volume 25 no. 2 summer 2015 gastroenterology today · want to manage your ibd patients ... ascribe...
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Summer 2015Volume 25 No. 2
In this issue Clinical Paper Case Reports BSG Posters
Gastroenterology Today
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LPS397 ENDOSCOPY ADVERT.indd 1 27/05/2015 09:16
CONTENTS5 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
CONTENTS
This issue edited by:A Poullis, Consultant Gastroenterologist, St George’s Hospitalc/o Media Publishing CompanyMedia House48 High StreetSWANLEY, Kent BR8 8BQ
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Next Issue Autumn 2015
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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’.
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Gastroenterology Today
www.assuresupport.co.ukSupport programme for
eligible patients prescribed Asacol.
RETURN TO EVERYDAY LIFEFor:
• FAST RELIEF FROM FLARES1
• EXTENSIVE MUCOSAL HEALING2
• EFFECTIVE MAINTENANCE OF REMISSION3
ASACOL 800MG MR TABLETS and help your patients return to everyday life.
RELIEVEAt 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 pointfrom baseline in the respective symptom score.
RESOLVEAt 4.8g/day, 80% of patients achieve mucosal healing (endoscopy subscore 0 or 1) by week 62
RESUMEWhen taken at 2.4g once daily, 4 out of 5 patients still remain in remission at 12 months3
2 weeks1,4
Week 62
TIMESCALEEFFICACY
12 months3
Relieve, resolve, resume(MESALAZINE)
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 modifi ed 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 modifi ed 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. Confi rmed 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 confi rmed 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 fl uid & 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 benefi ts outweigh the risk. Avoid during lactation unless essential. 800mg Tablets only: Mesalazine should be used with caution during pregnancy and lactation when the potential benefi t 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 defi ciency 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 fi brotic 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. Orchard TR. et al. Aliment Pharmacol Ther 2011; 33(9): 1028-1035.2. Lichenstein GR. et al. Aliment Pharmacol Ther 2011; 33: 672-678.3. Hawthorne B. et al. Infl amm Bowel Dis 2012; 18(10): 1885-1893.4. 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
Combined Abbreviated Prescribing Information:
In moderately active ulcerative colitis:
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.
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 defi ciency or glucose-galactose malabsorption should not take this medicine because of the presence of lactose monohydrate. Standard
Adverse events should be reported. 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
www.assuresupport.co.ukSupport programme for
eligible patients prescribed Asacol.
www.assuresupport.co.uk
eligible patients prescribed Asacol.
Combined Abbreviated Prescribing Information:
RETURN TO EVERYDAY LIFERETURN TO EVERYDAY LIFERETURN TO EVERYDAY LIFERETURN TO EVERYDAY LIFERETURN TO EVERYDAY LIFERETURN TO EVERYDAY LIFERETURN TO EVERYDAY LIFERETURN TO EVERYDAY LIFERETURN TO EVERYDAY LIFEFor:
• FAST RELIEF FROM FLARES1
• EXTENSIVE MUCOSAL HEALING2
• EFFECTIVE MAINTENANCE OF REMISSION• EFFECTIVE MAINTENANCE OF REMISSION3
In moderately active ulcerative colitis:
ASACOL 800MG MR TABLETS ASACOL 800MG MR TABLETS and help your patients return to everyday life.and help your patients return to everyday life.
12 months3RESUMERESUMEWhen taken at 2.4g once daily, 4 out of 5 patients still remain in remission at 12 months3
RELIEVERELIEVERELIEVERELIEVEAt 4.8g/day, 73% of patients achieve symptom At 4.8g/day, 73% of patients achieve symptom At 4.8g/day, 73% of patients achieve symptom At 4.8g/day, 73% of patients achieve symptom improvement* and 43% of patients achieve improvement* and 43% of patients achieve improvement* and 43% of patients achieve improvement* and 43% of patients achieve symptom resolution as early as 2 weekssymptom resolution as early as 2 weekssymptom resolution as early as 2 weekssymptom resolution as early as 2 weeks1,4
* Symptom improvement = decrease of at least 1 point* Symptom improvement = decrease of at least 1 point* Symptom improvement = decrease of at least 1 point* Symptom improvement = decrease of at least 1 pointfrom baseline in the respective symptom score.from baseline in the respective symptom score.from baseline in the respective symptom score.from baseline in the respective symptom score.
RESOLVERESOLVERESOLVERESOLVEAt 4.8g/day, 80% of patients achieve At 4.8g/day, 80% of patients achieve At 4.8g/day, 80% of patients achieve At 4.8g/day, 80% of patients achieve mucosal healing (endoscopy subscore 0 or 1) mucosal healing (endoscopy subscore 0 or 1) mucosal healing (endoscopy subscore 0 or 1) mucosal healing (endoscopy subscore 0 or 1) by week 62
2 weeks1,4
Week 62
TIMESCALETIMESCALEEFFICACYEFFICACY
Job code: UK/AS/0004/01-15c – January 2015
72284.30 Asacol_PlanA_Advert_297x210-3.indd 1 29/01/2015 10:09
EDITORS COMMENT
Biological Revolution
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 “gain-share” 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 PoullisSt George’s HospitalLondon
EDITORS COMMENT
“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.”
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Mesalazine, the Dr Falk way
Prescribing Information (Please refer to full SPC before prescribing):Salofalk gastro-resistant prolonged-release granulesPresentation: 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 diffi culties 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
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. Mesalazine-induced 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: Specifi c 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 benefi t outweighs the possible risks. Limited experience in the lactation period. Use during breast-feeding only if the potential benefi t outweighs the possible risks; if the infant develops diarrhoea, breast-feeding should be discontinued. Undesirable effects: Headache, dizziness, peri- and myocarditis, abdominal pain, diarrhoea, fl atulence, nausea, vomiting, aplastic anaemia, agranulocytosis, pancytopenia, neutropenia, leukopenia, thrombocytopenia, peripheral neuropathy, allergic and
fi brotic lung reactions (including dyspnoea, cough, bronchospasm, alveolitis, pulmonary eosinophilia, lung infi ltration, pneumonitis), acute pancreatitis, impairment of renal function including acute and chronic interstitial nephritis and renal insuffi ciency, 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 (UK- NHS 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
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 benefi t 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 fl avour.
Oh and if the infl ammation is in the distal colon, the granules are pretty good at getting there too.1
Optimisation with Salofalk Granules for patients inadequately maintained on previous mesalazine resulted in:2
47% lessroutinehospital visits
60% lesshospital visits due to UC fl are-up
44% lessGP visits due to UC fl are-ups
50% lesssteroid courses used
14237 SAG Optomisation Ad.indd 1 08/04/2015 13:58
CLINICAL PAPER
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PROSPECTIVE COMPREHENSIVE GENOMIC PROFILING OF ADVANCED GASTRIC CARCINOMA CASES REVEALS FREQUENT CLINICALLY RELEVANT GENOMIC ALTERATIONS AND NEW ROUTES FOR TARGETED THERAPIESSiraj 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
aFoundation 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; fDepartment of Pathology and Laboratory Medicine, Albany Medical College, Albany, New York, USADisclosures of potential conflicts of interest may be found at the end of this article.
KeyWords. Gastric cancer • Sequencing • Targeted therapy • Mutation • Profiling • MET
Abstract
Background. Gastric cancer (GC) is a major global cancer burden
and the second most common cause of global cancer-related deaths.
The addition of anti-ERBB2 (HER2) targeted therapy to chemotherapy
improves survival for ERBB2-amplified advanced GC patients; however,
the majority of GC patients do not harbor this alteration and thus cannot
benefit from targeted therapy under current practice paradigms.
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
(6.0%), and MET (6.0%). Receptor tyrosine kinase genomic alterations
were detected in 20.6% of cases, primarily ERBB2, FGFR2, and MET
amplification,with ERBB2 alterations evenly split between amplifications
and base substitutions. Rare BRAF mutations (2.6%) were also
observed. One MET-amplified GC patient responded for 5 months to
crizotinib, a multitargeted ALK/ROS1/MET inhibitor.
Conclusion. Comprehensive genomic profiling of GC identifies clinically
relevant GAs that suggest benefit from targeted therapy including MET-
amplified GC and ERBB2 base substitutions.
The Oncologist 2015;20:1–9
Implications for Practice
Despite description of many potentially clinically relevant genomic
alterations in retrospective research studies, these alterations are not
regularly assessed in a comprehensive manner in clinical practice.
This study demonstrates the feasibility of prospective comprehensive
genomic profiling (CGP) for advanced gastric carcinoma.
We demonstrated a high frequency of genomic alterations associated
with potential benefit from targeted therapies. CGP in this setting
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 cancer-
related death worldwide [1]. The majority of patients present with
advanced disease, and the overall 5-year survival rate is <28%,
compared with <5% for patients presenting with metastatic disease
[2–4]. The clinical heterogeneity of GC is highlighted by significant
worldwide geographic variations, differences in anatomic origin
(proximal vs. distal), risk factors including Helicobacter pylori infection
and dietary patterns, and a poorly understood relationship to Asian
ethnicity [5–7]. Within the common intestinal histologic subtype, there
are differences in ERBB2 amplification frequencies (proximal vs. distal)
and association with H. pylori and progression from a metaplastic
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: 617-418-2241; E-Mail: [email protected] Received September 24, 2014; accepted for publication February 4, 2015. ©AlphaMed Press1083-7159/2015/$20.00/0 http://dx.doi.org/10.1634/theoncologist.2014-0378
Mesalazine, the Dr Falk way
Prescribing Information (Please refer to full SPC before prescribing):Salofalk gastro-resistant prolonged-release granulesPresentation: 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 diffi culties 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
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. Mesalazine-induced 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: Specifi c 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 benefi t outweighs the possible risks. Limited experience in the lactation period. Use during breast-feeding only if the potential benefi t outweighs the possible risks; if the infant develops diarrhoea, breast-feeding should be discontinued. Undesirable effects: Headache, dizziness, peri- and myocarditis, abdominal pain, diarrhoea, fl atulence, nausea, vomiting, aplastic anaemia, agranulocytosis, pancytopenia, neutropenia, leukopenia, thrombocytopenia, peripheral neuropathy, allergic and
fi brotic lung reactions (including dyspnoea, cough, bronchospasm, alveolitis, pulmonary eosinophilia, lung infi ltration, pneumonitis), acute pancreatitis, impairment of renal function including acute and chronic interstitial nephritis and renal insuffi ciency, 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 (UK- NHS 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
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 benefi t 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 fl avour.
Oh and if the infl ammation is in the distal colon, the granules are pretty good at getting there too.1
Optimisation with Salofalk Granules for patients inadequately maintained on previous mesalazine resulted in:2
47% lessroutinehospital visits
60% lesshospital visits due to UC fl are-up
44% lessGP visits due to UC fl are-ups
50% lesssteroid courses used
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Efforts to identify predictive biomarkers to guide decision making
for systemic therapy have yielded inconsistent results. To date, the
only validated predictive biomarker for targeted therapy is ERBB2
amplification, which predicts benefit from the anti-ERBB2 (HER2)
antibody trastuzumab in advanced disease [8, 11, 12].
Systemic therapy for metastatic, relapsed, or refractory GC is largely
based on empiric 5-fluoropyrimidine and platinum combinations, and
there are no definitive clinical predictors of response [13]. Although
trastuzumab offers improved survival for the 7%–34% of GC patients
with ERBB2 amplification, there are no approved molecularly directed
therapies for the majority of patients [8, 14]. Although the recent
approval of the anti-VEGFR2 antibody ramucirumab increases the GC
armamentarium, there are no validated predictive biomarkers to identify
patients who may derive benefit from anti-VEGFR targeted therapies
[13, 15].
Large-scale retrospective whole-genome sequencing analyses have
highlighted recurrent genomic alterations in gastric cancer such
as ARID1A, CDH1, RHOA, and FGFR2 [10, 16–18]. Prospective
comprehensive genomic profiling based on a clinical next-generation
sequencing (NGS) assay in the course of clinical care can identify novel
and known clinically relevant genomic alterations (GAs) and increase
understanding of the underlying biology and immediately inform patient
management options. In this study, we present a large series of primarily
relapsed and metastatic gastric carcinoma clinical specimens that
underwent prospective comprehensive genomic profiling and highlight
therapeutic implications.
Materials and Methods
Comprehensive genomic profiling using a clinical NGS-based assay
(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)
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://
www.promega.com) and quantified using an Invitrogen PicoGreen
fluorescence assay (Thermo Fisher Scientific, Waltham, MA, http://www.
thermofisher.com). Library construction was performed with 50–200
ng of DNA sheared by sonication (E210; Covaris, Woburn, MA, http://
covarisinc.com) to~100–400 base pairs before end repair, dA addition,
and ligation of indexed Illumina sequencing adaptors (Illumina, San
Diego, CA, http://www.illumina.com). Prior to hybrid selection and
sequencing, libraries were amplified with polymerase chain reaction
(PCR) for 10 cycles using KAPA HiFi (Kapa Biosystems, Wilmington,
MA, http://www.kapabiosystems.com). Solution-based hybrid selection
was performed with a custom bait set of 120-bp biotinylated DNA
oligonucleotides (Integrated DNA Technology, Coralville, IA, http://www.
idtdna.com) covering 3,769 exons of 236 cancer-related genes and 47
introns of 19 genes frequently rearranged in cancer. The Illumina HiSeq
2000 and Illumina HiSeq 2500 platforms were used to perform 49 ×
49 paired-end sequencing. Sequence alignment, PCR duplicate-read
removal, and local alignment optimization were performed using Burrows-
Wheeler aligner bwa-0.5.9 (SourceForge; Slashdot Media, San Francisco,
CA, http://slashdotmedia.com), Picard 1.47 (Broad Institute, Cambridge,
MA, http://broadinstitute.github.io/picard/), SAM Tools samtools-0.1.12a
(SourceForge; Slashdot Media), and GATK 1.0.4705 (Broad Institute).
Variant calling was performed using custom tools. Base substitutions
were called using a Bayesian methodology, and short insertions-deletions
(indels) were called using local assembly. Somatic variants were
annotated using COSMIC, and germline variants were removed using
dbSNP. Rearrangements were called using chimeric read pairs clustered
by genomic position. Copy number alterations (CNAs) were detected
by fitting a statistical copy-number model to normalized coverage
and allele frequencies at all exons and ~3,500 genomewide single
nucleotide polymorphisms and accounting for stromal admixture. An
extensive validation was performed for base substitutions, short indels,
and CNAs. To validate CNA detection, seven tumor cell lines bearing 19
focal gene amplifications (6–15 copies, 15 genes) and 9 homozygous
gene deletions (6 genes) with their matched normal cell lines (thereby
maintaining consistent genotypes) were pooled to create five ratios
ranging from low to high tumor content (20%–75%), creating a total test
set of 210 CNAs.
High performance was achieved for both high-level amplifications (copy
number ≥8) and homozygous deletions when tumor purity was as low as
30%: sensitivity was 99% (91 of 92) with positive predictive value >99%
(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
Comprehensive genomic profiling was performed on 116 GC cases.
The median patient age at time of testing was 62 years (range: 26–87
years) (Table 1). Sixty-five (56%) specimens were from male patients.
The stage distribution is shown in Table 1. Of the samples, 69% (n=80)
were from the primary GC and 31% (n=36) were from metastatic sites
including ovary (n=7), peritoneum (n=4),omentum (n=3), colon (n=3),
bone (n=3), pleural fluid (n=3), lymph node (n=3), ascites (n=2),
esophagus (n=2), small intestine (n=2), mesentery (n=1), liver (n=1),
pelvis (n=1), and soft tissue (n=1).
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Table 1. Clinicopathological and genomic characteristics of 116 gastric
cancer cases prospectively assayed by a comprehensive genomic
profiling assay
Overall, 501 cancer-related genomic alterations were identified in
116 cases, yielding an average of 4.32 alterations per sample (Table
1; Fig. 1). Of 501 GAs identified, 210 (41%) were clinically relevant
alterations, yielding an average of 1.8 clinically relevant GAs per case
(Table 1). Moreover, 78% of GC cases harbored at least 1 clinically
relevant variant associated with targeted therapies approved by
the U.S. Food and Drug Administration (FDA) or mechanism-based
trials (Table 2).The most common clinically relevant GAs were KRAS,
CDKN2A, CCND1, ERBB2, PIK3CA, MLL2, MET, PTEN, ATM, DNMT3A,
NF1, NRAS, and MDM2 (Table 2).The most common GAs in the 116
cases were TP53 (58 cases, 50%), ARID1A (28 cases, 24%), and
CDH1 (17 cases, 15%).
Twenty-eight cases (24%) harbored loss-of-function ARID1A
alterations (Fig. 2). ARID1A-altered samples harbored an increased
frequency of CREBBP variants (p<.0005), PIK3CA variants (p=.0017),
and MLL2 variants (p=.019) and were less likely to harbor TP53
variants (p<.050). In this series, 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 (data not shown). All other ARID1A findings remained
significant with a type I error rate of <.05 with a multiple hypothesis
correction applied.
Somatic CDH1 mutations were found in 6 of 24 (25%) diffuse GC
cases compared with 11 of 92 (12%) nondiffuse GC cases (p=.12).
Matched normal tissue was not available to investigate germline
CDH1 status. Enrichment of APC, CREBBP, and MLL2 alterations
was observed in intestinal GC; 3 of 12 cases (25%) contained APC
mutations compared with 3 of 104 cases (2.9%) of nonintestinal GC
(p=.014). APC variants were not observed in any of the 24 diffuse
GC cases. CREBBP was altered in 4 of 12 (33%) intestinal cases
compared with 2 of 104 (1.9%) nonintestinal cases (p<.001), and
MLL2 was altered in 4 of 12 (33%) intestinal cases compared with 4
of 104 (3.8%) nonintestinal cases (p=.0038).
Alterations of genes involved in mismatch repair were observed in
this series at a frequency of 2.6% for MLH1, 0.8% for MSH2, and 0.8%
for MSH6. Three of these five cases harbored truncating alterations
that are predicted to cause loss of function, and no single case
contained more than one alteration in this pathway. No information on
microsatellite stability assessed by PCR testing was available.
Alterations in receptor tyrosine kinases (RTKs) were harbored by
24 cases (20.6%). Ten samples (8.6%) harbored ERBB2 alterations,
5 contained somatic base substitutions and 5 harbored amplifications
(6–24 copies), with these events being mutually exclusive. ERBB2
base substitutions in this series consisted of R678Q (two cases),
S310F (one case), L755S (one case), and V842I (one case). One case
harbored both ERBB2 R678Q and MET amplification. CDH1 alteration
was not associated with ERBB2 alteration in our GC sample (data not
shown).
Seven cases (6%) harbored MET amplifications (7–30 copies) and
seven cases (6%) had FGFR2 amplifications (12–32 copies) (Table 2).
One patient with MET-amplified gastric carcinoma received crizotinib
and achieved disease control (Fig. 3).
One FGFR2-altered case also harbored a coexisting ARID1A
alteration. EGFR alterations were detected in four cases (3.4%)
consisting of two amplifications, one point mutation (F795V), and one
case with a deletion of exons 2–7 (EGFR viii). Rare RTK alterations
identified included FLT3 (amplification; one case), KIT (D716N;
one case), and FGFR3 (amplification; one case) (supplemental
online Table 1). EGFR amplifications were not exclusive of other
RTK alterations because they coexisted with FGFR2 amplification
(one case) and both MET and ERBB2 amplifications (one case). No
ROS1 alterations, including fusions, were detected. Among clinically
relevant alterations in other kinases, BRAF alterations occurred at
a frequency of 2.6%, two cases harbored D594X and one case
harbored G469V (supplemental online Table 1). Alterations in vascular
endothelial growth factor receptors 1–3 (VEGFR1–3) were limited to
KDR (VEGFR2) R275* and FLT4 (VEGFR3) S637R in all 116 GC cases,
and neither alteration has been linked to benefit from ramucirumab
[13, 15].
Overall, 501 cancer-relatedgenomic alterationswere iden-tified in 116 cases, yielding an average of 4.32 alterations persample (Table 1; Fig. 1). Of 501 GAs identified, 210 (41%) wereclinically relevant alterations, yielding an average of 1.8clinically relevant GAs per case (Table 1). Moreover, 78% ofGC cases harbored at least 1 clinically relevant variantassociated with targeted therapies approved by the U.S. Foodand Drug Administration (FDA) or mechanism-based trials(Table 2).Themost common clinically relevantGAswereKRAS,CDKN2A, CCND1, ERBB2, PIK3CA, MLL2, MET, PTEN, ATM,DNMT3A,NF1,NRAS, andMDM2 (Table 2).Themost commonGAs in the 116 cases were TP53 (58 cases, 50%), ARID1A (28cases, 24%), and CDH1 (17 cases, 15%).
Twenty-eight cases (24%) harbored loss-of-functionARID1A alterations (Fig. 2). ARID1A-altered samples harboredan increased frequencyofCREBBPvariants (p, .0005),PIK3CAvariants (p5 .0017), andMLL2 variants (p5 .019) and wereless likely to harbor TP53 variants (p , .050). In this series,tumors with ARID1A alterations had less frequent amplifica-tions of cancer-related genes compared with cases with wild-type ARID1A. This finding was statistically significant but wasnot replicated in an independent set of 192 gastric carcinomas
(data not shown). All other ARID1A findings remained sig-nificant with a type I error rate of ,.05 with a multiple hy-pothesis correction applied.
SomaticCDH1mutationswere found in6of24 (25%)diffuseGC cases compared with 11 of 92 (12%) nondiffuse GC cases(p 5 .12). Matched normal tissue was not available to inves-tigate germline CDH1 status. Enrichment of APC, CREBBP, andMLL2 alterations was observed in intestinal GC; 3 of 12 cases(25%) contained APCmutations compared with 3 of 104 cases(2.9%) ofnonintestinal GC (p5 .014).APC variantswerenotob-served inanyof the24diffuseGCcases.CREBBPwasaltered in4of 12 (33%) intestinal cases compared with 2 of 104 (1.9%)nonintestinal cases (p, .001), andMLL2was altered in 4 of 12(33%) intestinal cases compared with 4 of 104 (3.8%) nonin-testinal cases (p5 .0038).
Alterations of genes involved in mismatch repair wereobserved in this series at a frequency of 2.6% forMLH1, 0.8%for MSH2, and 0.8% for MSH6. Three of these five casesharbored truncating alterations that are predicted to causeloss of function, and no single case contained more than onealteration in this pathway. No information on microsatellitestability assessed by PCR testing was available.
Alterations in receptor tyrosine kinases (RTKs) wereharbored by 24 cases (20.6%). Ten samples (8.6%) harboredERBB2 alterations, 5 contained somatic base substitutionsand 5 harbored amplifications (6–24 copies), with theseevents being mutually exclusive. ERBB2 base substitutions inthis series consisted of R678Q (two cases), S310F (one case),L755S (one case), and V842I (one case). One case harboredboth ERBB2 R678Q and MET amplification. CDH1 alterationwas not associated with ERBB2 alteration in our GC sample(data not shown).
Seven cases (6%) harboredMET amplifications (7–30 copies)and seven cases (6%) had FGFR2 amplifications (12–32 copies)(Table 2). One patient with MET-amplified gastric carcinomareceived crizotinib and achieved disease control (Fig. 3).
One FGFR2-altered case also harbored a coexisting ARID1Aalteration. EGFR alterations were detected in four cases (3.4%)consisting of two amplifications, one point mutation (F795V),and one case with a deletion of exons 2–7 (EGFR viii). Rare RTKalterations identified included FLT3 (amplification; one case),KIT (D716N; one case), and FGFR3 (amplification; one case)(supplemental online Table 1). EGFR amplifications were notexclusive of other RTK alterations because they coexisted withFGFR2 amplification (one case) and both MET and ERBB2amplifications (one case). No ROS1 alterations, including fu-sions, were detected. Among clinically relevant alterations inother kinases,BRAF alterations occurredata frequencyof2.6%,two cases harboredD594X and one case harboredG469V (sup-plemental online Table 1). Alterations in vascular endothelialgrowth factor receptors 1–3 (VEGFR1–3) were limited to KDR(VEGFR2) R275* and FLT4 (VEGFR3) S637R in all 116 GC cases,and neither alteration has been linked to benefit from ra-mucirumab [13, 15].
DISCUSSION
Thephase III ToGA trial demonstrated thepowerofmoleculartesting to prospectively identify a molecularly defined sub-group of patients who are likely to benefit from anti-ERBB2(HER2)-directed therapy; the addition of trastuzumab to
Table 1. Clinicopathological and genomic characteristics of
116 gastric cancer cases prospectively assayed by
a comprehensive genomic profiling assay
Characteristic Result
Patient age, average, years 59.5
Sex, %
Male 44
Female 56
Histology, n (%)
Diffuse type 24 (20.7)
Intestinal type 12 (10.3)
Gastric carcinoma NOS 80 (69.0)
Histologic grade, n (%)
1 2 (1.7)
2 24 (20.7)
3 90 (77.6)
Stage, n (%)
I 4 (3.4)
II 7 (6.0)
III 21 (18.1)
IV 84 (72.4)
Site of tumor, n (%)
Primary site 80 (69)
Metastatic sitesa 36 (31)
GA
Total alterations 501
Average per sample 4.3
Clinically relevant GA 201
Clinically relevant GA per sample 1.8aIncluding ovary (n5 7), peritoneum (n5 4), omentum (n5 3), colon (n5 3), bone (n5 3), pleural fluid (n5 3), lymphnode (n5 3), ascites (n52), esophagus (n5 2), small intestine (n5 2), mesentery (n5 1), liver (n5 1), pelvis (n5 1), and soft tissue (n5 1).Abbreviations: GA, genomic alteration; NOS, not otherwise specified.
www.TheOncologist.com ©AlphaMed Press 2015
Ali, Sanford, Klempner et al. 3
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Figure 1. Tile plot of genomic alterations in 116 consecutive gastric cancer cases.
Discussion
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 standard 5-fluorouracil/platinum chemotherapy led to a statistically significant 2.5-month improvement in overall survival for ERBB2-amplified gastric cancer [8]. The methods of molecular testing, however, are also important, as demonstrated by the negative results of the TyTAN trial. In that trial, the addition of lapatinib (an oral HER2 inhibitor) to paclitaxel did not lead to significant improvement in progression-free survival or overall survival (OS) when compared with single-agent paclitaxel as second-line treatment in EBRR2-amplified GC, as determined by fluorescence in situ hybridization (FISH) alone [20]. Subgroup analysis indicated that ERBB2 amplification and immunohistochemistry (IHC) 3+ derived a significant 6.4-month improvement in overall survival. Similarly, early reporting from the LoGIC trial demonstrated OS improvements in Asian patients and those aged <60 years but failed to demonstrate an association between OS and IHC score [21]. Neither of these trials included patients with ERBB2 mutations.
In contrast, the phase III EXPAND and REAL3 trials in an unselected gastric and esophageal cancer population failed to demonstrate improvement in outcomes with the addition of the EGFR-targeted therapies cetuximab or panitumumab to chemotherapy [22, 23]. Retrospective analysis of this trial has not identified any predictive response biomarkers to date [13]. Similar negative results have also been observed in the phase III GRANITE-1 trial of everolimus in unselected advanced GC patients, and few data support empiric use of targeted and biologic agents in advanced GC [24].
Prior reports characterizing the genomic landscape of gastric carcinoma have relied on banked, therapy-naive tissue from primary resections [10, 16–18, 25, 26]. Recent work from the Cancer Genome Atlas has defined four groups of gastric carcinomas, each harboring positivity for Epstein-Barr virus (EBV), microsatellite instability, or multiple copy number amplifications while genomically stable or characterized by chromosomal instability [27]. Characteristic single-gene alterations were often but not perfectly associated with each group; EBV-positive gastric carcinomas often harbored PIK3CA alterations, and the genomically stable group often harbored RHOA alterations [27]. These groups offer insight into common etiologies but do not currently direct therapeutic decision making.
In contrast, the prospective series presented in this study reflects samples characteristic of clinical practice because the series is composed of cases from patients typically with advanced gastric carcinoma. A high percentage of cases (78%) harbor clinically relevant genomic alterations, including 1 in 5 cases (20.6%) with alterations in RTKs, suggesting the utility of comprehensive genomic profiling to match patients with targeted therapies of specific potential benefit in clinical trials (Table 2). For the common genomic alterations KRAS, ARID1A, and TP53, their clinical relevance is best linked to possible benefit from clinical trials with targeted agents. The recent FDA approval of trametinib as a MEK pathway inhibitor for melanoma has resulted in the anecdotal use of trametinib in other tumors types and assessment in clinical trials for other indications [28].
standard 5-fluorouracil/platinum chemotherapy led to a sta-tistically significant 2.5-month improvement in overall sur-vival for ERBB2-amplified gastric cancer [8]. The methods ofmolecular testing, however, are also important, as demonstratedby thenegative resultsof theTyTANtrial. In that trial, theadditionof lapatinib (an oral HER2 inhibitor) to paclitaxel did not lead tosignificant improvement in progression-free survival or overallsurvival (OS) when compared with single-agent paclitaxel assecond-line treatment in EBRR2-amplified GC, as determined byfluorescence in situ hybridization (FISH) alone [20]. Subgroupanalysis indicated that ERBB2 amplification and immunohisto-chemistry (IHC)31derivedasignificant6.4-month improvementin overall survival. Similarly, early reporting from the LoGIC trialdemonstrated OS improvements in Asian patients and thoseaged ,60 years but failed to demonstrate an association bet-ween OS and IHC score [21]. Neither of these trials included pa-tients with ERBB2mutations.
In contrast, the phase III EXPAND and REAL3 trials in anunselected gastric and esophageal cancer population failed todemonstrate improvement in outcomes with the addition ofthe EGFR-targeted therapies cetuximab or panitumumab tochemotherapy [22, 23]. Retrospective analysis of this trial hasnot identified anypredictive response biomarkers to date [13].Similar negative results have also been observed in the phaseIII GRANITE-1 trial of everolimus in unselected advanced GCpatients, and few data support empiric use of targeted andbiologic agents in advanced GC [24].
Prior reports characterizing the genomic landscape of gastriccarcinoma have relied on banked, therapy-naive tissue from pri-mary resections [10, 16–18, 25, 26]. Recentwork from theCancerGenome Atlas has defined four groups of gastric carcinomas,each harboring positivity for Epstein-Barr virus (EBV), micro-satellite instability, or multiple copy number amplificationswhile genomically stable or characterized by chromosomalinstability [27]. Characteristic single-gene alterations were of-ten but not perfectly associatedwith each group; EBV-positivegastric carcinomas often harbored PIK3CA alterations, and thegenomically stable group often harbored RHOA alterations[27].These groups offer insight into common etiologies but donot currently direct therapeutic decision making.
In contrast, the prospective series presented in this studyreflects samples characteristic of clinical practice because theseries is composed of cases from patients typically with ad-vanced gastric carcinoma. A high percentage of cases (78%)harbor clinically relevant genomic alterations, including 1 in 5cases (20.6%) with alterations in RTKs, suggesting the utility ofcomprehensive genomic profiling to match patients withtargeted therapies of specific potential benefit in clinical trials(Table 2). For the common genomic alterations KRAS, ARID1A,andTP53, theirclinical relevance isbest linkedtopossiblebenefitfromclinical trialswith targetedagents.The recent FDAapprovalof trametinib as a MEK pathway inhibitor for melanoma hasresulted in the anecdotal use of trametinib in other tumorstypes and assessment in clinical trials for other indications [28].
Figure 1. Tile plot of genomic alterations in 116 consecutive gastric cancer cases.
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4 Clinical Genomic Profiling in Gastric Cancer
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Table 2. Therapeutic implications of recurrent somatic genomic alterations in 116 clinical gastric cancer cases analyzed by prospective genomic profiling
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 development,
such kevetrin (NCT01664000), and inhibitors of chromatin remodeling. A
recent development is the paradigm of master trials, such as the Novartis
Signature Trial, with multiple agents and genomically defined entry criteria for
advanced cancers rather than restriction to a tumor type. Such a trial design
can accommodate the addition of future therapies to be developed, and
genomic profiling can provide the rationale for entering patients.
We identified five GC cases with ERBB2-activating base substitutions, which
cannot be detected by IHC or FISH [29].
The recent description of somatic ERBB2 base substitutions in breast
carcinoma and micropapillary urothelial carcinoma suggests that such
alterations may also be oncogenic drivers in GC, and at least one such breast
carcinoma patient has responded to anti-ERBB2 (HER2)-targeted therapy
[29–32]. Both ERBB2 amplifications and base substitutions were observed in
our patient series but were mutually exclusive, consistent with observations
in breast carcinoma [33]. The low frequency in this series (4.3%) of ERBB2
amplification in contrast with the 20% frequency observed in previous studies
is likely is due to a selection bias, that is, cases submitted for genomic
profiling were previously tested for ERBB2 amplification and were negative 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 lapatinib (S310F, V842I) or
resistant to lapatinib (L755S) [30]. The frequency of 4.3% was very similar to
the frequency reported in other series, confirming that no selection bias was
present because standard of care testing does not detect these clinically
relevant alterations [34, 35]. Although ERBB2 R678Q was not found to be
activating or to confer resistance to anti-ERBB2 (HER2)-targeted therapy,
it has been observed multiple times in the context of cancer, which may
indicate biologic significance.
Similarly for TP53 and ARID1A, targeted therapies are in clinicaldevelopment, such kevetrin (NCT01664000), and inhibitors ofchromatin remodeling.A recentdevelopment is theparadigmofmaster trials, such as the Novartis Signature Trial, with multipleagents and genomically defined entry criteria for advancedcancersratherthanrestrictiontoatumortype.Suchatrialdesigncan accommodate the addition of future therapies to be de-veloped, and genomic profiling can provide the rationale forentering patients.
We identified five GC cases with ERBB2-activating basesubstitutions, which cannot be detected by IHC or FISH [29].
TherecentdescriptionofsomaticERBB2basesubstitutions inbreast carcinoma and micropapillary urothelial carcinomasuggests that such alterations may also be oncogenic drivers inGC,andat leastonesuchbreastcarcinomapatienthasrespondedto anti-ERBB2 (HER2)-targeted therapy [29–32]. Both ERBB2amplifications and base substitutions were observed in our
patient series but were mutually exclusive, consistent with ob-servations in breast carcinoma [33]. The low frequency in thisseries (4.3%) of ERBB2 amplification in contrast with the 20%frequency observed in previous studies is likely is due to aselectionbias, that is, cases submitted for genomic profilingwerepreviously tested for ERBB2 amplification and were negativefor ERBB2, prompting a search for therapeutic alternatives [34].
Among ERBB2 base substitutions in this series, some havebeen functionally characterized as activating and sensitive tolapatinib (S310F, V842I) or resistant to lapatinib (L755S) [30].The frequency of 4.3% was very similar to the frequency re-ported in other series, confirming that no selection bias waspresent because standardofcare testing doesnotdetect theseclinically relevant alterations [34, 35]. Although ERBB2 R678Qwas not found to be activating or to confer resistance to anti-ERBB2 (HER2)-targeted therapy, it has been observedmultipletimes in the context of cancer, which may indicate biologic
Table 2. Therapeutic implications of recurrent somatic genomic alterations in 116 clinical gastric cancer cases analyzed by
prospective genomic profiling
GeneType ofalteration Frequency (%)
Approvedanticancer drugs
Novel targeted therapies underclinical investigation
TP53 Sub/indel 50 None None
ARID1A Sub/indel 24 None None
KRAS Sub 16 None Trametinib
CDH1 Sub/indel 15 None None
CDKN2A Sub/indel 14 None LEE011
CCND1 Amp 9.5 None LEE011, palbociclib
ERBB2 Amp, sub 8.6 Pertuzumab, trastuzumab, lapatanib Afatinib, neratinib
PIK3CA Amp, sub 8.6 Everolimus, temsirolimus BYL719, BKM120,
MLL2 Sub 6.9 None None
FGFR2 Amp 6.0 Pazopanib, ponatinib Dovitinib, AZD4547
MET Amp 6.0 Crizotinib, cabozantinib Rilotumumab, AMG337
PTEN Sub/indel 5.2 Everolimus, temsirolimus None
ATM Sub 4.3 None Olaparib
DNMT3A Sub 4.3 None Decitabine, 5-azacitidine
NF1 Sub/indel 4.3 None Trametinib, everolimus, temsirolimus
NRAS Sub 4.3 None Trametinib
MDM2 Amp 4.3 None None
BRAF Mut 2.5 Vemurafenib; dabrafenib or trametinib 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.
Figure2. Lollipopplotgraphicallydepictingthe locationofARID1Agenomicalterations in the28ARID1A-alteredgastric cancercases (onearrowhead per genomic alteration [GA] in this series, with some cases harboring several ARID1A GAs).
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Figure 3. Response to crizotinib in a patient with MET-amplified gastric cancer identified by prospective comprehensive genomic profiling. (A): Precrizotinib
FDG-avid hepatic metastasis. (B–D): Ongoing response up to 5 months after crizotinib initiation.
Activating ERBB2 base substitutions appear to be sensitive to
neratinib, suggesting a possible pathway to clinical treatment, and
genomically selected basket trials of neratinib (NCT01953926) are
ongoing for ERBB2-altered tumors [30].
Previous studies have strongly associated ERBB2-amplified gastric
carcinomas with intestinal type histology and proximal gastric location
[8, 12]. All five ERBB2-amplified GC cases in this series had histology
diagnosed as or at least suggestive of the intestinal subtype but were
approximately evenly distributed in site of origin between the proximal
and distal stomach (supplemental online Table 1). In contrast, ERBB2
base substitutions were associated with signet ring features in three of
four cases with histology available for review. The differing histology of
these cases may suggest differing clinicopathologic characteristics of
ERBB2-amplified GC compared with ERBB2 base-substituted gastric
carcinomas, but this awaits independent confirmation in a larger
series.
Alterations in the FGFR family are well recognized as oncogenic
drivers [36, 37]. FGFR2 was amplified at 6% in this GC series, similar
to a previous study [18,38]. Limited clinical studies have shown that
FGFR2-amplified breast carcinoma patients responded favorably to
dovitinib, a multikinase inhibitor that inhibits FGFR family members
[39]. For FGFR2-amplified GC, preclinical evidence suggests such
tumors are sensitive to FGFR targeted therapy, and molecularly
stratified clinical trials are ongoing (NCT01719549) [40].
Amplification of MET is a known driver of gastroesophageal and lung
carcinomas and other tumor types [38, 41, 42]. We identified MET
amplification (>6 copies) in 6% of GC cases in this series. Based
on the genomic profile, one of the patients with MET amplification
(12 copies)was treated with crizotinib and had regression of liver
metastasis and disease control for 5 months (Fig. 3). This finding
is consistent with previous results for phase I trials for crizotinib in
which two advanced gastroesophageal carcinoma patients with MET
amplifications (FISH MET/CEN7P ratio of >2.2) had partial response
and stable disease with time to progression of 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 controlling for ploidy. The threshold of six
copies for the designation of MET amplification by FoundationOne in
cases with a diploid genome can be translated as exceeding a MET/
CEP7 ratio of 2.2 (Fig. 4).
Notably, the comprehensive genomic profiling assay used in this study
(FoundationOne) provides quantitative estimates of copy number
amplifications (Fig. 4). Copy number estimates made by the genomic
profiling assay used do not directly translate to a FISH ratio per se but,
as shown by our patient response, provide clinically relevant information
that can guide use of targeted therapy (Fig. 3). Comprehensive genomic
profiling provides the advantage of simultaneous assessment of many
possible clinically relevant copy number amplifications including MET,
FGFR2, and ERBB2 while minimizing consumption of the specimen [19].
In contrast, other forms of molecular testing are hypothesis driven,that
is, a “hotspot” exon examines only specific exons of genes of interest
and is often combined with FISH to assay for amplifications (i.e., ERBB2
and MET). A focused approach offers conceptual simplicity, but for
those cases harboring relevant genomic alterations outside the scope
of such hotspot testing, genomic profiling could be done to identify
potential benefits of targeted therapy instead of expending both time
and resources on hotspot testing that might not yield information to
guide treatment.
In one of the largest screening studies for KRAS mutations involving
GC samples from U.K., Japan, and Singapore, KRAS mutations
were found in 29 of 710 GC samples (4.1%). The frequency of KRAS
mutations was 5.8% among U.K. patients, 4.0% among Japanese
patients, and 1.5% among Singapore Chinese patients. The role of
KRAS mutation in GC is unknown, but in this series, KRAS mutations
were identified in 16% of GC cases. The most common alterations
were G12V (3.4%) and G12D (2.5%), which are both transversions.
This most likely reflects a selection bias in this sample population, with
patients sent for genomic profiling having poor prognosis and possible
KRAS enrichment.
significance. Activating ERBB2 base substitutions appear to besensitive to neratinib, suggesting a possible pathway to clinicaltreatment, and genomically selected basket trials of neratinib(NCT01953926) are ongoing for ERBB2-altered tumors [30].
Previous studies have strongly associatedERBB2-amplifiedgastric carcinomas with intestinal type histology and proximalgastric location [8, 12].All fiveERBB2-amplifiedGCcases in thisseries had histology diagnosed as or at least suggestive of theintestinal subtype but were approximately evenly distributedin site of origin between the proximal and distal stomach (sup-plemental online Table 1). In contrast, ERBB2 base substitu-tions were associated with signet ring features in three offour cases with histology available for review. The differinghistology of these cases may suggest differing clinicopatho-logic characteristics of ERBB2-amplified GC compared withERBB2 base-substituted gastric carcinomas, but this awaits in-dependent confirmation in a larger series.
Alterations in the FGFR family are well recognized as on-cogenic drivers [36, 37]. FGFR2 was amplified at 6% in this GCseries, similar toapreviousstudy[18,38].Limitedclinical studieshave shown that FGFR2-amplified breast carcinoma patientsresponded favorably to dovitinib, a multikinase inhibitor thatinhibits FGFR family members [39]. For FGFR2-amplified GC,preclinical evidence suggests such tumorsare sensitive toFGFR-targeted therapy, and molecularly stratified clinical trials areongoing (NCT01719549) [40].
Amplification of MET is a known driver of gastroesoph-ageal and lung carcinomas andother tumor types [38, 41, 42].We identified MET amplification (.6 copies) in 6% of GCcases in this series. Based on the genomic profile, one of thepatients withMET amplification (12 copies) was treated withcrizotinib and had regression of liver metastasis and diseasecontrol for 5 months (Fig. 3). This finding is consistent withprevious results for phase I trials for crizotinib in which twoadvanced gastroesophageal carcinoma patients with METamplifications (FISH MET/CEN7P ratio of .2.2) had partialresponse and stable disease with time to progression of3–4months [41].The comprehensive genomic profiling assay
in this series used a process-matched normal control toquantitatively estimate the absolute copies of MET whilecontrolling for ploidy. The threshold of six copies for thedesignation of MET amplification by FoundationOne incases with a diploid genome can be translated as exceedingaMET/CEP7 ratio of 2.2 (Fig. 4).
Notably, the comprehensive genomic profiling assay used inthis study (FoundationOne) provides quantitative estimates ofcopy number amplifications (Fig. 4). Copy number estimatesmadebythegenomicprofilingassayuseddonotdirectlytranslateto a FISH ratio per se but, as shown by our patient response,provide clinically relevant information that can guide use oftargeted therapy (Fig. 3). Comprehensive genomic profilingprovides the advantage of simultaneous assessment of manypossible clinically relevant copy number amplifications includingMET, FGFR2, and ERBB2 while minimizing consumption of thespecimen [19]. In contrast, other forms of molecular testing arehypothesisdriven,that is,a“hotspot”exonexaminesonlyspecificexons of genes of interest and is often combined with FISH toassay for amplifications (i.e., ERBB2 and MET). A focusedapproach offers conceptual simplicity, but for those cases har-boring relevant genomic alterations outside the scope of suchhotspot testing, genomic profiling could be done to identifypotential benefits of targeted therapy instead of expending bothtime and resources on hotspot testing that might not yield in-formation to guide treatment.
In one of the largest screening studies for KRAS mutationsinvolving GC samples from U.K., Japan, and Singapore, KRASmutations were found in 29 of 710 GC samples (4.1%). ThefrequencyofKRASmutationswas5.8%amongU.K.patients,4.0%among Japanese patients, and 1.5% among Singapore Chinesepatients.The role of KRASmutation in GC is unknown, but in thisseries, KRAS mutations were identified in 16% of GC cases. Themost common alterations were G12V (3.4%) and G12D (2.5%),which are both transversions.This most likely reflects a selectionbias in this sample population, with patients sent for genomicprofiling having poor prognosis and possible KRAS enrichment.
Figure 3. Response to crizotinib in a patient with MET-amplified gastric cancer identified by prospective comprehensive genomicprofiling. (A): Precrizotinib FDG-avid hepatic metastasis. (B–D): Ongoing response up to 5 months after crizotinib initiation.
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Figure 4. Copy number alteration plots for several cases harboring receptor tyrosine kinase amplifications.
Alterations in the tumor suppressors TP53 and ARID1A are common in gastric cancer. ARID1A encodes the AT-rich interactive domain-containing protein 1A, a member of the SWI/SNF chromatin-remodeling complex. Inactivating alterations in ARID1A are frequent in ovarian clear cell carcinomas, neuroblastomas, and gastric carcinomas and loss of expression in other tumor types, consistent with the hypothesized tumor suppressor role of this protein [43, 44]. Alterations of ARID1A in this series did not cluster around a hotspot (Fig. 2). The statistically significant enrichment of PIK3CA and the paucity of TP53 alterations in the set of ARID1A-altered GCs are consistent with previous findings in gastric carcinoma [43, 45]. In our series, ARID1A-altered cases were also enriched for CREBBP and MLL2 alterations.
Interestingly, our series identified somatic CDH1 mutation rates (25% diffuse, 12% nondiffuse) higher than previously reported (Fig. 5) [46]. The differences in alteration frequency may be related to the interrogation of the entire coding sequence of CDH1 in this assay compared with the limited hotspot assessment of exon 7–10 hotspot interrogation in prior series [46, 47]. CDH1 somatic mutation has been correlated with the shortest survival in GC, and selection bias may underlie increased CDH1 mutation rates in this series because clinicians may be likely to reach for mutational profiling when options are limited [46]. In reporting these results, caveats for directed germline testing are included.
Neither BRAF V600E or V600M alterations previously described in GC were observed in this series, but three nonBRAFV600 mutations were found in this series [13, 48–50] (supplemental online Table 1). The BRAF alterations in these series are variable activators of BRAF.
Interestingly, no alterations in VEGFR1–3 were identified in this series. Ramucirumab has been shown to improve OS in GC in second-line treatment as a single agent or in combination with paclitaxel. Ramucirumab is a monoclonal antibody against VEGFR2, but, like other antiangiogenic therapies, there are no clear predictive biomarkers [51, 52]. Current evidence is insufficient to examine whether VEGFR1–3 alterations serve as biomarkers for ramucirumab.
Identifying clinically relevant alterations in the course of clinical care of gastric carcinoma may drive clinical decisions making, which in turn will generate preliminary data on the efficacy of targeted therapies in gastric carcinoma and care of future patients and will support future systematic investigation through clinical trials. At present, most suggestion of benefit from targeted therapy in gastric carcinoma is guided by analogy to other tumor types. Such reasoning highlights the limitations of this approach, for example, BRAF V600E-mutant colorectal adenocarcinoma has not suggested benefit from vemurafenib monotherapy [53, 54].
Alterations in the tumor suppressors TP53 and ARID1A arecommon in gastric cancer. ARID1A encodes the AT-rich in-teractive domain-containing protein 1A, a member of theSWI/SNF chromatin-remodeling complex. Inactivating alter-ations in ARID1A are frequent in ovarian clear cell carcinomas,neuroblastomas, and gastric carcinomas and loss of expressionin other tumor types, consistent with the hypothesized tumorsuppressor role of this protein [43, 44]. Alterations of ARID1Ain this series did not cluster around a hotspot (Fig. 2). Thestatistically significant enrichment of PIK3CA and the paucity ofTP53 alterations in the set of ARID1A-altered GCs areconsistent with previous findings in gastric carcinoma [43, 45].In our series,ARID1A-altered caseswere also enriched forCREBBPandMLL2 alterations.
Interestingly, our series identified somatic CDH1mutationrates (25% diffuse, 12% nondiffuse) higher than previouslyreported (Fig. 5) [46]. The differences in alteration frequencymay be related to the interrogation of the entire coding se-quence of CDH1 in this assay compared with the limitedhotspot assessment of exon 7–10 hotspot interrogation inprior series [46, 47]. CDH1 somatic mutation has been cor-related with the shortest survival in GC, and selection biasmay underlie increased CDH1 mutation rates in this seriesbecause clinicians may be likely to reach for mutational
profiling when options are limited [46]. In reporting theseresults, caveats for directed germline testing are included.
Neither BRAF V600E or V600M alterations previouslydescribed in GC were observed in this series, but threenonBRAFV600mutations were found in this series [13, 48–50](supplemental online Table 1). The BRAF alterations in theseseries are variable activators of BRAF.
Interestingly, noalterations inVEGFR1–3were identified inthis series. Ramucirumab has been shown to improveOS inGCin second-line treatment as a single agent or in combinationwithpaclitaxel.Ramucirumab isamonoclonalantibodyagainstVEGFR2, but, like other antiangiogenic therapies, there are noclear predictive biomarkers [51, 52]. Current evidence is in-sufficient to examine whether VEGFR1–3 alterations serve asbiomarkers for ramucirumab.
Identifying clinically relevant alterations in the course ofclinical care of gastric carcinoma may drive clinical decisionsmaking, which in turn will generate preliminary data on theefficacy of targeted therapies in gastric carcinoma and care offuture patients andwill support future systematic investigationthrough clinical trials. At present, most suggestion of benefitfrom targeted therapy in gastric carcinoma is guided by analogyto other tumor types. Such reasoning highlights the limitationsof this approach, for example, BRAF V600E-mutant colorectal
Figure 4. Copy number alteration plots for several cases harboring receptor tyrosine kinase amplifications.
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Figure 5. Lollipop plot graphically depicting the location of CDH1 genomic alterations (GAs) in the 17 CDH1-altered gastric cancer cases (one
arrowhead per GA in this series). Abbreviation: TM, transmembrane.
Because new approaches such as the combination of vemurafenib
and erlotinib confer some benefit to similar patients, as noted,
it is hoped that analogous approaches can also benefit gastric
carcinoma patients [54].
Conclusion
The high frequency of clinically relevant genomic alterations in
this patient population reflective of routine clinical practice is
encouraging in a disease that continues to have a poor prognosis
with modern chemotherapy. The clinically relevant alterations
identified by this assay beyond those detected by standard of case
can drive increased clinical trial participation and development (e.g.,
ERBB2 base substitutions, MET amplifications) and clarify predictive
response and resistance biomarkers.
Acknowledgments
We acknowledge important contributions from other researchers that
could not be cited due to space constraints. No external funding or
grant support was involved in this study. This work is dedicated to the
patients profiled in this report. G.A.P. is currently affiliated with Nant
Health, Culver City, CA.
Author Contributions
Conception/Design: Siraj M. Ali, Eric M. Sanford, Juliann Chmielecki,
Vincent A. Miller
Provision of study material or patients: Daniel V. Catenacci, Fadi
Braiteh, Sai-Hong Ignatius Ou
Collection and/or assembly of data: Siraj M. Ali, Eric M. Sanford, Kai
Wang, Roman Yelensky, Doron Lipson, Daniel V. Catenacci, Fadi Braiteh,
Philip J. Stephens, Jeffrey S. Ross
Data analysis and interpretation: SirajM.Ali, EricM.Sanford, KaiWang,
Norma A. Palma, JuliannChmielecki, Roman Yelensky, Gary A. Palmer,
Doron Lipson, Daniel V. Catenacci, Jeffrey S. Ross, Sai-Hong Ignatius Ou
Manuscriptwriting: Siraj M. Ali, Eric M. Sanford, Samuel J. Klempner,
Douglas A. Rubinson, Kai Wang, Norma A. Palma, Juliann Chmielecki,
Gary A. Palmer, 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.
Ross, Vincent A. Miller
Disclosures
Siraj M. Ali: Foundation Medicine Inc. (E, OI); Eric M. Sanford:
Foundation Medicine Inc. (E, OI); Kai Wang: Foundation Medicine
Inc. (E, OI); Norma A. Palma: Foundation Medicine Inc. (E, OI);
Juliann Chmielecki: Foundation Medicine Inc. (E, OI); Roman
Yelensky: Foundation Medicine Inc. (E, IP); Gary A. Palmer:
Foundation Medicine Inc. (E, OI); Deborah Morosini: Foundation
Medicine Inc. (E, OI); Doron Lipson: Foundation Medicine
Inc. (E, OI, IP); Daniel V. Catenacci: Foundation Medicine Inc.
(C/A); Fadi Braiteh: Foundation Medicine, Caris Life Sciences,
Genomic Health, Molecular Health (C/A); Amgen, Bayer, Pfizer,
BMS, Celgene, Insys, incyte, Caris Life Sciences, Genomic Health
(H); Rachel Erlich: Foundation Medicine 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.
(C/A) Consulting/advisory relationship; (RF) Research funding; (E) Employment; (ET) Expert testimony; (H) Honoraria received; (OI) Ownership interests; (IP) Intellectual property rights/inventor/patent holder; (SAB) Scientific advisory board
adenocarcinoma has not suggested benefit from vemurafenibmonotherapy [53, 54]. Because new approaches such as thecombination of vemurafenib and erlotinib confer some benefitto similar patients, as noted, it is hoped that analogous ap-proaches can also benefit gastric carcinoma patients [54].
CONCLUSIONThehigh frequencyof clinically relevant genomic alterations inthis patient population reflective of routine clinical practice isencouraging in a disease that continues to have a poor prognosiswith modern chemotherapy. The clinically relevant alterationsidentified by this assay beyond those detected by standard ofcase can drive increased clinical trial participation and de-velopment (e.g., ERBB2base substitutions,MET amplifications)and clarify predictive response and resistance biomarkers.
ACKNOWLEDGMENTS
Weacknowledge important contributions fromother research-ers that could not be citeddue to space constraints. No externalfunding or grant support was involved in this study. This workis dedicated to the patients profiled in this report. G.A.P. iscurrently affiliated with NantHealth, Culver City, CA.
AUTHOR CONTRIBUTIONSConception/Design: SirajM. Ali, EricM. Sanford, Juliann Chmielecki,Vincent A.Miller
Provision of study material or patients: Daniel V. Catenacci, Fadi Braiteh, Sai-Hong Ignatius Ou
Collection and/or assembly of data: Siraj M. Ali, Eric M. Sanford, Kai Wang,Roman Yelensky, Doron Lipson, Daniel V. Catenacci, Fadi Braiteh, Philip J.Stephens, Jeffrey S. Ross
Dataanalysis and interpretation: SirajM.Ali, EricM.Sanford,KaiWang,NormaA. Palma, Juliann Chmielecki, RomanYelensky, Gary A. Palmer, Doron Lipson,Daniel V. Catenacci, Jeffrey S. Ross, Sai-Hong Ignatius Ou
Manuscriptwriting:SirajM.Ali, EricM.Sanford,Samuel J. Klempner,DouglasA.Rubinson, Kai Wang, Norma A. Palma, Juliann Chmielecki, Gary A. Palmer,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. Ross,Vincent A. Miller
DISCLOSURES
Siraj M. Ali: Foundation Medicine Inc. (E, OI); Eric M. Sanford:FoundationMedicine Inc. (E,OI);KaiWang: FoundationMedicine Inc.(E, OI); Norma A. Palma: Foundation Medicine Inc. (E, OI); JuliannChmielecki: Foundation Medicine Inc. (E, OI); Roman Yelensky:Foundation Medicine Inc. (E, IP); Gary A. Palmer: FoundationMedicine Inc. (E, OI); Deborah Morosini: Foundation Medicine Inc.(E, OI); Doron Lipson: Foundation Medicine Inc. (E, OI, IP); Daniel V.Catenacci: Foundation Medicine Inc. (C/A); Fadi Braiteh: FoundationMedicine, Caris Life Sciences, Genomic Health, Molecular Health(C/A); Amgen, Bayer, Pfizer, BMS, Celgene, Insys, incyte, Caris LifeSciences, Genomic Health (H); Rachel Erlich: Foundation MedicineInc. (E,OI);Philip J. Stephens:FoundationMedicine Inc. (E,OI); JeffreyS. Ross: Foundation Medicine Inc. (RF, E, OI, IP); Vincent A. Miller:Foundation Medicine Inc. (E, OI). The other authors indicated nofinancial relationships.(C/A) Consulting/advisory relationship; (RF) Research funding; (E) Employment; (ET) Expert
testimony; (H) Honoraria received; (OI) Ownership interests; (IP) Intellectual property rights/
inventor/patent holder; (SAB) Scientific advisory board
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Figure 5. Lollipop plot graphically depicting the location of CDH1 genomic alterations (GAs) in the 17 CDH1-altered gastric cancer cases(one arrowhead per GA in this series).
Abbreviation: TM, transmembrane.
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9. Wadhwa R, Song S, Lee JS et al. Gastric cancer molecular and clinical dimensions. Nat Rev Clin Oncol 2013;10:643–655.
10. Comprehensive molecular characterization of urothelial bladder carcinoma. Nature 2014;507:315–322.
11. Gravalos C, Jimeno A. HER2 in gastric cancer: A new prognostic factor and a novel therapeutic target. Ann Oncol 2008;19:1523–1529.
12. Hu B, El Hajj N, Sittler S et al. Gastric cancer: Classification, histology and application of molecular pathology. J Gastrointest Oncol 2012;3:251–261.
13. Okines AF, Gonzalez de Castro D, Cunningham D et al. Biomarker analysis in oesophagogastric cancer: Results from the REAL3 and TransMAGIC trials. Eur J Cancer 2013;49:2116–2125.
14. Smyth EC, Cunningham D. Gastric cancer in 2012: Defining treatment standards and novel insights into disease biology. Nat Rev Clin Oncol 2013;10:73–74.
15. Fuchs CS, Tomasek J, Yong CJ et al. Ramucirumab monotherapy for previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (REGARD): An international, randomised, multicentre, placebo-controlled, phase 3 trial. Lancet 2014;383:31–39.
16. Wang K, Kan J, Yuen ST et al. Exome sequencing identifies frequent mutation of ARID1A in molecular subtypes of gastric cancer. Nat Genet 2011;43:1219–1223.
17. Dulak AM, Schumacher SE, van Lieshout J et al. Gastrointestinal adenocarcinomas of the esophagus, stomach, and colon exhibit distinct patterns of genome instability and oncogenesis. Cancer Res 2012;72:4383–4393.
18. Deng N,Goh LK,Wang H et al. A comprehensive survey of genomic alterations in gastric cancer reveals systematic patterns of molecular exclusivity and co-occurrence among distinct therapeutic targets. Gut 2012;61:673–684.
19. Frampton GM, Fichtenholtz A, Otto GA et al. Development and validation of a clinical cancer genomic profiling test based on massively parallel DNA sequencing. Nat Biotechnol 2013;31:1023–1031.
20. Satoh T, Xu RH, Chung HC et al. Lapatinib plus paclitaxel versus paclitaxel alone in the second-line treatment of HER2-amplified advanced gastric cancer in Asian populations: TyTAN—a randomized, phase III study. J Clin Oncol 2014;32:2039–2049.
21. Hecht JR, Bang Y-J, Qin S et al. Lapatinib in combination with capecitabine plus oxaliplatin (CapeOx) in HER2-positive advanced or metastatic gastric, esophageal, or gastroesophageal adenocarcinoma (AC): The TRIO-013/LOGiC trial. J Clin Oncol 2013;31(suppl):LBA4001a.
22. Lordick F, Kang YK, Chung HC et al. Capecitabine and cisplatin with or without cetuximab for patients with previously untreated advanced gastric cancer (EXPAND):A randomised, open-label phase 3 trial. Lancet Oncol 2013;14:490–499.
23. Waddell T, Chau I, Cunningham D et al. Epirubicin, oxaliplatin, and capecitabine with or without panitumumab for patients with previously untreated advanced oesophagogastric cancer (REAL3): A randomised, open-label phase 3 trial. Lancet Oncol 2013;14:481–489.
24. Ohtsu A, Ajani JA, Bai YX et al. Everolimus for previously treated advanced gastric cancer: Results of the randomized, double-blind, phase III GRANITE-1 study. J Clin Oncol 2013;31:3935–3943.
25. Yamamoto H, Watanabe Y, Maehata T et al. An updated review of gastric cancer in the next generation sequencing era: Insights from bench to bedside and vice versa. World J Gastroenterol 2014; 20:3927–3937.
26. Wang K, Yuen ST, Xu J et al. Whole-genome sequencing and comprehensive molecular profiling identify new driver mutations in gastric cancer. Nat Genet 2014;46:573–582.
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.
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A FALSE POSITIVE MECKEL’S SCAN IN A YOUNG WOMAN WITH IRON DEFICIENCY ANAEMIAK WM Abeysekera, B Bunsa, N Beharry*, A Poullis.
Department of Gastroenterology and Radiology*St George’s Hospital, London
Case report
A 40 year old Indian woman who was referred initially to
Haematology Clinic having been found to have thrombocytosis
with a platelet count consistently above 500x109/l and IDA
with a ferritin of 17 µg/l by her general practitioner. On further
questioning she described a 3-year history of left iliac fossa
pain that was mild and never precipitated her to present to a
clinician previously. It had been relieved with non-steroidal anti-
inflammatories. She denied any history of vomiting, diarrhoea or
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
cyst removed at the age of 15 in India. Her only other medication included
the combined oral contraceptive pill. She had no family history of note
including colorectal cancer. She had moved to the UK in 2010 and visited
relatives in India annually. She worked as a nanny and was not vegetarian.
Her clinical examination was entirely unremarkable.
The Haematology team had tested her JAK-2 status, which was normal
and performed a trephine bone marrow biopsy, which showed normo-
cellular marrow and no evidence of a primary haematological disorder.
Her IDA was treated with a Ferinject™ (ferric carboxymaltose) infusion
following a failure to tolerate oral replacement.
In view of her normal haematology examination she was referred to the
gastroenterology clinic. The patient had a normal coeliac screen and
autoimmune screen. An oesophago-gastro duodenoscopy (OGD) was
performed which was macroscopically normal, with normal duodenal
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
scan was organized which identified a faint focus of tracer activity
demonstrated in the right side of the lower abdomen, and was felt to be
suspicious of functioning ectopic gastric mucosa within the distal ileum
(Figure 1).
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
cells were seen. Ziehl-Neelsen and fungi staining were negative as was
immunostaining for cytomegalovirus. However, despite a negative acid-
fast bacilli microscopy, Mycobacterium tuberculosis was isolated after
16 days of incubation with the tuberculosis polymerase chain reaction
sent also returning positive for Mycobacterium tuberculosis. The patient
was referred to the TB team and was been commenced on quadruple
therapy (Rifampicin, Pyrazinamide, Ethambutol, Isoniazid) for abdominal
tuberculosis. At follow up her abdominal symptoms have all resolved.
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 pre-
menopausal iron deficiency anaemia are not as meticulous as they
are in the post-menopausal state when a greater focus is placed
on detecting a neoplastic lesion due to the greater incidence of
colorectal cancer in women over the age of 50, with 95% of all
bowel cancers diagnosed after this age.2
The British Society of Gastroenterology (BSG) published clear
guidelines on the management of IDA in 2011.3 As happened with
our patient, her coeliac serology was tested which was negative.
Because she had vague abdominal pain she proceeded to have
an oesophago-duodenoscopy, which was normal. Our patient had
initially been referred to Haematology for a thrombocytosis as
well as IDA, so her JAK2 status and bone marrow were examined
to rule out essential thrombocythaemia. As this patient had no
family history of colorectal carcinoma she did not proceed to
colonoscopy, and she received appropriate iron replacement
therapy.
It was in view of her ongoing non-specific lower abdominal pain and
IDA despite iron replacement that a Meckel’s scan was organised
to rule out a Meckel’s diverticulum. Meckel’s scans are used to
detect the ectopic gastric mucosa in patients with symptomatic
Meckel’s diverticulum. Utilising the physiological mimicry that exists
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with ectopic gastric mucosa secreting chloride into the intestinal
lumen, Technetium-99m (99m Tc) pertechnetate acts as an analogue
of chloride. This allows the radiolabelled isotope to be secreted into
the intestinal lumen, which is highlighted on a scan. 4-6
Our patient had a positive scan within the terminal ileum/caecum,
with a radiological report commenting that this could indeed be a
false positive result, reflecting underlying Crohn’s disease, given
the history of abdominal pain and IDA. Meckel’s scans have a
specificity of 95% and sensitivity of 85% however this diminishes
after adolescence.7 False positive Meckel’s scans have a wide
differential. Any tissue containing ectopic gastric mucosa will be
detected on scan. Focal small bowel pathology such as Crohn’s,
abdominal abscesses or intussusception can be highlighted. It is
hypothesised this is related to localized hyperaemia associated
with these conditions. 4-7 Other causes include neoplastic lesions
e.g. colorectal carcinoma, leiomyosarcoma, ileal carcinoid
and vascular malformations such as haemangiomas and A-V
malformation. As 99m Tc pertechnetate is excreted renally, genito-
urinary false positive foci such as an extrarenal pelvis, horseshoe
kidneys, ureteric obstruction can be falsely identified as a positive
result. Occasionally iatrogenic causes such as laxatives and
endoscopy can causes false positive results, again postulated to
be due to hyperaemia caused by localized inflammation.7
Following the Meckel’s scan, the decision to perform colonoscopy
was taken. This identified caecal ulceration which whilst
macroscopically looking like Crohn’s disease, cultures and PCR
identified underlying abdominal TB. This has never previously been
documented as a cause of false positive Meckel’s scan result. It is
hypothesised that was likely caused by the chronic inflammation
creating a localised hyperaemia. Abdominal TB needs to be
considered within the differential of alternative causes for a false
positive Meckel’s scan in any patient that has travelled from an area
of endemic TB.
This case also poses the question regarding colonoscopy in young
women and whether it should have been performed earlier, given
that it elucidated the aetiology of this patient’s pathology through
cultures and PCR of the lesion. This is a controversial topic, not
least because sinister diagnoses like colorectal carcinoma in pre-
menopausal women are an elusive diagnosis and an emotional
topic.8 BSG guidelines highlight that dual upper and lower GI
pathology, while uncommon, does occur in 1-10% of patients.9-11
Whilst recto-sigmoid colorectal carcinoma remains the commonest
tumour 12, younger patients, especially those with ascending colon
cancers, often present late.13
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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.
>>>
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 pre-menopausal 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
Summary
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.
References:
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.
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
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.
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.
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ScheBo_GastroToday_Orange
Her way out......of chronic
constipation
Resolor® is indicated for symptomatic treatment of chronic constipationin 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 infl ammatory conditions of the intestinal tract, severe and clinically unstable concomitant diseases.
Her way out......of chronic...of chronic...of
constipationconstipation
NICE GUIDANCEPUBLISHED 1
Prescribing Information(Please refer to the full Summary of ProductCharacteristics before prescribing).
RESOLOR® (prucalopride)Selective serotonin (5-HT4) receptor agonist, enterokinetic agent, available as 1 mg and 2 mg fi lm-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 effi cacy 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 effi cacy 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 infl ammatory 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 effi cacy 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 effi cacy of oral contraceptives may be reduced and an additional contraceptive method is recommended. Contains lactose monohydrate. Patients with galactose intolerance, Lapp lactase defi ciency 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 fi rst 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 fi rst 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.
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).
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
00020-06 Resolor_GastroToday_297x210_AW.indd 1 26/05/2015 12:32
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• special INFAI test for patients with dyspepsia taking PPIs
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Phone +44 1904 435 228 - Fax +44 1904 435 229 - mail: [email protected] - Visit us at www.infai.com
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CASE REPORT
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AN UNUSUAL CASE OF BREATHLESSNESS: HEPATIC HYDROTHORAX
M Moore; S Chatu; A Saxena
Kings College Hospital, London, UK
Key Words: Chronic liver disease, pleural effusion, hepatic hydrothorax, refractory hydrothorax, cirrhosis
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
history of worsening breathlessness rendering her dyspnoeic at rest.
She did not report a cough, haemoptysis, fevers or chest pain and
there was no history of primary cardio-respiratory disorders. There was
no history of lower limb swelling or abdominal distension.
On examination she was breathless at rest. Her oxygen saturations
were 93% despite FiO2 of 60%. Her respiratory rate was 35 breaths per
minute, pulse rate 86 and blood pressure was 152/83 with no pyrexia.
There were peripheral stigmata of chronic liver disease. Respiratory
examination revealed reduced expansion of the right hemi-thorax,
with dull percussion note, reduced air-entry and reduced whispering
pectoriloquy. The trachea was deviated to the left. Heart sounds were
normal; there was no ascites or lower limb oedema.
Subsequent investigations included an arterial blood gas (ABG)
revealing type 1 respiratory failure with a pH 7.47, PO2 9.31 and PCO2
3.80 on supplemental oxygen with FiO2 of 60%.Laboratory results
revealed a CRP of 8.6 (normal ranges in brackets). , WBC 12.24,
eGFR >90 INR 1.52 and Bilirubin 170, ALP 121 AST 127 and gamma
GT 98. A chest x-ray (figure 1) demonstrated a complete whiteout of
the right lung consistent with a large right-sided pleural effusion with
contralateral mediastinal shift.
An ultrasound (USS) of the thorax confirmed a massive pleural effusion
(figure 1). Consequently, a 12F Seldinger chest drain was inserted
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
pH was 7.5 making an empyema unlikely. Following drainage of the
pleural effusion the patient’s breathlessness resolved.
A repeat chest x-ray was performed (figure 2) demonstrating
effective drainage of the pleural effusion. Liver USS confirmed
cirrhosis but there was no evidence of ascites, portal vein thrombosis
or hepatocellular carcinoma. A CT chest was subsequently
ordered excluding any underlying pulmonary pathology. An
oesophagogastroduodenoscopy (OGD) demonstrated oesophageal
varices and mild portal hypertensive gastropathy. A gastroenterology
opinion was sought and evaluation led to a diagnosis of a right hepatic
hydrothorax.
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
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.
Discussion and review of the literature
This case demonstrates an atypical presentation of an uncommon
condition. Hepatic hydrothorax is another manifestation of
extracellular fluid accumulation in patients with liver cirrhosis in
addition to ascites. Due to the lack of large randomized-controlled
trials, the prevalence of hepatic hydrothorax has been estimated to
be between 5-6%1. This has been based on an assortment of varying
frequencies being reported, such as autopsy and case reports9.
Defining features include established liver cirrhosis from any cause in
the context of a transudate pleural effusion > 500ml with no primary
cardiopulmonary disease2. Concurrent ascites has been reported in
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
literature since this is the case in the majority of patients 3-4.
There are several proposed mechanisms in the development
of a hepatic hydrothorax. The pathogenesis is thought to be
the same as developing ascites. It has been suggested that
hypoalbumineamia, azygos vein hypertension and arterial splanchnic
dilatation all cumulatively contribute to fluid accumulation. Arterial
splanchnic dilatation causes a fall in arterial blood volume, creating
an accumulation of fluid4. Consequent activation of the renin-
angiotensin-aldosterone system causes activation of sympathetic
nervous system and vasopressin release4.
These mechanisms do not explain the predilection to the right
lung, nor the absence of ascites. This has been attributed to
diaphragmatic defects categorised into four morphologies. This
includes small herniations, called pleuroperitoneal blebs, which
create communications between the peritoneal and pleural cavities4.
The right hemi-diaphragm is not as muscular and robust as the
left; blebs are also more common on the right side4. Negative
intrathoracic pressure during inspiration causes a migration of fluid.
Hydrothoraces occur when the pleural membranes exceed their
capacity to absorb the fluid creating the effusion5.
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CASE REPORT
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Initial management in this case was symptom control. The constrictive
nature of the pleural cavity means a small amount of fluid can cause
dramatic symptoms, unlike ascites where many litres of fluid may
accumulate. This patient drained an impressive 5 litres. Therapeutic
thoracentesis is the most effective method for symptom relief4. Current
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
to the rare nature of this condition there are few studies that have looked
at transplantation for patients with hepatic hydrothorax, uncomplicated or
complicated1. Despite this, the evidence shows that transplantation is the
best therapeutic option for permanent resolution of hepatic hydrothorax,
and has been associated with significant long-term survival rates7-8.
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
4. Hepatic hydrothorax Siddappa PK, Far P Trop Gastroenterol 2009 Jul-Sep; 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;18:672–675
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;24:281–284.
Figure 1. Figure 2.
Over 30 years of research and development in GI medicine
Tillotts Pharma firsts: GI health is our passion
New triethyl citrate formulationFor mild to moderate ulcerative colitisPrescribing information and references can be found overfleaf.
n Tillotts Pharma MR mesalazine is marketed in 47 countries2
n 2 million patient years’ experience3
n Tillotts’ pH-dependent mesalazine formulation is the most widely used around the world2,4
– Tillotts 800mg MR mesalazine is the biggest selling 800mg MR mesalazine formulation in Europe5
Milestones
1963 2002(Europe)
2010(UK)
2008(UK)
1985(UK)
1987(Europe)
2006(UK)
2014Tillotts est. in the UK
Developed and launched the first 800mg modified-release mesalazine
Obtained once-daily licence for 800mg dose
Developed and launched the first 400mg modified-release mesalazine
Studied the utility of 4.8g/day1
Launched 400mg pH-dependent mesalazine containing triethyl citrate to align with Europe
Launched the first integrated care pathway for mild to moderate ulcerative colitis in the UK
The first 400mg pH-dependent mesalazine containing triethyl citrate
Launched online patient support programme
1st 1st 1st 1st
2015(UK)
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24007_Tillotts First Ad_Gastro Today_AW.indd 1 25/03/2015 09:43
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
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
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
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,
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MEETING REPORT
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COELIAC UK’S RESEARCH CONFERENCE, HELD AT ROYAL COLLEGE OF PHYSICIANS, MARCH 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 follow-up 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.
UK/OC/0015/0215. Date of preparation: March 2015.
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].
ww
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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.
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to restore celiac patients’ immune tolerance to gluten, reduce
inflammation in the nutrient-absorbing villi that line the small
intestine, return the intestine to a healthy state, and allow patients to
eat a normal diet. (It is noted that there are other immunotherapies
in development by a variety of companies, but at the time of writing
none have successfully completed phase III studies.)
Dr Daniel Adelman, Chief Medical Officer at Alvine Pharmaceuticals,
Inc. from San Francisco presented information on gluten degradation
by ALV003, a novel drug candidate for CD. He reminded the
audience that at the moment the only treatment option for CD is
a lifelong adherence to a gluten free diet (GFD), but this brings
with it many complications and limitations to normal life quality.
Villous height/crypt depth ratio is an important marker of success
in management of CD and based on this outcome, it seems that
GFD may not be a totally adequate answer. A recent abstract in
Gastroenterology tells us that ALV003 consists of 2 co-administrated
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
alone. ALV003 proteolyzes various forms of gluten such as purified
gliadin (as well as secalins and hordeins), uncooked gluten flour and
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
play a role in gluten related disorders?’
Elafin is an immunomodulatory serine protease inhibitor found in
epithelial surfaces and has a potent inhibitory effect against various
forms of pro-inflammatory elastases as well as proteinase-3. It
shows an abnormally low expression in IBD patients. It was thought
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
mechanisms of CD.
Dr Luud JWJ Gilissen, researcher at Wageningen University and
research centre, The Netherlands told the audience about plant
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
wheat and changes in breeds have increased the number of
identifiable proteins and hence there is also non coeliac wheat
sensitivity. There is a correlation, she said, with irritable bowel
syndrome, with 30% improving on a GFD and the Low FODMAP Diet
(FODMAP=Fermentable Oligo-Di-Monosaccharides and Polyols)
FODMAPs are carbohydrates (sugars) that are found in foods. Not
all carbohydrates are considered FODMAPs but spelt wheat is low in
FODMAPS. Apparently, there is wheat content in 30% of supermarket
foods but that which is in bread, has been genetically selected and
currently the search is on for synthetic hexaploid wheats where it may
be possible to reduce or separate gliadin. It is interesting to note that
sourdough breads, popular in Germany are safe for CD patients as
there is breakdown of the culprit peptides in the bakery process.
He suggested a number of potential strategies to reduce the
incidence of CD, including:
• Improvement of the GFD so that the health of individuals with
persistent symptoms and villous atrophy despite adherence to
a GFD.
• 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
uncontaminated gluten-free oats as none of the gluten epitopes
known from wheat, barley and rye occur in oats.
• 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
involved. As well at the traditional GFD, there are now potential
immunotherapeutic and enzyme active agents which have the
potential to allow CD patients to access a normal diet, but none of
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
References
Coeliac UK Research Conference 2015, Abstract book.
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)
Glutenase ALV003 Attenuates Gluten-Induced Mucosal Injury in Patients With Celiac Disease, Gastroenterology, June 2014 Volume 146, Issue 7, Pages 1649–1658
Immunosant and Alvine Pharmaceuticals websites.
MEETING REPORT
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ADVERTORIAL
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NEW ADVANCES IN VIDEO ENDOSCOPYKARL STORZ is a fairly recent entrant in to the GI flexible video endoscopy market although the company has been making flexible endoscopes for other disciplines for many years. Well known as a market leader in surgical rigid endoscopy and imaging systems, KARL STORZ has recently launched their new generation ‘SILVER SCOPE®’ GI video endoscope range into the UK market and has linked this launch to their latest modular endoscopic HD camera system – IMAGE1 SPIES™. Looking at the GI SILVER SCOPE® range the most obvious visual differences are the silver grey ergonomically designed control bodies with their ‘silk touch’ coating, however the design improvements are more than merely aesthetic:
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NEWS
NEWS
Dutch scientists build colon cancer progression model
Utrecht, April 30,2015 - Scientists from
the Hubrecht Institute and the University
Medical Center Utrecht (UMC Utrecht)
have developed a cell culture model of
human colon cancer progression. This
model mimics the situation in patients
more closely than any other colon cancer
model so far. It enables researchers to
study processes involved in colon cancer
development and find new cancer drugs.
The work by Clevers and colleagues is
published online in Nature this week.
Colon cancer is one of the most common
and deadly forms of cancer. Like all cancers,
it arises through an accumulation of DNA
changes (mutations) in the cell’s genome
(the genetic information in a cell). In
contrast to healthy cells, many colon cancer
cells have very unstable genomes and
generally contain hundreds to thousands
of mutations. This makes it difficult to
determine which mutations are essential for
cancer development and survival. Those
mutations could be targeted for therapeutic
intervention. However, until now no good
human model systems to study such
mutations exist.
Organoids
The recent development of the organoid
technology by the research group of Hans
Clevers allows the culturing of healthy
human tissues under laboratory conditions.
Organoids functionally recapitulate the organ
of origin and are genetically stable. Utilizing
this technology, the Clevers lab has now
successfully engineered a colon cancer
progression model in organoids from human
small intestine and colon.
Genome editing
Jarno Drost, researcher in Hans Clevers’
research group, and his colleagues utilized
the genome editing system CRISPR/Cas9
to introduce specific mutations in four of
the most commonly altered genes in colon
cancer (KRAS, APC, TP53 and SMAD4) and
performed an in-depth analysis on their
contribution to cancer development. Drost
and colleagues showed that mutating these
four genes is sufficient to convert a healthy
intestinal cell into an invasive tumor cell. The
model published in Nature can be used to
study processes involved in colon cancer
development and for cancer drug discovery.
Reference
Drost J, Van Jaarsveld RH, Ponsioen B,
Zimberlin C, Van Boxtel R, Buijs A, et al.
Sequential cancer mutations in cultured human
Genomic Profiling of Gastric Cancer Identifies Drug-Targetable Mutations
Durham, NC – The majority of gastric
cancers harbor genomic alterations (GAs)
associated with potential benefit from
targeted therapies, according to a new
study published in The Oncologist on April
16, 2015. These findings suggest a role for
genotype-directed management of locally
advanced and metastatic gastric cancer.
GastroPanel®
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NEWS
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To date, the ERBB2 amplification is the only GA
in advanced gastric cancer associated with a
survival benefit in response to targeted therapy.
However, because most patients with gastric
cancer do not harbor this rare alteration, most
cannot benefit from targeted therapy under
current practice guidelines.
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.
“Our study demonstrates the potential utility
of comprehensive genomic profiling to match
patients to targeted therapies of specific
potential benefit in clinical trials,” Dr. Ali said.
“This is encouraging in a disease that continues
to have a poor prognosis with modern
chemotherapy.”
The research team performed comprehensive
genomic profiling on 116 gastric cancer
specimens harvested from patients with
primarily (90.0%) locally advanced or metastatic
disease. Thus, the tumor samples were
characteristic of gastric carcinomas seen in
clinical practice, where the majority of patients
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%).
Other common alterations that are currently
not associated with approved or investigational
targeted therapies included TP53 (50%), ARIDIA
(24%), and CDHI (15%).
Many current and emerging targeted therapies
used in other tumor types are directed to known
alterations in receptor tyrosine kinase (RTK)
signaling pathways. In the current series,
1 in 5 gastric cancer cases (20.6%) harbored
alterations in RTKs such as ERBB2, FGFR2,
and MET.
According to the study authors, comprehensive
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
current therapies and overall poor survival,”
said Samuel Klempner, MD, a member of the
research team. “The patient response to MET
inhibition encapsulates the genotype-directed
approach and underscores the need for
molecularly directed clinical trials to confirm
observations such as seen in our study.”
Faecal Immunochemical Tests (FIT) Patient presents at GP with abdominal symptons
Patients triaged based on risk factors
SUSPECTED COLORECTAL CANCER
FAECAL IMMUNOCHEMICAL TEST for Hb
NEGATIVE
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A FIT Assay for Suspected Colorectal Cancer (CRC)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 DiseasePJ 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 15/05/2015 14:59:29
UK
LIN
3076
A
pril
2015
Under licence from
A first-in-classtreatment to improve
the multiple symptomsof moderate-to-severe
Irritable Bowel Syndromewith Constipation
(IBS-C)2–6
Now inclu
ded in
NICE CG61
guidelines
1
PRESCRIBING INFORMATION(Please consult the Summary of ProductCharacteristics (SmPC) before prescribing.)Constella®t 290 micrograms hard capsules LinaclotideActive 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: [email protected] 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.
CONS15UKLO0247_Gastro_Nursing_Resize_210x297.indd 1 14/05/2015 10:08
NEWS
In addition to driving increased clinical trial
participation, identifying clinically relevant GAs
in patients with gastric cancer may shape
future drug development and research on
biomarkers of resistance and therapeutic
response.
Weill Cornell Investigators Discover a New Pathway that Prevents Chronic Inflammation in the Gut
Investigators Show How Immune Cells
are “Educated” Not to Attack Beneficial
Bacteria
New York (April 23, 2015) -- An international
research team led by Weill Cornell Medical
College investigators has discovered an
answer to why the human immune system
ignores roughly 100 trillion beneficial
bacteria that populate the gastrointestinal
tract. The findings, published April 23 in
the journal Science, advance investigators’
understanding of how humans maintain
a healthy gastrointestinal tract, and may
provoke new ways to treat inflammatory
bowel disease -- including Crohn’s disease
and ulcerative colitis -- whose origins have
been mysterious and treatment difficult.
The investigators studied T cells -- critical
components of the adaptive immune system
-- which have the capacity to recognize,
eliminate and remember foreign microbes
that invade our bodies. T cells are named
after the thymus, an organ where they
develop and are taught not to attack normal
human tissues and organs, leaving them
free to target and eradicate disease-causing
foreign invaders. One question that had
puzzled scientists until now is how these
cells learn to ignore beneficial bacteria in the
intestine that are also foreign, but not harmful.
In the study, the research team discovered
that once they leave the thymus, T cells are
again educated in the gastrointestinal tract,
or gut, to leave beneficial bacteria alone. This
dual education strategy is vital to supporting
healthy immune function, the investigators
say. Disruption in the pathway that facilitates
this education, they add, causes the immune
system to attack beneficial bacteria in
the intestine, which is often linked to the
development and progression of diseases
like inflammatory bowel disease, HIV, viral
hepatitis, cardiovascular disease, obesity,
diabetes and cancer. Therapeutic strategies
to promote and boost the activity of this
education pathway may be beneficial
in treating patients with these chronic
inflammatory disorders, the investigators say.
“In many chronic human diseases, the
immune system attacks bacteria in the
intestine that are normally beneficial. Although
we do not yet know whether this is a cause
or consequence of these complex diseases,
experimental evidence suggests that this
inflammatory process contributes to disease
progression,” says senior author Dr. Gregory
F. Sonnenberg, an assistant professor of
microbiology and immunology in medicine
and a member of the Jill Roberts Institute for
Research in Inflammatory Bowel Disease at
Weill Cornell. “Our study demonstrates that
there may be an efficient way to eliminate pro-
inflammatory T cells in the intestine that attack
beneficial bacteria. This would not only help
our patients with inflammatory bowel disease,
but also might give us clues about how to
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treat other chronic inflammatory diseases
caused by abnormal T cell responses, such
as allergic and autoimmune disorders.”
In earlier research, Dr. Sonnenberg and his
team identified that a recently discovered
member of the innate immune system
-- innate lymphoid cells (ILCs) -- critically
regulate immune cell interactions with
bacteria. These ILCs, and other cells of the
immune system, are found in the intestine,
which is constantly exposed to and colonized
by beneficial bacteria. “There is a physical
separation between the immune system and
most beneficial bacteria,” Dr. Sonnenberg
says.
The researchers had previously found that
ILCs reinforce a physical barrier between
the immune system and intestinal beneficial
bacteria, but in this study, they uncovered a
new key role for these cells -- that they act like
the cells in the thymus that educate T cells.
In a process that developed over evolution,
bits of human tissues and organs are
introduced to T cells in the thymus so they
“know” what not to attack after leaving
the organ. Specialized cells in the thymus
teach T cells this behavior by interacting
with a molecule known as the Major
Histocompatibility Complex class II (MHCII).
Any T cells with the potential to attack the
human body and organs and cause auto-
immunity are destroyed before they can
leave the thymus. However, T cells with the
potential to attack beneficial bacteria are
not educated or eliminated in the thymus. It
was therefore unclear what stopped these T
cells from attacking beneficial bacteria in the
intestine.
The scientists found a similar process
happening directly within the GI tract, an
organ that contains the majority of the body’s
total immune system.
“Due to the similarities of what we know
happens in the thymus, we have called
this new process ‘intestinal selection,’”
says first author Dr. Matthew R. Hepworth,
a postdoctoral associate in medicine who
works in Dr. Sonnenberg’s laboratory. “ILCs
also interact with T cells through MHCII
machinery to educate T cells in the intestine.
“In the thymus, T cells are educated not to
attack our organs,” he adds, “and in the GI
tract, using ILCs, they are further educated
not to attack beneficial bacteria.”
Using mice to test their findings, the
researchers discovered that ILCs destroy T
cells with the potential to attack beneficial
bacteria, and that impairing ILC function led
to severe intestinal inflammation. Then, with
the help of researchers at Children’s Hospital
in Philadelphia, the team looked at intestinal
biopsies of pediatric patients diagnosed with
Crohn’s disease, one of the major forms of
inflammatory bowel disease.
“We found ILCs in intestinal biopsies from
pediatric patients diagnosed with Crohn’s
disease, but they were not functioning
properly because, in many cases, they were
lacking MHCII machinery, so T cells were
not educated to ignore beneficial bacteria,”
Dr. Sonnenberg says. “In fact, we found the
loss of MHCII correlated with an increase in
pro-inflammatory cells from matched biopsies
of children with Crohn’s disease. That tells us
that this education process may be impaired
in patients with inflammatory bowel disease,
and that restoring adequate levels of MHCII
might help to eliminate pro-inflammatory
T cells and reduce chronic intestinal
inflammation.”
Dr. Sonnenberg says there are likely many
causes of inflammatory bowel disease, and
other pathways that help control T cells in
the gut. “But our work shows a previously
unrecognized pathway whereby ILCs educate
our immune system not to attack beneficial
bacteria,” he says.
Dr. Sonnenberg, his laboratory and the Jill
Roberts Institute for Research in IBD are
now exploring how scientists can utilize this
knowledge and design novel therapeutic
strategies to boost MHCII on ILCs and limit
chronic intestinal inflammation.
Co-authors include Thomas C. Fung from
Weill Cornell Medical College; Terri M. Laufer
from the University of Pennsylvania; Samuel
H. Masur, Judith R. Kelsen and Robert N.
Baldassano from Children’s Hospital of
Philadelphia; Fiona M. McConnell and David
R. Withers from University of Birmingham,
United Kingdom; Juan Dubrot, Stephanie
Hugues and Walter Reith from the University
of Geneva Medical School in Switzerland;
Michael A. Farrar from the University of
Minnesota; Gerard Eberl from Institut Pasteur,
France; and Charles O. Elson from the
University of Alabama at Birmingham.
Research in Dr. Sonnenberg’s laboratory
is supported by the National Institutes
of Health (DP5OD012116), the NIAID
Mucosal Immunology Studies Team (MIST),
Scholar Award in Mucosal Immunity and
the Institute for Translational Medicine and
Therapeutics, Transdisciplinary Program in
Translational Medicine and Therapeutics
(UL1-RR024134 from the U.S. National
Center for Research Resources). Other
investigator support includes a research
fellowship from the Crohn’s, and Colitis
Foundation of America (CCFA, #297365), a
Cancer Research Institute Student Training
and Research in Tumor immunology (STaRT)
grant, a Wellcome Trust Research Career
Development Fellowship, and the National
Institutes of Health (DK071176).
Weill Cornell Medical College
Weill Cornell Medical College, Cornell
University’s medical school located in New
York City, is committed to excellence in
research, teaching, patient care and the
advancement of the art and science of
medicine, locally, nationally and globally.
Physicians and scientists of Weill Cornell
Medical College are engaged in cutting-
edge research from bench to bedside
aimed at unlocking mysteries of the human
body in health and sickness and toward
developing new treatments and prevention
strategies. In its commitment to global health
and education, Weill Cornell has a strong
presence in places such as Qatar, Tanzania,
Haiti, Brazil, Austria and Turkey. Through the
historic Weill Cornell Medical College in Qatar,
the Medical College is the first in the U.S. to
offer its M.D. degree overseas. Weill Cornell
is the birthplace of many medical advances
-- including the development of the Pap test
for cervical cancer, the synthesis of penicillin,
the first successful embryo-biopsy pregnancy
and birth in the U.S., the first clinical trial of
gene therapy for Parkinson’s disease, and
most recently, the world’s first successful use
of deep brain stimulation to treat a minimally
conscious brain-injured patient. Weill Cornell
Medical College is affiliated with NewYork-
Presbyterian Hospital, where its faculty
provides comprehensive patient care at
NewYork-Presbyterian Hospital/Weill Cornell
Medical Center. The Medical College is also
affiliated with Houston Methodist. For more
information, visit weill.cornell.edu.
34
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2015 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.
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.
Endocuff Vision. UK & IE. Gastro Today. Whole page ad. 297 x 210mm. 3mm bleed. CMYK.
ENDOCUFF VISION – Improvingvisualisation, control and theefficiency of colonoscopy.
Introducing ENDOCUFF VISION from Norgine,a simple add-on to your existing endoscope*that gently holds the colonic wall to notablyincrease your vision. Studies showed that theAdenoma Detection Rate (ADR) increasedfrom 52% to 76% (24%).1
To find out more about how ENDOCUFFVISION can increase the success of yourcolonoscopies, visit www.endocuff.com.Alternatively speak to your local Norgine representative for further information.
IncreaseAdenomaDetection
Rate by upto 24%1
35
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First UK online assessment for Coeliac Disease launched to find the undiagnosed half a million
Coeliac UK, the national Charity for
people with coeliac disease, will launch
the UK’s first online assessment to help
fast track diagnosis among the half
a million people in the UK living with
undiagnosed coeliac disease.
The online assessment tool is a key
initiative of the Charity’s new campaign, ‘is
it coeliac disease?’, which is launching in
Coeliac UK’s Awareness Week (11-17 May)
and backed by the Charity’s new patron,
actress Caroline Quentin.
The two year campaign will highlight the
most common symptoms of coeliac disease
and prompt people experiencing these
symptoms to ask themselves, ‘is it coeliac
disease?’.
A dedicated website,
www.isitcoeliacdisease.org.uk will host
the new assessment questionnaire and
provide detailed information about coeliac
disease and outline the campaign activities.
Based on National Institute for Health and
Care Excellence (NICE) guidelines, the new
online assessment will give people more
confidence to seek further medical advice
from their GP. Upon completion of the
assessment, they will receive an email with
the results which will indicate whether their
symptoms are potentially linked to coeliac
disease.
Coeliac disease is a serious autoimmune
disease where the body’s immune system
damages the lining of the small bowel when
gluten, a protein found in wheat, barley
and rye, is eaten. There is no cure and no
medication; the only treatment is a strict
gluten-free diet for life. Left untreated,
coeliac disease can lead to a number of
complications including osteoporosis and in
rare cases even small bowel cancer.
Key symptoms caused by coeliac disease
include: frequent bouts of diarrhoea,
stomach pain and cramping, regular
mouth ulcers, ongoing fatigue, lots of gas
and bloating, nausea and vomiting, and
unexplained anaemia.
One in 100 people in the UK has coeliac
disease, with the prevalence rising to one
in ten for close family members. However,
current statistics show only 24% of those
with the condition are diagnosed, leaving
an estimated half a million people in the UK
undiagnosed.
The ‘is it coeliac disease?’ campaign will
also target healthcare professionals to
refresh their knowledge of the condition
and its symptoms, and will be promoted
through radio and digital advertisements,
social media activity and information in GP
surgeries.
Outreach events will also take place
across the country over the next two years
providing more information for the general
Torbet Laboratories Ltd., Unit 1 Chestnut Drive, Wymondham, Norfolk, NR18 9SB.Tel: 01953 607856 Fax. 01953 713649 E-mail: [email protected]
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 LtdPrescribers are recommended to consult the summary of product characteristics before prescribing.
1 NICE Guidelines: Dyspepsia and gastro-oesophageal reflux disease: Guidelines [CG184] Published date: September 20142 Gisbert JP, Pajares JM.: 13C-urea breath test in the diagnosis of Helicobacter pylori infection—a critical review. Aliment Pharmacol Ther 2004;20:1001–173 ¹³C-urea breath test – a reliable diagnostic technique for assessment of eradication. Gut 1996: 39 (suppl 3): A37.
2PYL12/1501b
For the reliable and quick in vivo diagnosis for the gastro-duodenal presence of Helicobacter pylori.
When to use Pylobactell 13C-Urea Breath Test (UBT)
Uninvestigated Dyspepsia Offer H pylori ‘test and treat’ to patients with dyspepsia1
Peptic Ulcer Disease Test to confirm before treating and to confirm eradication 6-8 weeks after commencement of treatment1
The UBT using [13C] urea remains the best test to diagnose H pylori infection, has a high accuracy and is easy to perform2
Precise
98.3%3 and non-invasive
Easy to use
can be performed at home or under the supervision of healthcare staff
Highly sensitive
and specific to Helicobacter pylori
Results within 48 (working) hours
36
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public to ask questions and gain advice
from experts. Further details of these events
can be found at:
www.isitcoeliacdisease.org.uk.
Sarah Sleet, chief executive of Coeliac UK,
said:
“With half a million people living with
undiagnosed coeliac disease we must
take radical action to turn around this
horrendous situation. We hope that
giving people direct access to an online
assessment tool will put those who
are suffering with the symptoms of
undiagnosed coeliac disease on a pathway
to diagnosis and avoid potentially life
threatening long term health complications.
As well as help reduce the unacceptable
length of time to gain a diagnosis which is
currently, on average, 13 years.”
Caroline Quentin, who is close to
completing her own diagnosis journey after
an initial positive blood test two years ago
and more recently a genetic test, said:
“Coeliac UK’s campaign to reach the half a
million people still undiagnosed with coeliac
disease really resonates with me because I
struggled for years with constant stomach
pains, vomiting and total exhaustion.”
A confirmed medical diagnosis of coeliac
disease enables people to receive
appropriate follow-up care and support, as
well as providing evidence for close family
members to also be tested.
Sarah Sleet continued:
“Awareness of coeliac disease has
increased greatly in recent years with the
Charity’s Helpline supporting hundreds of
callers seeking a diagnosis. Yet, around
500,000 people in the UK are still suffering
unnecessarily. Please check your symptoms
through our online assessment tool, and if
you think you may have coeliac disease,
go to your doctor and ask for a blood test
but don’t stop eating gluten until you are
tested otherwise critical follow up tests will
not work,”
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?
Have you attended an interesting meeting that you would like to share with your colleagues?
If so, please submit the details to: info@mediapublishingcom pany.com for editorial consideration.
LASTING REMISSION1
• Maintenance of clinical and endoscopic remission for 12 months.1
• Well documented safety and tolerability.1
LOW PILL BURDEN2
ONCE-DAILY3
A simple step to lasting remission
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 myo- or 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 erythematosus-like 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 [email protected].
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).
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.
MEZ-15-490 Gastro Today 297x210.indd 1 29/05/2015 11:53
A model to assess the cost of flare in ulcerative colitis to the NHS Ash Bassi1, Keith Tolley2, Gwen Wiseman3, Sarah Shaw4
1Gastroenterology Department, Whiston Hospital, Prescot, Merseyside; 2Tolley Health Economics Ltd, Buxton; 3Medical Affairs, Warner Chilcott (UK) Ltd; 4Policy Matters LLP, Surrey
PTU-066
Background• Diseaseflaresofactiveulcerativecolitis(UC)canresultinsubstantial
costimplicationstotheNHS,affectingbothprimaryandsecondarycare.1
• Insecondarycare,flaresofactiveUCareassociatedwitha2-foldincreaseincostsfornon-hospitalisedcasesandmorethan20-foldincreaseforhospitalisedcases,comparedwiththemaintenancephase.1
• WhilethecostsassociatedwithtreatmentandmanagementofUCinsecondarycarearewell-documented,estimatesofthecostofflareacrossthespectrumofcarepathwaysarelacking.
• Acostanalysiswasperformedtoestimatethehealthcarecostsassociatedwithmanagingaflarebymodellingresourceuseacrossalternativepathwaysinprimaryandsecondarycare.
• Thismodelwasthenusedtoestimatecostsassociatedwithincreasedflares,whichmayresultfromnon-adherencetoAsacol®(mesalazine).
Methods• AdecisiontreemodelwasdevelopedinExceltoestimatethedirect
healthcarecostsofflaresofvaryingclinicalseverity.
• Themodelformsthebasisforestimatingtheaveragecostofflareinamodelcohort,whichallowsforsensitivityanalysesandadaptingthemodeltolocalpatientpopulations.
• Treatmentandmanagementstrategieswerebasedonbestpracticeguidelines,publisheddatasourcesandexpertopinion.2
• DrugcostswerecalculatedusingtheBritishNationalFormulary(BNF)andhealthcaremanagementcostswerebasedonpublishedunitcosts.
• Amarketforcesfactorof1.08(theUKaverage)wasappliedtoaccountforcostdifferencesbetweenhealthcareprovidersduetogeographicallocation.3,4
Costs of UC in remission (base case)• Withinthemodel,thebaselineUCpatientcohortwasassumedto
bemaintainedonAsacolatamaximumdoseof2.4g/day,givenas800mgMRtablets.Thisisthemaximumdailydoserecommendedformaintenanceofremissionandprovidesanupperestimateofthedrugcosts.5
• Annualmanagementcostsforpatientsinremissionwereestimatedassumingonesecondarycareconsultationperyear,2colonicsurveillanceevery5years6androutinemonitoringtestsperyear, suchasfullbloodcount,liverfunctionandrenalfunctiontests.7
Costs associated with flare• Illustrativecarepathwaysweremapped,assumingthatpatientswith
aflareofactivediseasewouldeitherbetreatedandmanagedinprimarycare,orasanoutpatient,oradmittedtohospital.
AcknowledgementsThismodelwasdevelopedbyPolicyMattersLLPandTolleyHealthEconomicsLtd,sponsoredbyWarnerChilcottUKLtd.EditorialsupportwasprovidedbyAcumenHealthcareCommunicationsLtd,fundedbyWarnerChilcottUKLtd.
Citation:BassiAet al.AmodeltoassessthecostofflareinulcerativecolitistotheNHS. British Society of Gastroenterology Annual Meeting,16–19June2014, Manchester,PosterPTU-066.
• Takingaconservativeapproach,costsforsurgeryandpost-surgicalmanagement,e.g.stomacare,wereexcludedasinclusionwouldhaveskewedthedataandsignificantlyincreasedaverageflarecostestimates.
Average cost of flare• Tocalculateanestimatedaveragecostofflare,defaultvaluesfor
proportionsofpatientswereassignedtoeachtreatmentpathway,basedonclinicalexperience.2
• Thedefaultvaluesprovideanillustrativeexampleofamodelpopulation.
Costs associated with non-adherence• Usingacohortapproach,costsassociatedwithanincreaseinflare
inpatientswhoarenon-adherenttoAsacolwereestimatedforapopulationof100,000people(Table1).
ResultsCosts of remission and flare
• TheestimatedannualcosttomanageapatientwithUCinremissionwas£955(basecase;Table2).
• Theadditionalestimatedcosttocontrolaflareinprimarycarewas£175andforsecondarycareoutpatientmanagementwas£578(Figure1).
• Forsecondarycareinpatientmanagement,theestimatedcostwas£3,488(Figure1).
• Ifabiologic/ciclosporinwasneeded,theestimatedcostroseto£4,272(Figure1).Allcostswereinclusiveofclinicalinvestigationsandtreatmentreviews.
• Applyingthedefaultvaluesforproportionsofpatientstoeachofthe3pathwaysproducedanestimatedaveragecostofflareof£984intheUCcohort(Table3).
Table 1. The model population in the adherence analysis.
Total population 100,000
Prevalence of UC per 100,000 2408
Estimated proportion of patients on Asacol 39.5%9
Estimated number of patients on Asacol in cohort 95
Table 2. Annual costs of ulcerative colitis in remission (base case).
Annual drug costs Management costs
Asacol2.4g/day (800mgMRtablets)5
£715.52 Secondarycareconsultationunitcost10
Endoscopy10
Monitoringtests7
£111.52a
£123.43a
£5.00
Annualcostsinremission
£955 per patient
aMarketforcesfactorapplied
Table 3. Calculating the average cost of flare.
Proportion of patients managed via this pathway
(illustrative examples)
Pathway via which flare is managed
Estimated cost per
flare
Model population (default values)2
Increased management in
primary care
Reduced management in
primary care
Primarycare £175 10.0% 20.0% 5.0%
Secondarycare(outpatient) £578 76.5% 71.5% 79.0%
Secondarycare(inpatient)a £3,880 13.5% 8.5% 16.0%
Estimated average cost of a flare £984 £778 £1,086
aCrudeaverageofcontrolledandsevereflare
Figure 1. Estimated costs associated with flare in ulcerative colitis: A. Illustrative primary and secondary care pathways for treatment and management of flare; B. break down of costs.
• Insensitivityanalysistheproportionofpatientsmanagedviaeachroutewerevariedtoreflectdifferencesinpatientpopulationcharacteristicsacrosslocalities(Table3).
Adherence analysis• Theestimatedannualcostofflareper100,000peoplewas£5,086for
patientsadherenttoAsacoland£28,204forthosewhowerenon-adherent(Figure2A).
• Apotentialannualcostsavingof£1,156–£3,468per100,000peoplecouldbeachievedif5–15%ofthesenon-adherentpatientsbecameadherent(Figure2B).
References: 1. Bassi A et al.Gut2004;53:1471-8;2. BassiA.ExpertopiniontoWarnerChilcott.2013;3. Monitor.AguidetotheMarketForcesFactor.2013;4.Monitor.Annex6A:MarketForcesFactorpaymentvalues2014-15.www.monitor.gov.uk/nt[LastaccessedApril2014];5.JointFormularyCommittee2013.BritishNationalFormulary(online).www.medicinescomplete.com[LastaccessedSeptember2013];6.NationalInstituteforHealthandCareExcellence.CG118:ColonoscopicSurveillanceforPreventionofColorectalCancerinPeoplewithUlcerativeColitis,Crohn’sDiseaseorAdenomas.2011;7. NationalClinicalGuidelineCentre.Ulcerativecolitisclinicalguideline.AppendixK:Costsofdrugsusedinthetreatmentofulcerativecolitis.2013;8. NationalInstituteforHealthandCareExcellence.CG166:Ulcerative
colitis:Managementinadults,childrenandyoungpeople.2013;9. WarnerChilcott.Dataonfile.IMSHealth:MarketshareUK/AS/0185/08-13.2013;10.DepartmentofHealth.PaymentbyresultsintheNHS:Tariffinformationspreadsheet2013-14Version6.www.gov.uk [LastaccessedApril2014];11. CurtisL(ed).PSSRUunitcostsofhealthandsocialcare.2012;12.RoyalCollegeofPhysicians.ReportoftheresultsforthenationalclinicalauditofadultinflammatoryboweldiseaseinpatientcareintheUK.Round3.2012;13. HanauerSBet al.
Am J Gastroenterol 2005;100:2478-85;14. HanauerSBet al.Can J Gastroenterol2007;21:827-34;15. SandbornWJet al.Gastroenterology2009;137:1934-43;16. RoyalCollegeofPhysicians.Theinauguralnationalreportoftheresultsfortheprimarycare questionnaireresponses.PartoftheUKinflammatoryboweldiseaseaudit3rdround.2012;17.NHSmapofmedicinehealthguides.Severeulcerativecolitisandtoxicmegacolon.http://healthguides.mapofmedicine.com[LastaccessedApril2014];18.RoyalCollege
ofPhysicians.Nationalclinicalauditofbiologicaltherapies:UKInflammatoryBowelDisease(IBD)audit.Adultnationalreport.2013;19. NationalInstituteforHealthandCareExcellence.NICETA163infliximabforacuteexacerbationsofulcerativecolitis.2008; 20. CegedimStrategicData(CSD).PatientRetentionAnalysis.2012;21. Kane S et al.Am J Med2003;114:39-43;22. IBDStandardsGroup.StandardsforthehealthcareofpeoplewhohaveInflammatoryBowelDisease(IBD):2013Update.2013.
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.
A
Adherent patients Non-adherent patients
%patientsadherent 50%20 %patientsnon-adherent 50%20
Numberofadherentpatients 47 Numberofnon-adherentpatients 47
%adherentpatientsexperiencingflare 11%21 %non-adherentpatientsexperiencingflare 61%21
Estimatednumberofflares 5.17 Estimatednumberofflares 28.67
Averagecostofflare £984 Averagecostofaflare £984
Cost of flares in patients adherent to Asacol
£5,086
Cost of flares in patients non-adherent to Asacol
£28,204
B
% of non-adherent patients who become adherent 5% 15%
Numberofpatientswhobecomeadherent 2.4 7.1
Estimatedreductioninnumberofflares 1.18 3.53
Estimated reduction in cost of flares £1,156 £3,468
Adherenceintervention
aAsacoldosewasdoubledto4.8g/dayfor6weeks;5,13,14,15 bPrednisolone(30mg/day,withataperingdose)andalendronate(10mg/day)for6weeks;2,5,12,16 cAzathioprine(125mg/day)for12weeks;2,5,12 dIntravenoushydrocortisone(100mg,threetimesdaily)for5days;5,12,17 eInfliximab(3dosesof312.5mg),5,12,18,19adalimumab(160mginductiondosefollowedby80mg,then3dosesof40mg),5,12,18andciclosporin(250mg/dayfor7days)5,12,17,19wereprescribedforsevereflare;fMarketforcesfactorapplied;gUnlicensedindication
B Drug costs Investigations Treatment review & resource use
Prim
ary
care Asacol,4.8g/day(800mgtabs)a
Prednisolone(14.7%ofpatients)b
Alendronate(70%ofpatientsonsteroids)b
£82.33
£0.93
£0.30
GPconsultation11
Monitoringtests7
£43.00
£5.00
GPconsultation11 £43.00 Primarycare
£175 per flare
Seco
ndar
y ca
re
(out
pati
ent)
Asacol,4.8g/day(800mgtabs)a
Prednisolone(75%ofpatients)b
Alendronate(70%ofpatientsonsteroids)b
Azathioprine(25%ofpatients)c
£82.33
£4.73
£1.51
£6.79
Sigmoidoscopywithbiopsy(14%ofpatients)1,10
Monitoringtests7
Testsassociatedwithazathioprineuse (25%ofpatientsusingit)2,5,7
£51.23f
£5.00
£10.00
Consultantgastroenterologistinitialconsultation10
Multidisciplinarygastroenterologyfollowupconsultation10
£195.97f
£220.87f
Secondarycare(outpatient)
£578 per flare
Seco
ndar
y ca
re
(inpa
tien
t)
Asacol,4.8g/day(800mgtabs)a
Prednisolone(74%ofpatients)b
Alendronate(70%ofpatientsonsteroids)b
Azathioprine(25%ofpatients)c
IVhydrocortisone(80%ofpatients)d
£82.33
£4.66
£1.49
£6.79
£12.24
Sigmoidoscopywithbiopsy(70%ofpatients)1,10
Monitoringtests7
Testsassociatedwithazathioprineuse (25%ofpatientsusingit)5,7,12
£256.17f
£5.00
£10.00
Multidisciplinarygastroenterologyfollowupconsultation10
Hospitalstay10,12
£220.87f
£2,888.13f
Secondarycare(inpatient,controlled)
£3,488 per flare
Severe flare – additional drug costs Secondarycare(inpatient,severeflare)
£4,272 per flare
Infliximab(14%ofpatients)e
Adalimumab(2%ofpatients)e
Ciclosporin(23%ofpatients)e,g
£708.99 £60.85 £14.76
A
Decision point
Pa�ent hasUC flare
Primary careinves�ga�ons
Primary caretreatment review
Secondary careinves�ga�ons
Secondary caretreatment review
Secondary careinves�ga�ons
Secondary caretreatment review
Controlled
Controlled
Controlled
Severe flareAdd
ciclosporin/biologic
Controlled
Not controlled,referral to outpa�ent
Uncontrolled,admit tohospital
Uncontrolled,considersurgery (not costed)
Primary care review
Outpa�ent review
Admit tohospital direct
or via A&E
OutcomePathway terminates
£48.00 £126.56
£66.23 £512.20
£271.17 £3,216.51
£784.60
Conclusion• Adecisiontreemodelwasdevelopedtoestimatethecostoftreatinga
flareofactiveUCviaillustrativeprimaryorsecondarycarepathways.
• Thefindingssupporttheargumentforfocusingservicestowardspromptdetectionandearlymanagementofflares,22tohelpavoidA&Eattendances,unplannedhospitaladmissionsandothercostlysecondarycareresourceuse.
– Inthebasecase,theestimatedannualcosttomanageapatientwithUCinremissionwas£955.
– Dependingontheseverityoftheepisode,coststomanageasingleflarerangedfrom£175to£4,272withanaverageof£984.
– Apotentialannualcostsavingof£1,156–£3,468per100,000peoplecouldbeachievedif5–15%ofnon-adherentpatientsbecameadherent.
• Whilefurtherinvestigationisrequiredtoassessreal-worldvalidity,thiscostmodelrepresentsavaluabletoolforexploringresourceutilisationinUCflaremanagement.
38
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R 2015
A model to assess the cost of flare in ulcerative colitis to the NHS Ash Bassi1, Keith Tolley2, Gwen Wiseman3, Sarah Shaw4
1Gastroenterology Department, Whiston Hospital, Prescot, Merseyside; 2Tolley Health Economics Ltd, Buxton; 3Medical Affairs, Warner Chilcott (UK) Ltd; 4Policy Matters LLP, Surrey
PTU-066
Background• Diseaseflaresofactiveulcerativecolitis(UC)canresultinsubstantial
costimplicationstotheNHS,affectingbothprimaryandsecondarycare.1
• Insecondarycare,flaresofactiveUCareassociatedwitha2-foldincreaseincostsfornon-hospitalisedcasesandmorethan20-foldincreaseforhospitalisedcases,comparedwiththemaintenancephase.1
• WhilethecostsassociatedwithtreatmentandmanagementofUCinsecondarycarearewell-documented,estimatesofthecostofflareacrossthespectrumofcarepathwaysarelacking.
• Acostanalysiswasperformedtoestimatethehealthcarecostsassociatedwithmanagingaflarebymodellingresourceuseacrossalternativepathwaysinprimaryandsecondarycare.
• Thismodelwasthenusedtoestimatecostsassociatedwithincreasedflares,whichmayresultfromnon-adherencetoAsacol®(mesalazine).
Methods• AdecisiontreemodelwasdevelopedinExceltoestimatethedirect
healthcarecostsofflaresofvaryingclinicalseverity.
• Themodelformsthebasisforestimatingtheaveragecostofflareinamodelcohort,whichallowsforsensitivityanalysesandadaptingthemodeltolocalpatientpopulations.
• Treatmentandmanagementstrategieswerebasedonbestpracticeguidelines,publisheddatasourcesandexpertopinion.2
• DrugcostswerecalculatedusingtheBritishNationalFormulary(BNF)andhealthcaremanagementcostswerebasedonpublishedunitcosts.
• Amarketforcesfactorof1.08(theUKaverage)wasappliedtoaccountforcostdifferencesbetweenhealthcareprovidersduetogeographicallocation.3,4
Costs of UC in remission (base case)• Withinthemodel,thebaselineUCpatientcohortwasassumedto
bemaintainedonAsacolatamaximumdoseof2.4g/day,givenas800mgMRtablets.Thisisthemaximumdailydoserecommendedformaintenanceofremissionandprovidesanupperestimateofthedrugcosts.5
• Annualmanagementcostsforpatientsinremissionwereestimatedassumingonesecondarycareconsultationperyear,2colonicsurveillanceevery5years6androutinemonitoringtestsperyear, suchasfullbloodcount,liverfunctionandrenalfunctiontests.7
Costs associated with flare• Illustrativecarepathwaysweremapped,assumingthatpatientswith
aflareofactivediseasewouldeitherbetreatedandmanagedinprimarycare,orasanoutpatient,oradmittedtohospital.
AcknowledgementsThismodelwasdevelopedbyPolicyMattersLLPandTolleyHealthEconomicsLtd,sponsoredbyWarnerChilcottUKLtd.EditorialsupportwasprovidedbyAcumenHealthcareCommunicationsLtd,fundedbyWarnerChilcottUKLtd.
Citation:BassiAet al.AmodeltoassessthecostofflareinulcerativecolitistotheNHS. British Society of Gastroenterology Annual Meeting,16–19June2014, Manchester,PosterPTU-066.
• Takingaconservativeapproach,costsforsurgeryandpost-surgicalmanagement,e.g.stomacare,wereexcludedasinclusionwouldhaveskewedthedataandsignificantlyincreasedaverageflarecostestimates.
Average cost of flare• Tocalculateanestimatedaveragecostofflare,defaultvaluesfor
proportionsofpatientswereassignedtoeachtreatmentpathway,basedonclinicalexperience.2
• Thedefaultvaluesprovideanillustrativeexampleofamodelpopulation.
Costs associated with non-adherence• Usingacohortapproach,costsassociatedwithanincreaseinflare
inpatientswhoarenon-adherenttoAsacolwereestimatedforapopulationof100,000people(Table1).
ResultsCosts of remission and flare
• TheestimatedannualcosttomanageapatientwithUCinremissionwas£955(basecase;Table2).
• Theadditionalestimatedcosttocontrolaflareinprimarycarewas£175andforsecondarycareoutpatientmanagementwas£578(Figure1).
• Forsecondarycareinpatientmanagement,theestimatedcostwas£3,488(Figure1).
• Ifabiologic/ciclosporinwasneeded,theestimatedcostroseto£4,272(Figure1).Allcostswereinclusiveofclinicalinvestigationsandtreatmentreviews.
• Applyingthedefaultvaluesforproportionsofpatientstoeachofthe3pathwaysproducedanestimatedaveragecostofflareof£984intheUCcohort(Table3).
Table 1. The model population in the adherence analysis.
Total population 100,000
Prevalence of UC per 100,000 2408
Estimated proportion of patients on Asacol 39.5%9
Estimated number of patients on Asacol in cohort 95
Table 2. Annual costs of ulcerative colitis in remission (base case).
Annual drug costs Management costs
Asacol2.4g/day (800mgMRtablets)5
£715.52 Secondarycareconsultationunitcost10
Endoscopy10
Monitoringtests7
£111.52a
£123.43a
£5.00
Annualcostsinremission
£955 per patient
aMarketforcesfactorapplied
Table 3. Calculating the average cost of flare.
Proportion of patients managed via this pathway
(illustrative examples)
Pathway via which flare is managed
Estimated cost per
flare
Model population (default values)2
Increased management in
primary care
Reduced management in
primary care
Primarycare £175 10.0% 20.0% 5.0%
Secondarycare(outpatient) £578 76.5% 71.5% 79.0%
Secondarycare(inpatient)a £3,880 13.5% 8.5% 16.0%
Estimated average cost of a flare £984 £778 £1,086
aCrudeaverageofcontrolledandsevereflare
Figure 1. Estimated costs associated with flare in ulcerative colitis: A. Illustrative primary and secondary care pathways for treatment and management of flare; B. break down of costs.
• Insensitivityanalysistheproportionofpatientsmanagedviaeachroutewerevariedtoreflectdifferencesinpatientpopulationcharacteristicsacrosslocalities(Table3).
Adherence analysis• Theestimatedannualcostofflareper100,000peoplewas£5,086for
patientsadherenttoAsacoland£28,204forthosewhowerenon-adherent(Figure2A).
• Apotentialannualcostsavingof£1,156–£3,468per100,000peoplecouldbeachievedif5–15%ofthesenon-adherentpatientsbecameadherent(Figure2B).
References: 1. Bassi A et al.Gut2004;53:1471-8;2. BassiA.ExpertopiniontoWarnerChilcott.2013;3. Monitor.AguidetotheMarketForcesFactor.2013;4.Monitor.Annex6A:MarketForcesFactorpaymentvalues2014-15.www.monitor.gov.uk/nt[LastaccessedApril2014];5.JointFormularyCommittee2013.BritishNationalFormulary(online).www.medicinescomplete.com[LastaccessedSeptember2013];6.NationalInstituteforHealthandCareExcellence.CG118:ColonoscopicSurveillanceforPreventionofColorectalCancerinPeoplewithUlcerativeColitis,Crohn’sDiseaseorAdenomas.2011;7. NationalClinicalGuidelineCentre.Ulcerativecolitisclinicalguideline.AppendixK:Costsofdrugsusedinthetreatmentofulcerativecolitis.2013;8. NationalInstituteforHealthandCareExcellence.CG166:Ulcerative
colitis:Managementinadults,childrenandyoungpeople.2013;9. WarnerChilcott.Dataonfile.IMSHealth:MarketshareUK/AS/0185/08-13.2013;10.DepartmentofHealth.PaymentbyresultsintheNHS:Tariffinformationspreadsheet2013-14Version6.www.gov.uk [LastaccessedApril2014];11. CurtisL(ed).PSSRUunitcostsofhealthandsocialcare.2012;12.RoyalCollegeofPhysicians.ReportoftheresultsforthenationalclinicalauditofadultinflammatoryboweldiseaseinpatientcareintheUK.Round3.2012;13. HanauerSBet al.
Am J Gastroenterol 2005;100:2478-85;14. HanauerSBet al.Can J Gastroenterol2007;21:827-34;15. SandbornWJet al.Gastroenterology2009;137:1934-43;16. RoyalCollegeofPhysicians.Theinauguralnationalreportoftheresultsfortheprimarycare questionnaireresponses.PartoftheUKinflammatoryboweldiseaseaudit3rdround.2012;17.NHSmapofmedicinehealthguides.Severeulcerativecolitisandtoxicmegacolon.http://healthguides.mapofmedicine.com[LastaccessedApril2014];18.RoyalCollege
ofPhysicians.Nationalclinicalauditofbiologicaltherapies:UKInflammatoryBowelDisease(IBD)audit.Adultnationalreport.2013;19. NationalInstituteforHealthandCareExcellence.NICETA163infliximabforacuteexacerbationsofulcerativecolitis.2008; 20. CegedimStrategicData(CSD).PatientRetentionAnalysis.2012;21. Kane S et al.Am J Med2003;114:39-43;22. IBDStandardsGroup.StandardsforthehealthcareofpeoplewhohaveInflammatoryBowelDisease(IBD):2013Update.2013.
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.
A
Adherent patients Non-adherent patients
%patientsadherent 50%20 %patientsnon-adherent 50%20
Numberofadherentpatients 47 Numberofnon-adherentpatients 47
%adherentpatientsexperiencingflare 11%21 %non-adherentpatientsexperiencingflare 61%21
Estimatednumberofflares 5.17 Estimatednumberofflares 28.67
Averagecostofflare £984 Averagecostofaflare £984
Cost of flares in patients adherent to Asacol
£5,086
Cost of flares in patients non-adherent to Asacol
£28,204
B
% of non-adherent patients who become adherent 5% 15%
Numberofpatientswhobecomeadherent 2.4 7.1
Estimatedreductioninnumberofflares 1.18 3.53
Estimated reduction in cost of flares £1,156 £3,468
Adherenceintervention
aAsacoldosewasdoubledto4.8g/dayfor6weeks;5,13,14,15 bPrednisolone(30mg/day,withataperingdose)andalendronate(10mg/day)for6weeks;2,5,12,16 cAzathioprine(125mg/day)for12weeks;2,5,12 dIntravenoushydrocortisone(100mg,threetimesdaily)for5days;5,12,17 eInfliximab(3dosesof312.5mg),5,12,18,19adalimumab(160mginductiondosefollowedby80mg,then3dosesof40mg),5,12,18andciclosporin(250mg/dayfor7days)5,12,17,19wereprescribedforsevereflare;fMarketforcesfactorapplied;gUnlicensedindication
B Drug costs Investigations Treatment review & resource use
Prim
ary
care Asacol,4.8g/day(800mgtabs)a
Prednisolone(14.7%ofpatients)b
Alendronate(70%ofpatientsonsteroids)b
£82.33
£0.93
£0.30
GPconsultation11
Monitoringtests7
£43.00
£5.00
GPconsultation11 £43.00 Primarycare
£175 per flare
Seco
ndar
y ca
re
(out
pati
ent)
Asacol,4.8g/day(800mgtabs)a
Prednisolone(75%ofpatients)b
Alendronate(70%ofpatientsonsteroids)b
Azathioprine(25%ofpatients)c
£82.33
£4.73
£1.51
£6.79
Sigmoidoscopywithbiopsy(14%ofpatients)1,10
Monitoringtests7
Testsassociatedwithazathioprineuse (25%ofpatientsusingit)2,5,7
£51.23f
£5.00
£10.00
Consultantgastroenterologistinitialconsultation10
Multidisciplinarygastroenterologyfollowupconsultation10
£195.97f
£220.87f
Secondarycare(outpatient)
£578 per flare
Seco
ndar
y ca
re
(inpa
tien
t)
Asacol,4.8g/day(800mgtabs)a
Prednisolone(74%ofpatients)b
Alendronate(70%ofpatientsonsteroids)b
Azathioprine(25%ofpatients)c
IVhydrocortisone(80%ofpatients)d
£82.33
£4.66
£1.49
£6.79
£12.24
Sigmoidoscopywithbiopsy(70%ofpatients)1,10
Monitoringtests7
Testsassociatedwithazathioprineuse (25%ofpatientsusingit)5,7,12
£256.17f
£5.00
£10.00
Multidisciplinarygastroenterologyfollowupconsultation10
Hospitalstay10,12
£220.87f
£2,888.13f
Secondarycare(inpatient,controlled)
£3,488 per flare
Severe flare – additional drug costs Secondarycare(inpatient,severeflare)
£4,272 per flare
Infliximab(14%ofpatients)e
Adalimumab(2%ofpatients)e
Ciclosporin(23%ofpatients)e,g
£708.99 £60.85 £14.76
A
Decision point
Pa�ent hasUC flare
Primary careinves�ga�ons
Primary caretreatment review
Secondary careinves�ga�ons
Secondary caretreatment review
Secondary careinves�ga�ons
Secondary caretreatment review
Controlled
Controlled
Controlled
Severe flareAdd
ciclosporin/biologic
Controlled
Not controlled,referral to outpa�ent
Uncontrolled,admit tohospital
Uncontrolled,considersurgery (not costed)
Primary care review
Outpa�ent review
Admit tohospital direct
or via A&E
OutcomePathway terminates
£48.00 £126.56
£66.23 £512.20
£271.17 £3,216.51
£784.60
Conclusion• Adecisiontreemodelwasdevelopedtoestimatethecostoftreatinga
flareofactiveUCviaillustrativeprimaryorsecondarycarepathways.
• Thefindingssupporttheargumentforfocusingservicestowardspromptdetectionandearlymanagementofflares,22tohelpavoidA&Eattendances,unplannedhospitaladmissionsandothercostlysecondarycareresourceuse.
– Inthebasecase,theestimatedannualcosttomanageapatientwithUCinremissionwas£955.
– Dependingontheseverityoftheepisode,coststomanageasingleflarerangedfrom£175to£4,272withanaverageof£984.
– Apotentialannualcostsavingof£1,156–£3,468per100,000peoplecouldbeachievedif5–15%ofnon-adherentpatientsbecameadherent.
• Whilefurtherinvestigationisrequiredtoassessreal-worldvalidity,thiscostmodelrepresentsavaluabletoolforexploringresourceutilisationinUCflaremanagement.
• 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.
• 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.
• The aim was to significantly reduce cancer-related 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.
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.
76.9% of TWR patients had an endoscopic procedure compared to 62.9% of non-TWR patients (p=0.09).
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%).
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.
The mean cost of investigations and follow-up was significantly higher in the TWR cohort (£754.10 vs £613.10, p=0.04).
• In our sample of patients, those referred under the TWR pathway underwent a higher burden of invasive
investigation with no significant increase in cancer pick up, despite being significantly more costly.
• Of concern, a large proportion of this group did not have a formal diagnosis by after 3 months of follow up.
• We suggest alternative referral pathways to be considered in a bid to improve cancer diagnosis in high risk patients.
Investigations, cancer diagnoses and cost: A prospective study of two week rule versus non-two week rule gastroenterology referrals at a district general hospital
A. Shalabi, C. Alexakis, S. Moodie Department of Gastroenterology, Epsom General Hospital
• 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.
INTRODUCTION
METHOD
CONCLUSION REFERENCES
RESULTS AND DISCUSSION
The majority of TWR referrals were vomiting, weight loss and anaemia respectively. The bulk of non-TWR referrals was abdominal pain.
17.3
9.6
3.8
19.2
26.9
7.7 7.7 7.7 6.7
33.7
10.1
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15.7 14.6 14.6
4.5
0
5
10
15
20
25
30
35
40
Perc
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Primary reason for referral in both patient groups
TWR
Non TWR
0%
10%
20%
30%
40%
50%
60%
1 Radiological Investigation (%) 2 Radiological Investigations (%)
TWRNon-TWR
0%
5%
10%
15%
20%
25%
Patients with cancer diagnosis Patients with no diagnosis
TWRNon-TWR
0%
10%
20%
30%
40%
50%
60%
70%
TWR Non-TWR
48.1%
36%
51.9%
64%
Gender of patients presenting to clinic
MaleFemale
0%
20%
40%
60%
80%
100%
TWR Non-TWR
Percentage of patients undergoing an endoscopic procedure
£0 £100 £200 £300 £400 £500 £600 £700 £800
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• 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.
• 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.
• The aim was to significantly reduce cancer-related 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.
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.
76.9% of TWR patients had an endoscopic procedure compared to 62.9% of non-TWR patients (p=0.09).
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%).
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.
The mean cost of investigations and follow-up was significantly higher in the TWR cohort (£754.10 vs £613.10, p=0.04).
• In our sample of patients, those referred under the TWR pathway underwent a higher burden of invasive
investigation with no significant increase in cancer pick up, despite being significantly more costly.
• Of concern, a large proportion of this group did not have a formal diagnosis by after 3 months of follow up.
• We suggest alternative referral pathways to be considered in a bid to improve cancer diagnosis in high risk patients.
Investigations, cancer diagnoses and cost: A prospective study of two week rule versus non-two week rule gastroenterology referrals at a district general hospital
A. Shalabi, C. Alexakis, S. Moodie Department of Gastroenterology, Epsom General Hospital
• 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.
INTRODUCTION
METHOD
CONCLUSION REFERENCES
RESULTS AND DISCUSSION
The majority of TWR referrals were vomiting, weight loss and anaemia respectively. The bulk of non-TWR referrals was abdominal pain.
17.3
9.6
3.8
19.2
26.9
7.7 7.7 7.7 6.7
33.7
10.1
0
15.7 14.6 14.6
4.5
0
5
10
15
20
25
30
35
40
Perc
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Reason for referral
Primary reason for referral in both patient groups
TWR
Non TWR
0%
10%
20%
30%
40%
50%
60%
1 Radiological Investigation (%) 2 Radiological Investigations (%)
TWRNon-TWR
0%
5%
10%
15%
20%
25%
Patients with cancer diagnosis Patients with no diagnosis
TWRNon-TWR
0%
10%
20%
30%
40%
50%
60%
70%
TWR Non-TWR
48.1%
36%
51.9%
64%
Gender of patients presenting to clinic
MaleFemale
0%
20%
40%
60%
80%
100%
TWR Non-TWR
Percentage of patients undergoing an endoscopic procedure
£0 £100 £200 £300 £400 £500 £600 £700 £800
Non-TWR
TWR
Mean cost per patient
SELF PROVIDED GUIDED MEDICAL HISTORY IS FAST, COMPLETE AND ACCURATEChloe van Someren 1, Niall van Someren 2Andrew Millar 1Gwen Edwards 11Gastroenterology, North Middlesex University Hospital, 2Gastroenterology, Chase Farm Hospital, London, United Kingdom
AIMS
Increased:
1) Clinical EfficiencyReduced 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 SafetyA more comprehensive medical history will protect patients and via an
integration engine could feed directly into existing databases andelectronic patient records
INTRODUCTION
A number of studies have demonstrated the benefits of touch screenhistory taking in the primary care setting (Main, Quintela et al. 2004)
This project aims to evaluate the set up of a self directed automatedclinic using of a new innovative touch screen program (Pre-DocTM)designed by NHS professionals to establish key parts of a patient’shistory. The screen layout is designed to be clear and intuitive and theanswers to questions are delivered in an annotated form for rapidreading. We wish to establish whether this technology will providebetter clinical information than traditional history taking or paper formsand whether its use can improve clinical efficiency and the patientexperience of healthcare.
METHODS
We have developed a large database of questions that could be askedduring history taking. A computerised algorithm selects the next relevantquestion depending on the previous answer. A designer interface allowsquestionnaires to be developed and adjusted readily. The questions arephrased in plain English, but the program translates the answers intomedical terminology. The history is then available in PDF format forpresentation to the clinician. Patients self completed their history using atouch screen, and checked the results before printing. Comments about theprocess were recorded from patients and clinical staff. The system wastrialed in a hepatitis assessment clinic. Patients are fully informed about thisvoluntary and secure system prior to use.
RESULTS
443 patients used the touch screen. 12 did not complete theirhistory because of language problems (8) or indifference (3).The average time to complete was 14.7 minutes (range 7-21minutes). 7 patients were identified who were at high risk ofhepatitis infection, and a monospot test was offered andaccepted in all of these and further serological testsundertaken. 180 patients with known positive serologycompleted their history for use in a new patient hepatitisoutpatients clinic.
CONCLUSION
Patients found the touch screen easy to use, and were able tocomplete 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 risksand treatment options, and were able to ask supplementaryquestions rather than repeatedly obtaining basic data. Printoutsof the PDF were retained in the notes as part of the medicalrecord. This technology has shown great potential in allowingmore new patients to be seen, increasing efficiency in carryingout regular reviews, gathering better clinical information andreducing patient distress when asking sensitive questions.
Perceived benefits are – more rapid and thorough clinicalassessment; semi-automated follow up; health screening; andpatient surveys. There are applications for this technology inmany fields of medical practice.
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 CaReNet." Ann Fam Med 2(5): 421-424.
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SELF PROVIDED GUIDED MEDICAL HISTORY IS FAST, COMPLETE AND ACCURATEChloe van Someren 1, Niall van Someren 2Andrew Millar 1Gwen Edwards 11Gastroenterology, North Middlesex University Hospital, 2Gastroenterology, Chase Farm Hospital, London, United Kingdom
AIMS
Increased:
1) Clinical EfficiencyReduced 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 SafetyA more comprehensive medical history will protect patients and via an
integration engine could feed directly into existing databases andelectronic patient records
INTRODUCTION
A number of studies have demonstrated the benefits of touch screenhistory taking in the primary care setting (Main, Quintela et al. 2004)
This project aims to evaluate the set up of a self directed automatedclinic using of a new innovative touch screen program (Pre-DocTM)designed by NHS professionals to establish key parts of a patient’shistory. The screen layout is designed to be clear and intuitive and theanswers to questions are delivered in an annotated form for rapidreading. We wish to establish whether this technology will providebetter clinical information than traditional history taking or paper formsand whether its use can improve clinical efficiency and the patientexperience of healthcare.
METHODS
We have developed a large database of questions that could be askedduring history taking. A computerised algorithm selects the next relevantquestion depending on the previous answer. A designer interface allowsquestionnaires to be developed and adjusted readily. The questions arephrased in plain English, but the program translates the answers intomedical terminology. The history is then available in PDF format forpresentation to the clinician. Patients self completed their history using atouch screen, and checked the results before printing. Comments about theprocess were recorded from patients and clinical staff. The system wastrialed in a hepatitis assessment clinic. Patients are fully informed about thisvoluntary and secure system prior to use.
RESULTS
443 patients used the touch screen. 12 did not complete theirhistory because of language problems (8) or indifference (3).The average time to complete was 14.7 minutes (range 7-21minutes). 7 patients were identified who were at high risk ofhepatitis infection, and a monospot test was offered andaccepted in all of these and further serological testsundertaken. 180 patients with known positive serologycompleted their history for use in a new patient hepatitisoutpatients clinic.
CONCLUSION
Patients found the touch screen easy to use, and were able tocomplete 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 risksand treatment options, and were able to ask supplementaryquestions rather than repeatedly obtaining basic data. Printoutsof the PDF were retained in the notes as part of the medicalrecord. This technology has shown great potential in allowingmore new patients to be seen, increasing efficiency in carryingout regular reviews, gathering better clinical information andreducing patient distress when asking sensitive questions.
Perceived benefits are – more rapid and thorough clinicalassessment; semi-automated follow up; health screening; andpatient surveys. There are applications for this technology inmany fields of medical practice.
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 CaReNet." Ann Fam Med 2(5): 421-424.
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Dried blood Spot Testing for Hepatitis B and C
Aim
The aim was to set up a single viral hepatitis
community screening event to offer testing to
members of the Chinese community in Belfast
in an effort to determine the prevalence of
Hepatitis B (HBV) and Hepatitis C (HCV).
Introduction
The epidemiology of hepatitis B and C is
changing through out Europe, with immigration
cited by the European Centre for Disease Control
and Prevention as the main reason (ECDC, 2014)
Northern Ireland still has a very low prevalence of
viral hepatitis, with an average of 80 -100 HBV
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.
Annelies.McCurley1, Seana Murray1, Neil McDougall2 Hepatitis B&C Managed Clinical Network1, Regional Liver Unit2, Royal Victoria Hospital, Belfast
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.
The Liver Unit Royal Victoria Hospital
Methods
Members of the Belfast Chinese Community were
invited to attend a Hepatitis B&C awareness and
testing session held in the Chinese Welfare Centre. As
part of the criterion only those individuals that were
registered with a GP were eligible for screening. All
those attending for testing were educated regarding
the advantages and disadvantages of screening
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.
Results
•Prior to the event, 97 individuals expressed an interest via telephone in attending the screening event. 19 of
this cohort were not registered with a GP in Northern Ireland, and had to be excluded from the screening. A
further 10 individuals who attended the session on the day were again excluded as they too were not
registered with a GP giving a total of 29 individuals that were not eligible (figure1). The final number of
candidates included in the screening event was 55 . A synopsis of the demographic is as follows ; 62%
female, 38% male, mean age 47, range 22 -67.
•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).
Conflict of interest Funding for the dried blood spot testing kits and the analysis of these were paid for by Roche Pharmaceuticals
34(62%)
21(38%)
Gender of those who came forward for testing
Female
Male
N55
Figure 1:
4(7%)
13(24%)
1(2%) 37(67%)
Dry Blood Spot Test Results
HBsAG +
HBV core Ab +
HCV +
Neg results
N55
6(11%)
43(78%)
6(11%)
Number of individuals tested who reported being vaccinated
Yes
No
Not Sure
N55
Figure 3:
Figure 4: Figure 2:
in the Chinese Community living in Northern Ireland
19
10 55
84 individuals requested screening for Hepatitis B&C
At initial registrationtold they could not betested as notregistered with GP
Turned up at event.Not Registered withGP and could also notbe offered testing
Tested
N84
GASTROENTEROLOGY SOLUTION DRIVES DEPARTMENTAL EFFICIENCY AND SUPPORTS PATIENT SELF-MANAGEMENTUniversity 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 systemsAscribe, 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 careA 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.”
Reduced referrals and cost savingsThe 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.” Improved clinical engagementMulti-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 reportingAscribe’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 [email protected]
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“We expect to save at least £350,000 per year by
improving correct drug use in gastroenterology”
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• 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)
22 – 25 June 2015
A combined meeting of ACPGBI, AUGIS, BAPEN, BASL & BSG
ExCeL London, UK
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
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.
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!
Contact Details
To contact the DDF Conference Secretariat MCI UK LTD, please contact: [email protected]
If you are interested in Exhibition & Sponsorship Opportunities, please contact: [email protected]
For further information on DDF 2015, please visit conference website: www.ddf2015.org.uk
Full Interactive Online Programme LIVEEarlybird Registration – 20 March 2015
www.DDF2015.org.uk
REGISTER
TODAY
@DDFConference15 To discuss use #DDF2015
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:
FIT FOR THE FUTUREMeasurement 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 guaiac-based 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 Scotland’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 µg 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-home-screening-test-1610.aspx
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.
COMPANY NEWSG
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• 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)
22 – 25 June 2015
A combined meeting of ACPGBI, AUGIS, BAPEN, BASL & BSG
ExCeL London, UK
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
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.
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!
Contact Details
To contact the DDF Conference Secretariat MCI UK LTD, please contact: [email protected]
If you are interested in Exhibition & Sponsorship Opportunities, please contact: [email protected]
For further information on DDF 2015, please visit conference website: www.ddf2015.org.uk
Full Interactive Online Programme LIVEEarlybird Registration – 20 March 2015
www.DDF2015.org.uk
REGISTER
TODAY
@DDFConference15 To discuss use #DDF2015
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:
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: [email protected]