2
Hepatitis B&C Managed Clinical Network1, Regional Liver Unit2, Royal Victoria Hospital, Belfast
Introduction
Results
The epidemiology of hepatitis B and C is
•Prior to the event, 97 individuals expressed an interest via telephone in attending the screening event. 19 of
changing through out Europe, with immigration
this cohort were not registered with a GP in Northern Ireland, and had to be excluded from the screening. A
cited by the European Centre for Disease Control
further 10 individuals who attended the session on the day were again excluded as they too were not
and Prevention as the main reason (ECDC, 2014)
registered with a GP giving a total of 29 individuals that were not eligible (figure1). The final number of
Northern Ireland still has a very low prevalence of
candidates included in the screening event was 55 . A synopsis of the demographic is as follows ; 62%
viral hepatitis, with an average of 80 -100 HBV
female, 38% male, mean age 47, range 22 -67.
and 100 -120 HCV cases being diagnosed every year. Certain groups however are at higher risk of infection including those born in high or intermediate endemic areas.
Aim
•13 (24%) individuals tested HBsAg negative and HBcAb positive, - suggesting previous infection. Five (9%) individuals tested positive for chronic viral hepatitis – 4 were HBsAg positive and 1 was HCV PCR positive. All 5 subsequently attended a hepatology clinic for follow-up (figure3). •43 (78%) of those presenting for testing reported they had never been vaccinated against HBV (figure 4). Figure 3:
Figure 1:
84 individuals requested screening for Hepatitis B&C
The aim was to set up a single viral hepatitis community screening event to offer testing to
At initial registration told they could not be tested as not registered with GP
members of the Chinese community in Belfast in an effort to determine the prevalence of
Dry Blood Spot Test Results
19
Hepatitis B (HBV) and Hepatitis C (HCV). 10 55
HBsAG +
4(7%)
HBV core Ab + 13(24%)
Turned up at event. Not Registered with GP and could also not be offered testing
HCV + 37(67%)
1(2%)
Neg results
Tested
Methods Members of the Belfast Chinese Community were
N55
N84
Figure 4:
Figure 2:
invited to attend a Hepatitis B&C awareness and
Number of individuals tested who reported being vaccinated
Gender of those who came forward for testing
testing session held in the Chinese Welfare Centre. As part of the criterion only those individuals that were
6(11%)
registered with a GP were eligible for screening. All
GASTROENTEROLOGY TODAY - SUMMER 2015
No
Male 43(78%)
Not Sure
through a presentation (translated) and literature. Dry blood spot (DBS) testing was used as an alternative to venous sampling to try and encourage participation. All patients (and their GPs) were informed of results by letter. Those with positive HBsAg or positive HCV antibody individuals were also contacted by telephone with the assistance of an interpreter and asked to attend a hospital clinic. Those who tested HBsAg negative and HBcAb positive were advised to attend their GP surgery for follow up HBV serology and HBV DNA. HIV testing was offered to all those with a positive result for either HBV or HCV.
44
34(62%)
the advantages and disadvantages of screening
Yes
Female
21(38%)
those attending for testing were educated regarding
6(11%)
N55
N55
Conclusion DBS testing of a sample of the Chinese community living in a low prevalence area of the UK can detect chronic viral hepatitis in 9%. In addition, one third of those requesting screening were not registered with a GP and therefore could not be detected by current NHS services. This suggests that the NHS need to consider setting up screening services for ethnic communities even in low prevalence areas of the UK.
Conflict of interest Funding for the dried blood spot testing kits and the analysis of these were paid for by Roche Pharmaceuticals
COMPANY NEWS
GASTROENTEROLOGY SOLUTION DRIVES DEPARTMENTAL EFFICIENCY AND SUPPORTS PATIENT SELF-MANAGEMENT University Hospital Southampton NHS Foundation Trust is expecting to achieve significant cost and time savings by implementing a new Ascribe gastroenterology system. The gastroenterology department at Southampton sees around 4,000 Inflammatory Bowel Disease (IBD) patients. To meet new IBD quality standards as well as participate in the UK IBD registry and UK Biologics Audit, they required a system that would efficiently populate the audit databases, whilst providing clinicians with sufficient incentives to use the system and patients with more knowledge about their conditions to facilitate self-management. Integrating clinical systems Ascribe, part of EMIS Group, worked with the Southampton IBD team to develop a new integrated IBD solution. The trust uses several Ascribe clinical systems, including patient administration system (PAS), unscheduled care, and specialised clinical modules. As an integrated solution, clinicians have immediate access to all the investigations including relevant to managing the patient endoscopy, blood tests, histology, pathology and surgical history without leaving the IBD system in a meaningful format. Facilitating supported self-management of care A key objective was to improve patient self-management. Dr Fraser Cummings, consultant gastroenterologist and lead clinician for the project, said “there is a drive to improve patient knowledge about their conditions to help them self-manage their care. By enabling clinicians to record real-time data into one system, patients leave hospital fully informed about their conditions, which we hope will reduce health care resource utilization in the future.”
Improved clinical engagement Multi-disciplinary teams (MDT) now have one system and a single pathway for each patient in the IBD system, improving communication between the teams and fully recording all discussions regarding patient diagnosis or actions required. Dr Cummings comments “MDT scheduling and meeting screens are built into our Ascribe software to remove the need for separate spreadsheets and systems. Patient care is improved by ensuring all decisions are captured and available at any point for reference immediately after meetings.”
Comprehensive, accurate clinical procedure recording and reporting Ascribe’s endoscopy solutions help clinicians improve their procedure recording and reporting capability. Based on national and professional standards, our solutions can help quickly and efficiently produce reports for standards that meet BSG Guidelines. By having a more informed record of patient procedures, we can help improve patient care and safety. To find out more, please contact marketing@ascribe.com
“We expect to save at least £350,000 per year by improving correct drug use in gastroenterology”
GASTROENTEROLOGY TODAY - SUMMER 2015
Reduced referrals and cost savings The trust anticipates that they could save around £350,000 per annum using a management system for high cost drugs (anti-TNF biologic drugs), facilitating referral to research teams, and efficient use of nurse and administration time to run Virtual clinics and flare lines. Dr Cummings comments “clinicians and nurses have quicker and simpler access to accurate up to date patient data presented in a clinically meaningful way which saves significant time in the clinics as well as improving patient safety. Flare line activity is also recorded which means the reduction in emergency department referrals, further admissions and unnecessary clinic visits provided by this service can be captured and an accurate record of the contact recorded.”
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COMPANY NEWS
FIT FOR THE FUTURE Measurement of faecal haemoglobin concentration (f-Hb) is now well established in screening for significant colorectal neoplasia, that is, colorectal cancer and higher-risk adenoma. However, this is now moving to a quantitative faecal immunochemical test (FIT), rather than the traditional guaiacbased faecal occult blood test (gFOBT). In February 2015 the Scottish government announced that it would be introducing a new bowel cancer test to simplify the sample collection process in a bid to increase participation in Scotlandâ&#x20AC;&#x2122;s national bowel screening programme and save even more lives1. This new FIT screening test will see participants returning a small sample from just one bowel motion in a hygienic sample picker device, instead of the three samples on a test card as required for the current test. In addition to simplification for the user this FIT based assay ensures improved specificity and sensitivity and also offers great potential for managing the pathway of symptomatic patients. Scotland has performed an evaluation of feasibility and clinical outcomes of FIT as a first-line test2 and a two-centre assessment is currently underway in England. Interestingly, most clinical guidelines still state that faecal tests should not be used in the assessment of symptomatic patients, but these recommendations apply to gFOBT, not to the very different and much better FIT. Evidence is rapidly accumulating that f-Hb is an excellent rule-out test for both colorectal neoplasia and inflammatory bowel disease (IBD) with very high Negative Predictive Values (NPV) using a low cut off of less than 10 Âľg of Hb /g of faeces. At a meeting of the Colorectal Cancer Screening Committee, World Endoscopy Organization, held in Vienna in October 2014, there was
much discussion on FIT in screening. However, the presentation that stimulated much interest was that of Professor Bob Steele from the University of Dundee. Professor Steele described the published pilot study done in Dundee on assessment of those with suspected colorectal disease using f-Hb3. This was performed to assess whether f-Hb could assist in rationalising referrals for colonoscopy, which have rapidly increased recently through the Be Clear on Cancer and Detect Cancer Early campaigns as well as through referrals from the screening programmes and subsequent surveillance needs. However, although lower abdominal symptoms are common, significant colorectal disease is not. He then described some concepts arising from a more extensive study, based on the novel but routine referral pathway existing in NHS Tayside, investigating the use of f-Hb AND faecal calprotectin in assessment of the symptomatic. He showed that, if a patient has undetectable f-Hb, significant colorectal disease is very unlikely. Using this rule-out strategy, although some cases of adenoma and IBD would be missed, 40% of urgent referrals for colonoscopy could be saved. Patient pathways using diagnostics in digestive health are changing. Quantitative f-Hb and calprotectin are now evidence-based tools to assess the symptomatic and rationalise referrals for colonoscopy: they should be adopted ubiquitously. Alpha Laboratories (www.alphalabs.co.uk) has been a key supplier of faecal tests for haemoglobin and calprotectin for many years. In anticipation of the increasing clinical indications for FIT analyses, Alpha Laboratories has partnered with Kyowa Medex for provision of the HM-JACKarc automated quantitative FIT system to the Bowel Screening Programmes and for development in symptomatic testing. As per the progress made with the now NICE-approved calprotectin analyses, Alpha Laboratories is developing a similar approach with f-Hb measurements on HM-JACKarc. References 1. http://news.scotland.gov.uk/News/New-bowel-cancer-homescreening-test-1610.aspx
GASTROENTEROLOGY TODAY - SUMMER 2015
46
2. Steele RJ, et al. Clinical outcomes using a faecal immunochemical test for haemoglobin as a first-line test in a national programme constrained by colonoscopy capacity. United European Gastroenterol J. 2013;1:198-205. 3. McDonald PJ, et al. Low faecal haemoglobin concentration potentially rules out significant colorectal disease. Colorectal Dis 2013;15:e151-9.
R TE IS AY EG D R
TO
A combined meeting of ACPGBI, AUGIS, BAPEN, BASL & BSG
COMPANY NEWS
22 – 25 June 2015 ExCeL London, UK
www.DDF2015.org.uk
@DDFConference15
After the success of the Digestive Disorders Federation 2012 conference, we are pleased to announce the 2nd Digestive Disorders Federation conference will take place 22 – 25 June 2015 in London ExCel. Five societies and Associations in the field of Digestive Disorders are joining together in a combined conference to replace their annual conferences in 2015:
• • • • •
To discuss use #DDF2015
Full Interactive Online Programme LIVE Earlybird Registration – 20 March 2015
The Association of Coloproctology of Great Britain and Ireland (ACPGBI) Association of Upper Gastrointestinal Surgeons (AUGIS) British Association for Parenteral and Enteral Nutrition (BAPEN) British Association for the Study of the Liver (BASL) British Society of Gastroenterology (BSG)
This is a major four day international conference in the vibrant city of London. The first day: Postgraduate education day & multi-disciplinary professional interaction. Suitable for Consultant CPD and Trainee Postgraduate education
If you are a Hepatologist, Surgeon, Gastroenterologist, Non Clinical Scientist, Nurse, Dietician, GI Pharmacist, Nutrition Specialist or an Allied Health Professional in the field of Gastroenterology, you should not miss this exciting conference!
To contact the DDF Conference Secretariat MCI UK LTD, please contact: DDF2015@mci-group.com If you are interested in Exhibition & Sponsorship Opportunities, please contact: DDF2015industry@mci-group.com For further information on DDF 2015, please visit conference website: www.ddf2015.org.uk
GASTROENTEROLOGY TODAY - SUMMER 2015
The main scientific programme (days 2-4): Clinical and translational research symposia, clinical updates, state of the art lectures, moderated poster rounds covering topics in surgical and medical gastroenterology, nutrition and hepatology.
Contact Details
Why You Should Consider Alternative EWD Chemistries The alternative EWD chemistries project was started nearly two years ago. The Project partners were Audere Medical Services Ltd, Amity International, and the project leader was Peskett Solutions Ltd (Ruhof UK) We are pleased to announce that the project was a resounding success and we are now in a position to offer our services to all hospitals using EWD’s During the EWD project the following questions were raised: Will the Trust save money changing to alternative EWD Chemistries? • We have saved our project Hospital £56,000 per annum on their EWD detergent, disinfectant.
Are there any other added benefits with using alternative chemistries? • Our alternative EWD project has been running for nearly two years. The customer has been monitoring the chemical effects to the EWD’s and Endoscopes. • The endoscope manufacturer has reported a 23% reduction in scope damage from the cleaning and disinfectant chemistries. • The customer has reported an impressive increase of 41% up time. This has been contributed to the alternative chemistries and improved servicing and parts.
How do you deal with Type Testing? • The type testing for the chemistries is performed by the validation company on site. The alternative chemistries were selected to chemically match the chemistries supplied by the EWD manufacturer. This decision was based on ensuring EWD and Endoscope compatibility.
What about Patient safety? • To offer alternative chemistries we needed to ensure that all the required EWD validation testing was carried out to current relevant standards. The endoscopes over the last 2 years have shown no significant signs of deterioration. We are confident that this will continue and there should be no impact on Patient Safety.
Please contact Matthew to discuss the alternative EWD chemistries project further. Tel: 01323 511038 Email: support@peskettsolutions.com