Gastroenterology Today Summer 2016

Volume 26 No. 1

Summer 2016

Gastroenterology Today In this issue Colorectal Cancer - Dying of Embarassment Piloting “Virtual� PEG Service Posters

CONTENTS

CONTENTS 4

EDITORS COMMENT

6

PAPER Colorectal cancer - dying of embarrassment

8

CASE REPORT Old foe to the rescue: Resistant GAVE and angiodysplasia treated with thalidomide

13

FEATURE P iloting “virtual” PEG service: single centre experience & predictors of mortality

22

NEWS

28

BSG POSTERS

37

COMPANY NEWS

Gastroenterology Today This issue edited by: Dr M Goldman BSc, MBBS, MRCP, FFPM c/o Media Publishing Company Media House 48 High Street SWANLEY, Kent BR8 8BQ ADVERTISING & CIRCULATION: Media Publishing Company Media House, 48 High Street SWANLEY, Kent, BR8 8BQ Tel: 01322 660434 Fax: 01322 666539 E: info@mediapublishingcompany.com www.MediaPublishingCompany.com PUBLISHING DATES: February, June and October.

COPYRIGHT: Media Publishing Company Media House 48 High Street SWANLEY, Kent, BR8 8BQ PUBLISHERS STATEMENT: The views and opinions expressed in this issue are not necessarily those of the Publisher, the Editors or Media Publishing Company.

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GASTROENTEROLOGY TODAY - SUMMER 2016

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3

EDITORS COMMENT

EDITORS COMMENT What the eye does not see Many of you will be aware that there is a primary care gastroenterology society, as it sometimes has sessions within the BSG, but it also has an independent existence with its own meetings and journal.

GASTROENTEROLOGY TODAY - SUMMER 2016

“The point as I saw it is that gastroenterological symptoms are very common – possibly resulting in up to 40% of primary care consultations.

This tidal wave of discomfort needs to be sorted and triaged so that the procedure heavy outpatient services of secondary care are not overwhelmed.”

I was recently a guest at a keynote meeting of the society together with the European society, in London.

For the first time in either society’s joint 51 year history and to celebrate 20 years of the ESPCG the two societies for Primary Care Gastroenterology combined their Spring meetings.

The meeting included talks, a quiz, a trade show and discussions relevant to general practitioners with a special interest in gastroenterology. As you might expect, their trade show did not include the now popular showings of the latest piece of computer controlled equipment, but it was fascinating to learn just how many of the audience were active endoscopists.

Amongst the talks was a presentation on the role of primary care in the Rome IV process. The Rome IV criteria relate to functional gastrointestinal disease and its diagnosis, and are symptom-based criteria. They are producing algorithms for evaluation of symptoms and clearly the objective is to progress to a rational management plan. The thinking is that the previous Rome III criteria resulted in underdiagnosis of functional conditions. The point as I saw it is that gastroenterological symptoms are very common – possibly resulting in up to 40% of primary care consultations. This tidal wave of discomfort needs to be sorted and triaged so that the procedure heavy outpatient services of secondary care are not overwhelmed. Some of the conditions may never receive therapy that is truly curative or suppressive, and primary care is clearly a very important clearinghouse for lesser complaints. The Rome IV web site is quite interesting, although it is a pity that the manuals are somewhat costly and this may be a dis-incentive. I was particularly enamoured by the Bristol Stool Chart T-shirt that was for sale on the web site.

Another fascinating session was entitled ‘Gut-brain-behaviour: biological barriers, nutrition and food intolerance’. This focused on the idea that there are links between nutrition and behaviour. Whilst secondary care may be provided with specialists in nutrition, because of compartmentalization, non-specific nutritional issues may not come the way of the hospital doctor. However, it seems that functional gastroenterological disorders are over-expressed in autism, and milk and wheat sensitivities have been linked to schizophrenia.

Similarly there are links between autism and diet and comments were made about a gluten-free casein-free diet (GFCF diet) or gluten-free dairy-free diet (GFDF diet) which eliminates dietary intake of the naturally occurring proteins gluten (found most often in wheat, barley, rye, and commercially available oats), and casein (found most often in milk and dairy products). The theory is that there is elimination of peptides which may be opioid receptor activators, and dietary impact is related to a particular phenotype in autism.

Another gut-brain link is also thought to be related to A1 beta casein in cows’ milk and it was noted that autism might be improved by camel milk! There is thought to be evidence for a leaky gut in cases of autism and this change in barrier properties may be a point of focus.

There must also be a significant amount of gastroenterology that never comes the way of either primary or secondary care. You only have to go into a pharmacy or supermarket to see just how many remedies are available over the counter, and some of them even without the intervention of a pharmacist or other professional. Cost and time have driven the population to self medicate, and the plethora of alternative therapists also offering advice.

The view of gastroenterology available to doctors is probably very narrow, and we should all remain aware of the fact that just because we do not see it in our practice, or the theory sounds a bit loopy, that gastroenterology is a huge label to capture an unbelievable amount of patient distress.

Dr M Goldman BSc, MBBS, MRCP, FFPM, Editor

4

EDITORS COMMENT

In patients with mild to moderate acute exacerbations of ulcerative colitis affecting the distal colon

Plan A RETURN TO EVERYDAY LIFE

The RETURN of ASACOL 1 g FOAM ENEMA means you can now meet the needs and preferences of more UC patients, more flexibly using a brand you trust.

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MESALAZINE

Combined Abbreviated Prescribing Information: bedtime. 500mg: A maximum of 3 a day, in divided doses, with the last dose at bedtime. Foam Enema: 1 (disease of rectosigmoid region) or 2 (disease of descending colon) metered doses as single daily dose for 4-6 weeks.

ELDERLY: The normal adult dosage may be used unless renal function is impaired. CHILDREN: 800mg Tablets: Not recommended. 400mg Tablets, Suppositories, Foam Enema: No dosage recommendation.

Contra-indications: A history of sensitivity to salicylates or renal sensitivity to sulfasalazine. Confirmed severe renal impairment (GFR <20ml/min). 400mg Tablets, Suppositories and Foam Enema only: Children under 2 years of age. 800mg Tablets only: Hypersensitivity to any of the ingredients. Severe hepatic impairment. Gastric or duodenal ulcer, haemorrhagic tendency.

Precautions: Use in the elderly should be cautious and subject to patients having a normal renal function. Asacol should be used with extreme caution in patients with confirmed mild to moderate renal impairment. Concurrent use of nephrotoxic agents, eg NSAIDs and azathioprine may increase risk of renal reactions. Renal function should be monitored (with serum creatinine levels measured) prior to start of treatment, and periodically during treatment, taking into account individual history & risk factors. Mesalazine should be discontinued if renal function deteriorates. If dehydration develops, normal fluid & electrolyte balance should be restored as soon as possible. Serious blood dyscrasias (some with fatal outcome) have been very rarely reported with mesalazine. Haematological investigations including a complete blood count may be performed prior to therapy initiation, during therapy, and are required immediately if the patient develops unexplained bleeding, bruising, purpura, anaemia, fever or sore throat. Stop treatment if suspicion or evidence of blood dyscrasia. 400mg Tablets and 800mg Tablets: Lactulose or similar preparations which lower stool pH should not be concomitantly administered. 400mg tablets, Suppositories, Foam Enema: Only use during pregnancy if benefits outweigh the risk. Avoid during lactation unless essential. 800mg Tablets only: Mesalazine should be used with caution during pregnancy and lactation when the potential benefit outweighs the possible hazards in the opinion of the physician. If neonate develops suspected adverse reactions consideration should be given to discontinuation of breast-feeding or discontinuation of treatment of the mother. Discontinue treatment immediately if acute symptoms of intolerance occur including vomiting, abdominal pain or rash. Patients with the rare

(MESALAZINE)

hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine because of the presence of lactose monohydrate. Standard haematological indices (including the white cell count) should be monitored repeatedly in patients taking azathioprine, especially at the beginning of such combination therapy, whether or not mesalazine is prescribed.

Undesirable Effects: Common: Nausea, diarrhoea, abdominal pain, headache. Rare reports of leucopenia, neutropenia, agranulocytosis, aplastic anaemia, thrombocytopenia, peripheral neuropathy, pancreatitis, abnormalities of hepatic function and hepatitis, myocarditis, pericarditis, alopecia, lupus erythematosus-like reactions and rash (inc. urticaria), drug fever, interstitial nephritis and nephrotic syndrome with oral mesalazine treatment, usually reversible on withdrawal. Renal failure has been reported.

Suspect nephrotoxicity in patients developing renal dysfunction. Very rarely, mesalazine may be associated with exacerbation of the symptoms of colitis, Stevens Johnson syndrome & erythema multiforme. 400mg Tablets, Suppositories, Foam Enema: Rare reports of allergic and fibrotic lung reactions. 800mg Tablets only: Common: vomiting, arthralgia / myalgia.

Rare reports of vertigo, bronchospasm, eosinophilic pneumonia, bullous skin reactions. Very rarely, interstitial pneumonitis. Suppositories, Foam Enema: Rarely, local irritation may occur after use of rectal dosage forms of mesalazine.

Legal category: POM. Marketing Authorisation Holder: Warner Chilcott UK Ltd, Old Belfast Road, Millbrook, Larne, County Antrim, BT40 2SH, UK. Asacol is a trademark. Refer to Summary of Product Characteristics before prescribing.

Date of preparation March 2014 Job Bag Number: UK/AS/0095/04-13(1)

Relieve, resolve, resume

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 UK/AS/0043/05-15g Date of preparation: August 2015

GASTROENTEROLOGY TODAY - SUMMER 2016

Asacol 400mg MR Tablet, Asacol 800mg MR Tablet, Asacol 250mg and 500mg Suppositories and Asacol Foam Enema Presentation: Asacol 400mg MR Tablets, PL 10947/0011; each modified release tablet contains 400mg mesalazine (5-aminosalicylic acid). Bottles of 120, £39.21. Bottles of 90, £29.41. Asacol 800mg MR Tablets, PL 10947/0012; each modified release tablet contains 800mg mesalazine (5- aminosalicylic acid). Bottles of 180, £117.62. Asacol 250mg Suppositories, PL 10947/0013, each containing 250mg mesalazine. Packs of 20, £4.82. Asacol 500mg Suppositories, PL 10947/0014, each containing 500mg mesalazine. Packs of 10, £4.82. Asacol Foam Enema, PL 10947/0015, 1g mesalazine per metered dose. Carton containing can of 14 metered doses, 14 disposable applicators and 14 disposable plastic bags, £26.72 Indications: Ulcerative colitis: Treatment of mild to moderate acute exacerbations. Maintenance of remission. Suppositories particularly appropriate for distal disease, Foam enema for distal colon disease only.

400mg Tablets, 800mg Tablets, Suppositories: Maintenance of remission.

400mg Tablets and 800mg Tablets only: Crohn’s ileo-colitis: Maintenance of remission.

Dosage and administration: ADULTS: 400mg Tablets: Acute disease: 6 tablets a day, in divided doses, with concomitant corticosteroid therapy where clinically indicated. Maintenance therapy: 3 to 6 tablets a day, once daily or in divided doses. 800mg Tablets: Mild acute exacerbations of ulcerative colitis: 3 tablets a day in divided doses. Moderate acute exacerbations of ulcerative colitis: 6 tablets a day in divided doses. Maintenance of remission of ulcerative colitis: Up to 3 tablets a day, once daily or in divided doses. Maintenance of remission of Crohn’s ileocolitis: Up to 3 tablets a day in divided doses.

Suppositories: 250mg: 3 to 6 a day, in divided doses, with the last dose at

5

PAPER

COLORECTAL CANCER DYING OF EMBARRASSMENT Dr Guy Chung-Faye, Head of Colorectal Cancer Screening (Kings College Hospital, London Professor Mike Parker, Consultant Laparoscopic, General and Colorectal Surgeon (Kent) Dr. Georges Kaye, General Practitioner (London) The alarming rise in the number of colorectal cancer cases in the UK

In 2012, a total of 16,187 people died from colorectal cancer in the UK.5

is a major cause for concern for both the public and the healthcare

In part, some of those 16,187 people did die from embarrassment, by not

community. Over a 30 year period, the incidence has risen by a

seeking medical attention or not undertaking screening tests. It is becoming

substantial 29% for men, while women have experienced a 7%

increasingly clear that we are in dire need of a national push for wide-scale

increase and in 2011, over 40,000 patients were diagnosed with

awareness around colorectal cancer screening and education is one of the

colorectal cancer.1

best weapons available. By informing patients about the symptoms of cancer, the importance of early detection and their screening options, and the fact

Although colorectal cancer is the second most common cause of all cancer

that the condition is often symptomless, particularly at an early stage, we

mortality in the UK, awareness is disproportionately small compared to other

can increase the need for prompt action and urge the public to get screened

cancers, such as breast and cervical cancer. Furthermore, the uptake of

sooner rather than later.

potentially life-saving screening tests is disappointingly low at around 50%.

The current screening programme for colorectal cancer in the UK involves, As with many cancers, there are many variables which can be attributed

either a low sensitivity test looking for blood in the stool or an invasive

to the rise of colorectal cancer, including a mix of lifestyle factors and

endoscopy examination of part of the bowel. With so many people citing

genetics.2 However, the real issue is a lack of awareness or understanding

embarrassment and inconvenience as a barrier to undergoing colorectal

of the importance of colorectal screening often resulting in delayed or late

screening, the recent introduction of a highly sensitive, non-invasive, at-

diagnosis, which adversely affects the outcome in many patients.

home collection kit, is welcome news. The first of its kind to look at stool

This is very disappointing, as the chance of a cure for those diagnosed in the early stages are around 90%, compared to 10% in those diagnosed at a very late stage of disease.3 Despite a clear and compelling rationale, evidence of cost-effectiveness, and widespread endorsement by authoritative groups, it seems colorectal cancer screening is a victim of lack of publicity. Screening rates today remain far below what would be necessary to achieve significant reductions in colorectal incidence and mortality.

Why is participation in colorectal cancer screening programmes so low?

Focus groups show that negative public sentiment towards colorectal cancer screening is centred on feelings of fear, embarrassment and projected GASTROENTEROLOGY TODAY - SUMMER 2016

discomfort, an insight that reveals the critical gap in public understanding of

screening kit for men and women, 50 years of age and above, who are at average risk for colorectal cancer. The test allows patients to screen for cancer and pre-cancer, being able to collect their sample for testing easily in the comfort of their own homes. Compared with existing screening techniques, which are less accurate, Cologuard is much more sensitive and will pick up many more cancers and also examines the whole of the colon, not just part of it – and thus picking up early cancers, and ultimately, saving lives.

As physicians, it is our responsibility to raise awareness of colorectal cancer and educate the public about all screening options available. While the advances in technology may result in more convenient, non-invasive screening options, it is the combination of education and technology that will provide our potential patients with the best colorectal screening options and treatment.

4

the process and the condition. It’s this lack of understanding, coupled with complex administrative and appointment processes, that has cultivated a strong public resistance against taking up colorectal cancer screening. Other screenings initiatives, such as in breast and cervical cancer, are greatly aided by social pressure, self-responsibility and widespread media coverage. The public perception of colorectal cancer screening ranges from embarrassment to

References 1. Cancer Research UK. Cancer Statistics. Bowel Cancer. Incidence.

Available at: http://www.cancerresearchuk.org/cancer-info/cancerstats/ types/bowel/incidence/uk-bowel-cancer-incidence-statistics (Last accessed April 2015)

projected discomfort of the test, which may explain the low level of participation.

2. Beating Bowel Cancer. What causes bowel cancer? Available at: https://www. beatingbowelcancer.org/causes-bowel-cancer (Last accessed April 2015)

Mr Phil Robarts, a Director at Baddow Hospital in Essex, with previous

3. Bowel Cancer UK. Improving capacity, saving lives: Endoscopy in the UK. 2012

experience of mass screening programmes cited that “It’s unfathomable that in this day and age, people are ultimately dying of embarrassment. There are effective screening methods available but they are of no use if people don’t use them. Ideally, we need what Jade Goody did for cervical cancer screening. The general public needs someone to relate to, to normalise the concept of testing for colorectal cancer.”

6

DNA, Cologuard® from Exact Sciences, is an easy-to-use colorectal cancer

4. Patient-reported barriers to colorectal cancer screening Am Jour Prev Med (2010) 38;5:508-16 5. Cancer Research UK. Cancer statistics. Bowel Cancer. Available at: http:// www.cancerresearchuk.org/cancer-info/cancerstats/types/bowel/ (Last accessed April 2015)

FEATURE

Because ulcerative colitis is a life-long condition

up to

33.7%

modified release mesalazine

400mg and 800mg

saving vs Asacol® (mesalazine) MR1

For mild to moderate ulcerative colitis

■ 2 million patient years’ experience2 ■ Offers significant cost savings in line with QIPP agenda1 ■ Patient online resource to help optimise adherence ‘There is no evidence to show that any one oral preparation of mesalazine is more effective than another; however, the delivery characteristics of oral mesalazine preparations may vary. If it is necessary to switch a patient to a different brand of mesalazine, modified release mesalazine 800mg the patient should be advised to report any changes in symptoms’3

GASTROENTEROLOGY TODAY - SUMMER 2016

Heritage and value

For mild to moderate ulcerative colitis

BNF, Mesalazine, September 2015-March 2016 Prescribing information can be found overfleaf

UK/OC/0036/1015a. Date of preparation: November 2015.

7

CASE REPORT

OLD FOE TO THE RESCUE: RESISTANT GAVE AND ANGIODYSPLASIA TREATED WITH THALIDOMIDE Andreas V. Hadjinicolaou, 1Sukhdev Chatu, 1Asif Mahmood Department of Gastroenterology, Division of Medicine, St Helier Hospital, Wrythe Lane, Carshalton, SM5 1AA, London, UK

1 1

Corresponding author: Dr A Mahmood Department of Gastroenterology, St Helier Hospital, Wrythe Lane, Carshalton, SM5 1AA, London, UK Tel: 0208 296 2000 Email: asif.mahmood@esth.nhs.uk Key Words: Gastrointestinal vascular malformations, Gastric antral venous ectasia (GAVE), Angiodysplasia, Thalidomide, Angiogenesis inhibitor, Blood transfusion

Abstract A 63-year-old man with immune thrombocytopaenic purpura and end-stage renal failure requiring haemodialysis presented with a 6-month history of intermittent melaena and was investigated for anaemia. A diagnosis of gastric antral venous ectasia and intestinal angiodysplasia was made and various

requiring endoscopic therapy. Recognised risk factors include hereditary haemorrhagic telangiectasia, von Willebrand disease and other bleeding tendencies, chronic kidney disease and aortic stenosis. Current treatment protocols are primarily based on invasive procedures such as endoscopy-guided ablation and coagulation, vessel embolization and surgical intervention to resect affected tissue. These procedures are

treatments were implemented to control the

not only intrusive and aggressive but are also

disease and its symptoms. A number of learning

relatively inefficient mainly because of natural

points were highlighted in the management of

lesion recurrence and because the exact site

the patient including the potential benefits of

of the lesions cannot be identified accurately

thalidomide administration in such cases.

especially if located in the small intestine.

We felt that the remarkable improvement of the In order to overcome problems posed with these

effects was important to report. This is a unique

procedures, various systemic pharmacological

case where the use of thalidomide controlled

agents have been tried. These include oestrogen

symptoms of gastrointestinal tract vascular

and progestagen hormonal therapy and the

malformations escaping the need for regular

somatostatin analogue octreotide, both of

invasive interventions and thus, improving quality

which have shown promising results in reducing

of life.

blood loss initially but their long-term efficacy

Journal: Gastroenterology Today Tillotts: Octasa Core Ad – PI Column Job no: 00475 Size: 247 x 57 mm Bleed: 0 mm Supply as: HR PDF

patient treated with thalidomide, without adverse

has remained inconclusive 3 4. More recently,

Introduction

based on findings suggesting overexpression

References 1. MIMS. Accessed online, November 2015.

2. Data on file, Tillotts Pharma AG. [Patient years – 2014].

3. British National Formulary. BNF70, September 2015-March 2016.

Accessed online, November 2015.

Vascular malformations in the gastrointestinal

within gastrointestinal vascular malformations,

UK/OC/0036/1015a. Date of preparation: November 2015.

Adverse events should be reported.

Reporting forms and information can be found at https://yellowcard.mhra.gov.uk.

Adverse events should also be reported to Tillotts Pharma UK Ltd. (address as above) Tel: 01522 813500.

www.tillotts.com

GASTROENTEROLOGY TODAY - SUMMER 2016

OCTASA 400mg Modified Release Tablets (mesalazine) and OCTASA 800mg Modified Release 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. No 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 liver or 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, mesalazine or any of the excipients, severe impairment of hepatic or renal function (GFR less than 30 ml/min). Warnings and Precautions: Urinary status (dip sticks) should be determined prior to and during treatment, at discretion of treating physician. Caution in patients with raised serum creatinine or proteinuria. Stop treatment immediately if renal impairment is evident. Haematological investigations are recommended prior to and during treatment, at discretion of treating physician. Stop treatment immediately if blood dyscrasias are suspected or evident. Caution in patients with impaired hepatic function. Liver function should be determined prior to and during treatment, as the discretion of the treating physician.

Do not use in patients with previous mesalazine-induced cardiac hypersensitivity and use caution in patients with previous myo- or pericarditis of allergic background. 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). Use with caution in patients with gastric or duodenal ulcers. Intact tablets in the stool may be largely empty shells. If this occurs repeatedly patients should consult their physician. Use with caution in the elderly subject to patients having normal or non-severely impaired renal and liver function. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption, should not take this medicine. Interactions: No interaction studies have been performed. May increase the myelosuppressive effects of azathioprine, 6-mercaptopurine or thioguanine. Monitoring of blood cell counts is recommended of these are used concomitantly. Fertility, pregnancy and lactation: Only to be used during pregnancy when the potential benefit outweighs the possible hazards. No effects on fertility have been observed. Adverse reactions: Dyspepsia, rash, eosinophilia (as part of an allergic reaction), altered blood counts (aplastic anemia, granulocytosis, pancytopenia, neutropenia, leucopenia, thrombocytopenia), hypersensitivity reactions such as allergic exanthema, drug fever, lupus erythematosus syndrome, pancolitis, myocarditis, pericarditis, allergic and fibrotic lung reactions (including dyspnoea, cough, bronchospasm, alveolitis, pulmonary eosinophilia, lung infiltration, pneumonitis), interstitial pneumonia, eosinophilic pneumonia, lung disorder, acute pancreatitis, changes in liver function parameters (increase in transaminases and cholestasis parameters), hepatitis, cholestatic hepatitis, 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, 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: May 2015.

(GI) tract such as gastric antral venous ectasia

thalidomide, an anti-angiogenic drug that

(GAVE) and intestinal angiodysplasias are

inhibits cellular VEGF expression, has been

uncommon but an increasingly recognized

proposed as a potential long-term treatment for

cause of GI haemorrhage and iron-deficiency anaemia

. Clinical presentation ranges

1, 2

GAVE and intestinal angiodysplasias 5 6. Here, we present the unique case of a patient with

from melaena to being asymptomatic and is

multiple gastrointestinal vascular malformations,

identified upon investigations for iron-deficiency

including GAVE, on haemodialysis for end-

anaemia or Gastrointestinal haemorrhage. This

stage renal failure and on a background of

disease spectrum can have a significant impact

haemorrhagic tendency due to idiopathic

on patient quality of life since it may require

thrombocytopenic purpura (ITP) that was

repeated blood transfusions, hospitalization,

successfully treated with thalidomide. To our

outpatient follow-up and emergency admission

knowledge, this is amongst the few cases

8 00475_Octasa Core Advert_Gastro Today_AW.indd 2

of vascular endothelial growth factor (VEGF)

23/05/2016 17:11

CASE REPORT displaying thalidomide effectiveness in gastrointestinal vascular malformations reported in the UK and the first one to acknowledge this outcome on a background of so many relevant comorbidities.

Case Presentation

Outcome and Follow-up Over the ensuing 12 months he had undergone 18 OGDs each time receiving ablative treatment in the form of APC for GAVE (Figure 2).

A 63-year-old male was referred to Gastroenterology service for evaluation due to a six-month history of episodic melaena. His medical history included end-stage renal failure of unknown aetiology requiring haemodialysis, hypertension, immune thrombocytopenic purpura (ITP), gout and hypothyroidism. Family history was unremarkable. His regular medication included bisoprolol, levothyroxine and amlodipine.

He reported periodically passing malodorous, tarry, black stool. As his haemoglobin level was 7.2gm/dl, he was transfused with three units of packed red cells and had an urgent oesophagoduodenogastroscopy (OGD). This showed two non-bleeding acute duodenal ulcers, gastric antral vascular ectasia (GAVE), and brushings were positive for Campylobacter-like organism (CLO) urease test (Figure 1). A colonoscopy showed a 4mm tubule-villous adenoma, which was resected, but no other cause for anaemia was seen. He was treated with eradication therapy for Helicobacter pylori infection.

Figure 2. Small bowel after argon photocoagulation (APC)

Despite this he remained transfusion-dependent. As he was refractory to endoscopic therapy, he was referred for surgical opinion. Following this, he underwent a distal partial gastrectomy.

Histological evaluation of the specimen confirmed extensive and severe GAVE. Following the surgery, he remained relatively well and transfusion-free for five months. Unfortunately, he developed melaena again with accompanying anaemia so again he became transfusion-dependent. Repeat OGD showed disease recurrence Figure 1. Gastric antral venous ectasia (GAVE) before any treatment

in his gastric remnant. In addition this time he also had extensive lesions in his small bowel, demonstrated on repeat small bowel video capsule endoscopy (Figure 3). His blood transfusion

Investigations

requirement did not alter despite regular endoscopic ablative therapy. Therefore, he was commenced on low dose thalidomide (50mg daily). He remained well on haemodialysis, transfusionfree with a stable haemoglobin level between 9.5-11.5 gm/dl and

alternative causes for anaemia. He continued to require frequent

with no further episodes of melaena until his last follow-up at 12

endoscopy and APC therapy due to on-going blood loss despite

months. During this period, based on endoscopic evaluation,

aggressive iron replacement, which included blood transfusions (2-3

the angiodysplastic lesions were reduced both in terms of size

units every 7-14 days), synthetic erythropoietin (EPREX; 10,000 units

and number (Figure 4). Treatment was tolerated well with no

three times per week) and intravenous iron sucrose infusions (Venofer;

reported adverse effects. Despite this remarkable improvement,

200mg per week during haemodialysis) for his anaemia.

the patient sadly died soon after his last follow-up due to his other comorbidities.

He continued to have intermittent bleeding with accompanying anaemia.

The repeat OGD showed complete healing of duodenal ulcers, however fresh blood was seen oozing from the areas of GAVE requiring treatment with argon plasma coagulation (APC). A push enteroscopy showed areas of widespread but non-bleeding angiodysplasia in the duodenum. A subsequent small bowel video capsule endoscopy did not show any other lesions in the distal small bowel and excluded other possible causes of GI-related anaemia including small bowel malignancy and Crohnâ&#x20AC;&#x2122;s disease.

Figure 3. Small bowel angiodysplasia before any treatment

GASTROENTEROLOGY TODAY - SUMMER 2016

Further investigations and expert haematological evaluation excluded

9

CASE REPORT cirrhosis, chronic kidney disease as well as connective tissue diseases.

Angiodysplasias are vascular malformations made up of dilated veins and capillaries (ectasias) that progress to fistulate and form areas that become prone to bleeding 8.The elderly are particularly susceptible as a result of chronic hypoxia in the GI tract that induces production of VEGF that leads to vascular endothelial cells proliferation and neovascularization with fragile vessels that lack smooth muscle and are vulnerable to damage 9. The increased risk of GI bleeding in end-stage renal failure requiring haemodialysis is thought to be due to uraemiainduced platelet dysfunction and intermittent heparin use during dialysis.

In fact, studies have shown that both angiodysplasias and GAVE are more common in patients with chronic renal failure than subjects with normal kidney function 10. In this case, the patient had coexisting ITP, which further increased the risk of haemorrhage.

Current treatments include surgery and endoscopic procedures, mainly argon photocoagulation (APC). Serial treatment with APC in GAVE can reduce transfusion requirement and raise haemoglobin levels 11, 12.

Figure 4. Small bowel after thalidomide treatment

However, inevitable recurrences with the need for regular intervention as well as risk of bowel perforation are significant issues 13, 14. In this case, GAVE was particularly aggressive and not only proved refractory

Discussion

to repeated endoscopic therapy but recurred very soon after partial gastrectomy.

Gastrointestinal vascular malformations including GAVE and intestinal angiodysplasia are uncommon but established causes of GI bleeding.

Thalidomide possesses both anti-inflammatory and anti-angiogenic qualities and could potentially target vascular malformations at the

GAVE was first described in 1953 but its aetiology remains unknown 7.

root of the problem 6 15. The use of thalidomide in the context of

Females are affected more than males. GAVE can be associated with

gastrointestinal vascular malformations has been published in the form

We can supply brush kits to suit each and every scope there is. By using the scope model numbers we can easily match which kit will suit each scope, if we do not already have a kit to suit, we will simply make a new one.

Most kits come supplied with a single use port cleaning brush but these can be supplied separately if required.

GASTROENTEROLOGY TODAY - SUMMER 2016 Unit 21, Agecroft Enterprise Park, Shearer Way, Swinton, Manchester, M27 8WA United Kingdom

10

During all procedures where a biopsy is taken, the irrigation tap allows the end user to flush over the top of the biopsy tool whilst it is still inserted in the body and also washes the blood present to increase visibility around the area where the biopsy has been taken to ensure sufficient sample tissue has been taken. Providing the end user is using a Pentax scope which have a standard luer fitting on the exit of all their working channels.

Tel: +44 (0)161 743 9772 E-mail: sales@h4medical.co.uk Web: www.h4medical.co.uk

Our single use biopsy bungs are brand new to the market, the sky blue is suitable for Olympus and Fujinon and the claret ones are made to fit Pentax scopes. Can be supplied sterile or non-sterile.

CASE REPORT of case reports and case series but only one randomised controlled trial exists to support its effects 16-22. Of these studies, only one has evaluated the impact of thalidomide in end-stage renal failure 23.

Our findings are in keeping with the literature whereby thalidomide use was an effective systemic therapy for vascular malformations with significant improvement in quality of life, healing of GI lesions and reduction or even abolition of need of frequent interventions such as APC and blood transfusions.

Our case is the first one to report the remarkable sudden and sustained benefit of thalidomide on GI vascular malformations, on a background of coexisting end-stage renal failure and bleeding tendency (ITP).

Fortunately, none of thalidomideâ&#x20AC;&#x2122;s side effects, which include fatigue, peripheral neuropathy and constipation, were precipitated in this case.

This suggests that, at least in the presence of end-stage renal failure, the low doses of thalidomide used in our case are sufficient to achieve therapeutic effects for GI vascular malformations whilst maintaining safety which can be an issue with high doses of 200-400mg/ day regularly reported in the current literature. Regular monitoring of electrolytes is nevertheless essential especially for potassium since thalidomide can provoke hyperkalaemia in patients with renal impairment 24.

This report should encourage further large-scale clinical studies and randomised controlled trials to assess the beneficial effects of thalidomide especially for patients with treatment-resistant vascular malformations on a background of end-stage renal failure, a cohort known to have increased prevalence of this disease. We believe that thalidomide should be trialled in patients with GAVE and/or intestinal andiodysplasia that fail to respond to conventional therapy since it appears to be effective and well tolerated.

References 1. Ell C, Remke S, May A, Helou L, Henrich R, Mayer G. The first prospective controlled trial comparing wireless capsule endoscopy with push enteroscopy in chronic gastrointestinal bleeding.

Endoscopy 2002;34(9):685-9.

8. Sinha S, Williams JL, Eddington H, Chrysochou C, Lamerton E, Babbs C, et al. Small bowel angiodysplasia in a patient on haemodialysis: difficulties in diagnosis and management. BMJ Case Rep 2009;2009.

9. Szilagyi A, Ghali MP. Pharmacological therapy of vascular malformations of the gastrointestinal tract. Can J Gastroenterol 2006;20(3):171-8.

10. Chalasani N, Cotsonis G, Wilcox CM. Upper gastrointestinal bleeding in patients with chronic renal failure: role of vascular ectasia. Am J Gastroenterol 1996;91(11):2329-32.

11. Gostout CJ. Gastrointestinal bleeding in the elderly patient. Am J Gastroenterol 2000;95(3):590-5.

12. Yusoff I, Brennan F, Ormonde D, Laurence B. Argon plasma coagulation for treatment of watermelon stomach. Endoscopy 2002;34(5):407-10.

13. Ben-Soussan E, Antonietti M, Savoye G, Herve S, Ducrotte P, Lerebours E. Argon plasma coagulation in the treatment of hemorrhagic radiation proctitis is efficient but requires a perfect colonic cleansing to be safe. Eur J Gastroenterol Hepatol 2004;16(12):1315-8.

14. Rosenfeld G, Enns R. Argon photocoagulation in the treatment of gastric antral vascular ectasia and radiation proctitis. Can J Gastroenterol 2009;23(12):801-4.

15. Tramontana JM, Utaipat U, Molloy A, Akarasewi P, Burroughs M, Makonkawkeyoon S, et al. Thalidomide treatment reduces tumor necrosis factor alpha production and enhances weight gain in patients with pulmonary tuberculosis. Mol Med 1995;1(4):384-97.

16. Alberto SF, Felix J, de Deus J. Thalidomide for the treatment of severe intestinal bleeding. Endoscopy 2008;40(9):788; author reply 789.

17. Bauditz J, Schachschal G, Wedel S, Lochs H. Thalidomide for treatment of severe intestinal bleeding. Gut 2004;53(4):609-12.

18. Dabak V, Kuriakose P, Kamboj G, Shurafa M. A pilot study of thalidomide in recurrent GI bleeding due to angiodysplasias. Dig Dis Sci 2008;53(6):1632-5.

19. Dunne KA, Hill J, Dillon JF. Treatment of chronic transfusiondependent gastric antral vascular ectasia (watermelon stomach) with thalidomide. Eur J Gastroenterol Hepatol 2006;18(4):455-6.

3. Junquera F, Saperas E, Videla S, Feu F, Vilaseca J, Armengol JR, et al. Long-term efficacy of octreotide in the prevention of recurrent bleeding from gastrointestinal angiodysplasia. Am J Gastroenterol 2007;102(2):254-60.

20. Garrido A, Sayago M, Lopez J, Leon R, Bellido F, Marquez JL. Thalidomide in refractory bleeding due to gastrointestinal angiodysplasias. Rev Esp Enferm Dig;104(2):69-71.

4. Junquera F, Feu F, Papo M, Videla S, Armengol JR, Bordas JM, et al. A multicenter, randomized, clinical trial of hormonal therapy in the prevention of rebleeding from gastrointestinal angiodysplasia.

Gastroenterology 2001;121(5):1073-9.

5. Junquera F, Saperas E, de Torres I, Vidal MT, Malagelada JR. Increased expression of angiogenic factors in human colonic angiodysplasia. Am J Gastroenterol 1999;94(4):1070-6.

6. Dâ&#x20AC;&#x2122;Amato RJ, Loughnan MS, Flynn E, Folkman J. Thalidomide is an inhibitor of angiogenesis. Proc Natl Acad Sci U S A 1994;91(9):4082-5.

7. Rider JA, Klotz AP, Kirsner JB. Gastritis with veno-capillary ectasia as a source of massive gastric hemorrhage. Gastroenterology 1953;24(1):118-23.

21. Ge ZZ, Chen HM, Gao YJ, Liu WZ, Xu CH, Tan HH, et al. Efficacy of thalidomide for refractory gastrointestinal bleeding from vascular malformation. Gastroenterology;141(5):1629-37 e1-4.

22. Shurafa M, Kamboj G. Thalidomide for the treatment of bleeding angiodysplasias. Am J Gastroenterol 2003;98(1):221-2.

23. Mimidis K, Kaliontzidou M, Tzimas T, Papadopoulos V. Thalidomide for treatment of bleeding angiodysplasias during hemodialysis. Ren Fail 2008;30(10):1040-1.

24. Harris E, Behrens J, Samson D, Rahemtulla A, Russell NH, Byrne JL. Use of thalidomide in patients with myeloma and renal failure may be associated with unexplained hyperkalaemia. Br J Haematol 2003;122(1):160-1.

GASTROENTEROLOGY TODAY - SUMMER 2016

2. Regula J, Wronska E, Pachlewski J. Vascular lesions of the gastrointestinal tract. Best Pract Res Clin Gastroenterol 2008;22(2):313-28.

11

FEATURE For distal ulcerative colitis1,2

An oral treatment that delivers like a rectal?

What a relief.

When you’ve just been diagnosed with ulcerative colitis, rectal therapy isn’t always the most welcome of prospects.

Thankfully, Salofalk Granules, with their nifty dual release mechanism, allow continuous mesalazine release throughout the entire colon.1 Which means they work rather well, even for those with distal disease.2

Where it works is why it works

4 hrs 20 mins

9 hrs 30 mins

24 hrs

GASTROENTEROLOGY TODAY - SUMMER 2016

Prescribing Information (Please refer to full SPC before prescribing): Salofalk gastro-resistant prolonged-release granules Presentation: Stick-formed or round, greyish white gastro-resistant prolongedrelease granules in sachets containing 500mg, 1000mg, 1.5g or 3g mesalazine per sachet. Indications: Treatment of acute episodes and the maintenance of remission of ulcerative colitis. Dosage: Adults: Once daily 1 sachet of 3g granules, 1 or 2 sachets of 1.5g granules or 3 sachets of 1000mg or 500mg granules (equivalent to 1.5 – 3.0g mesalazine daily) preferably to be taken in the morning, according to the individual clinical requirement. It is also possible to take the prescribed daily dose in three divided doses (1 sachet of 500mg granules three times daily or 1 sachet of 1000mg granules three times daily) if this is more convenient. Maintenance: 0.5g mesalazine three times daily (in the morning, at midday and in the evening) corresponding to a total dose of 1.5g mesalazine per day. For patients known to be at increased risk for relapse for medical reasons or due to difficulties to adhere to application of three daily doses the dosing schedule can be adapted to 3.0g mesalazine given as a single daily dose, preferably in the morning. Children: There is only limited documentation for an effect in children (age 6-18 years). Children 6 years of age and older: Active disease: To be determined individually, starting with 30-50mg/kg/day once daily preferably in the morning or in divided doses.

Maximum dose: 75mg/kg/day. The total dose should not exceed the maximum adult dose. Maintenance treatment: To be determined individually, starting with 15-30mg/kg/day in divided doses. The total dose should not exceed the recommended adult dose. It is generally recommended that half the adult dose may be given to children up to a body weight of 40kg; and the normal adult dose to those above 40kg. Method of administration: The granules should be taken on the tongue and swallowed, without chewing, with plenty of liquid.

Contra-indications: Hypersensitivity to salicylates or any of the excipients.

Severe impairment of renal or hepatic function. Warnings/Precautions: Blood tests (differential blood count; liver function parameters such as ALT or AST; serum creatinine) and urinary status (dip sticks) should be determined prior

12

Spread of Salofalk Granules in the gut shown using gamma-scintigraphy

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: Specific interaction studies have not been performed. Lactulose or similar preparations that lower stool pH: possible reduction of mesalazine release from granules due to decreased pH caused by bacterial metabolism of lactulose. In patients who are concomitantly treated with azathioprine, 6-mercaptopurine or thioguanine a possible increase in the myelosuppressive effects of azathioprine, 6-mercaptopurine or thioguanine should be taken into account. There is weak evidence that mesalazine might decrease the anticoagulant effect of warfarin. Use in pregnancy and lactation: There are no adequate data. Do not use during pregnancy unless the potential benefit outweighs the possible risks. Limited experience in the lactation period. Use during breast-feeding only if the potential benefit outweighs the possible risks; if the infant develops diarrhoea, breast-feeding should be discontinued. Undesirable effects: Headache, dizziness, periand myocarditis, abdominal pain, diarrhoea, flatulence, nausea, vomiting, aplastic anaemia, agranulocytosis, pancytopenia, neutropenia, leukopenia, thrombocytopenia, peripheral neuropathy, allergic and fibrotic lung

Mesalazine, the Dr Falk way

reactions (including dyspnoea, cough, bronchospasm, alveolitis, pulmonary eosinophilia, lung infiltration, pneumonitis), acute pancreatitis, impairment of renal function including acute and chronic interstitial nephritis and renal insufficiency, alopecia, myalgia, arthralgia, hypersensitivity reactions such as allergic exanthema, drug fever, lupus erythematosus syndrome, pancolitis, changes in hepatic function parameters, hepatitis, cholestatic hepatitis and oligospermia (reversible). Legal category: POM. Basic cost: Salofalk 500mg granules, pack size 100 sachets – £28.74; €41.55. Salofalk 1000mg granules, pack size 50 sachets – £28.74; €38.28. Salofalk 1.5g Granules, pack size 60 sachets – £48.85; €56.05. Salofalk 3g Granules pack size 60 sachets – £97.70; €129.07 (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. Brunner M et al. Aliment Pharmacol Ther 2003; 17: 1163–9.

2. Leifeld L et al. Aliment Pharmacol Ther 2011; 34: 1115–22.

Date of preparation: March 2016

DrF 16/026

FEATURE

PILOTING “VIRTUAL” PEG SERVICE: SINGLE CENTRE EXPERIENCE & PREDICTORS OF MORTALITY Corresponding author: Ms Deepika Reddy; Department of Gastroenterology, King’s College Hospital London, Deepika.reddy@nhs.net Dr Sukhdev Chatu; Department of Gastroenterology, King’s College Hospital London, sukhdev.chatu@nhs.net Miss Louise Bensaid; Department of Gastroenterology, King’s College Hospital London, louisebensaid@nhs.net Dr Bu Hayee; Department of Gastroenterology King’s College Hospital London, b.hayee@nhs.net Dr Patrick Dubois; Department of Gastroenterology, King’s College Hospital London, Patrick.dubois@nhs.net

Abstract Objective: To evaluate the safety and effectiveness of a virtual Percutaneous Endoscopic Gastrostomy (PEG) referral pathway compared to conventional approach.

Design: Retrospective evaluation of a prospectively collected database of all patients referred for PEG by the conventional and virtual referral

Judging whether placement of a PEG tube is in the patient’s best interest is complex and assessment by a multidisciplinary team is recommended. As part of a service improvement initiative to impact on increasing work load on Gastroenterology services we piloted a virtual PEG service, whereby the referring team complete a comprehensive electronic referral form which is assessed by a multidisciplinary team on-line to inform decision making as to the suitability of a PEG.

pathway. Principle outcomes were compared between both groups.

The aim of this study was to evaluate the safety and effectiveness of

Setting: Single centre study.

conventional PEG service which has been established at our institution

Patients: Over a two year period 179 patients were referred for PEG.

mortality after PEG insertion.

Only those that underwent a PEG (n=93) were included in the analysis.

our virtual PEG service by comparing pertinent endpoints with the for many years. In addition we evaluated factors associated with

Of these 43 were referred by the conventional and 50 by virtual pathway.

Methods

Interventions: Patients were referred either by the conventional (review

An application was submitted to the trust Research and Development

by a nutrition team member) or virtual pathway (an electronic request

department. This was a retrospective study and all patients referred

form evaluated by a team to reach a consensus).

for a PEG in 2011 and 2012 were eligible for inclusion in the analysis. Clinical data including indication, demographic details

Main outcome measures: Included mean age at referral, gender,

and outcomes are recorded prospectively into the departmental

morbidity associated with PEG insertion, 30 day and 12 month all cause

database. In addition the electronic medical records were evaluated

mortality rates.

retrospectively for each patient to validate and add to the database.

During the study period the same endoscopist performed the

Results: Within the conventional group 17 cases had documented

procedure, allowing comparison between the two patient groups.

morbidity associated with PEG insertion, compared with 11 in the Our PEG multi-disciplinary team comprises Gastroenterologists,

all-cause mortality between the conventional and virtual referral group

Palliative Care Physician, Clinical Gerontologist, Nurse Endoscopist,

(p= 0.74). Advanced age (≥65years) was associated with increased 12

Dieticians and Speech and Language Therapists. The conventional

month mortality (hazard ratio 2.34; CI: 1.11-4.90 p=0.03).

practice at our institution was for all PEG referrals to be reviewed

Conclusion: A virtual PEG referral pathway is as safe and effective when compared to conventional approach and should be considered as a tool to impact on the increasing workload on Gastroenterological services. We found elderly patients had a greater than 2 fold risk of overall mortality within 12 months of PEG insertion.

Introduction

by at least one member of the multidisciplinary team, usually the Gastroenterologist. As part of service development since the beginning of 2012 we implemented a “virtual” PEG assessment service. In close liaison with our IT department we developed and piloted a PEG request form (figure 1) available on the hospitals electronic patient records (EPR).

Following submission of the on-line PEG insertion request form, each member of the team receives the completed referral form by

Percutaneous Endoscopic Gastrostomy (PEG) is an established means

email. This form contains several mandatory fields, including contact

of achieving nutritional needs in those patients who have a functionally

details of Dieticians and Speech and Language Therapists who have

normal gastrointestinal tract but cannot maintain their requirements

reviewed the patient (figure 1).The referral is reviewed virtually through

with an oral diet. This technique was first described in 1980 and is

email or telephone consultation with colleagues within the PEG team

widely practiced[1]. It is estimated that approximately 17,000 PEGs are

and those directly involved in the patient’s care, facilitated by referring

undertaken annually in the UK[2].

to electronic medical notes and results on EPR.

GASTROENTEROLOGY TODAY - SUMMER 2016

virtual group (p>0.05). There was no significant difference in 12 month

13

FEATURE

Happy with her selfie When the symptoms of Crohn’s disease are already harming her self-esteem, steroid-related side-effects can make things even worse.1 Budenofalk is different - it offers the efficacy of a systemic steroid, but the side-effect level is more like mesalazine.2,3

Now that’s something to smile about.

Eudragit L/S coating modified release formulation meaning the drug is released in the terminal ileum and caecum4

50x

greater receptor affinity than prednisolone meaning a lower effective steroid dose is required5,6

90%

pre-systemic clearance meaning the potential risk of side-effects is limited2

Corticosteroids, the Dr Falk way

GASTROENTEROLOGY TODAY - SUMMER 2016

Prescribing Information (Please refer to full SPC before prescribing) Presentation: Budenofalk® 9 mg gastro-resistant granules, each sachet contains 9mg budesonide, 828mg sucrose, 36mg lactose monohydrate and 900mg sorbitol. Budenofalk® 3mg gastro-resistant capsules, each containing 3mg budesonide, 240mg sucrose and 12mg lactose monohydrate. Indications: (granules and capsules) Induction of remission of mild to moderate active Crohn’s disease affecting the ileum and/or the ascending colon.

Extraintestinal symptoms unlikely to respond. Induction of remission of active collagenous colitis. Autoimmune hepatitis (capsules only). Dosage: Adults: Granules: One sachet daily, in the morning, half an hour before food, taken with liquid without chewing or crushing granules. Capsules: For Crohn’s disease and collagenous colitis, three capsules once daily, in the morning, half an hour before food and taken with liquid. One capsule three times daily if more convenient. Both formulations: limit treatment to 8 weeks. Treatment should not be stopped abruptly but withdrawn gradually. For autoimmune hepatitis, one capsule three times daily. Combine with azathioprine in suitable cases. For maintenance of remission: one capsule twice daily (morning and evening).

Revert to 3 capsules daily in the event of elevated transaminases ALAT and/or ASAT. Continue treatment for maintenance of remission of autoimmune hepatitis for 24 months. Children: Not recommended in children younger than 12 years. Safety and efficacy in adolescents aged 12 -18 years has not been established. See SmPC sections 4.8 and 5.1 for data. No specific dose recommendations in renal/hepatic impairment.

Contraindications: hypersensitivity to budesonide or any of the ingredients. Hepatic cirrhosis. Warnings/ Precautions: Transfer of patients from other steroid therapy may result in symptoms relating to the lowering of systemic steroid levels. Use with caution in patients with tuberculosis, hypertension, diabetes mellitus, osteoporosis, peptic ulcer, glaucoma, cataracts or family history of glaucoma or diabetes, or any other condition in which glucocorticoids may have undesirable effects. Not appropriate for use in upper GI Crohn’s disease or for extraintestinal symptoms e.g., of the eyes, skin, joints. Long term, high dose use may result in systemic effects of corticosteroids such as Cushing’s syndrome, adrenal suppression, growth retardation, decreased bone mineral density, cataract, glaucoma and rarely, psychiatric/behavioural effects. Infection: suppression of the inflammatory response and immune function increases susceptibility to infections and their severity, with risk of deterioration of bacterial, fungal, amoebic and viral infections. The clinical presentation of infections may be atypical and the presentation of serious infections e.g. septicaemia and tuberculosis, may be masked.

Chickenpox can be fatal in immunosuppressed patients. Those without definite medical history of this infection should avoid close personal contact with chickenpox or herpes zoster and seek medical attention if exposed.

Passive immunisation is needed by exposed non-immune patients receiving (or who have received within the previous 3 months) systemic corticosteroids, within 10 days of exposure to chickenpox. Urgent specialist care is required if chickenpox is confirmed; corticosteroids should not be stopped and dosage may need to be increased. Measles: Immunosuppressed patients who come into contact with measles should receive normal immunoglobulin as soon as possible after exposure. Live vaccines should not be given to patients with chronic corticosteroid use/impaired immune responsiveness. Antibody response to other vaccines may be diminished. Patients with liver function disorders: increased systemic bioavailability of budesonide expected where there is severe impairment. Other: Corticosteroids may suppress the HPA axis and reduce the stress response. Supplementary systemic glucocorticoid treatment is recommended in patients subject to surgery or other stress. Concomitant treatment with ketoconazole or other CYP3A4 inhibitors should be avoided. Do not use in patients with rare hereditary problems of galactose or fructose intolerance, glucose – galactose malabsorption, sucrase – isomaltase insufficiency or Lapp lactase deficiency or congenital lactase deficiency. In autoimmune hepatitis evaluate transaminase levels every 2 weeks for the first month and then every 3 months.

Can lead to positive results in doping tests. Interactions: Concomitant administration of cardiac glycosides may

14

potentiate the activity of the glycoside (due to increased excretion of potassium); simultaneous treatment with saluretics may exacerbate the hypokalaemia. Avoid concomitant administration with ketoconazole, grapefruit juice or other CYP3A4 inhibitors (e.g. ritonavir, itraconazole and clarithromycin) because they may markedly increase the plasma concentrations of budesonide. CYP3A4 inducers (e.g. carbamazepine and rifampicin) may reduce systemic and local (gut mucosa) exposure, necessitating dose adjustment of budesonide. CYP3A4 substrates may compete with budesonide leading to possible increases in plasma concentrations of either budesonide or substrate, depending on their relative affinities for this enzyme. Elevated plasma concentrations and enhanced effects of corticosteroids have been reported with oestrogens or oral contraceptives, although not with oral low dose contraceptives. Cimetidine has a small (non-significant) effect on the kinetic effects of budesonide. Omeprazole has no effect on the pharmacokinetics of budesonide. Steroid-binding compounds (e.g. cholestyramine) and antacids may reduce the efficacy of budesonide, therefore they should be given at least 2 hours apart. Use in pregnancy and lactation: Budenofalk should be avoided during pregnancy unless essential. Avoid breastfeeding during Budenofalk treatment. Undesirable effects: Cushing’s syndrome e.g., moon-face, truncal obesity, reduced glucose tolerance, diabetes mellitus, hypertension, sodium retention with oedema, increased excretion of potassium, inactivity or atrophy of the adrenal cortex, red striae, steroid acne, disturbance of sex hormone secretion (e.g. amenorrhoea, hirsutism, impotence). Growth retardation in children, glaucoma, cataracts, stomach complaints, constipation, gastroduodenal ulcers, pancreatitis, increase in risk of infections, muscle and joint pain and weakness and twitching, osteoporosis, aseptic necrosis of bone, headache, pseudotumor cerebri (including papilloedema) in adolescents, depression, irritability and euphoria, a range of psychiatric/behavioural effects, allergic exanthema, petechiae, ecchymosis, contact dermatitis, delayed wound healing, increased risk of thrombosis, vasculitis (after withdrawal from long-term treatment), tiredness and malaise, dizziness, nausea, vomiting, hyperacusis. Occasionally side effects characteristic of systemic corticosteroid therapy may occur although clinical studies have shown that the frequency of these side effects is lower with Budenofalk (approximately half) than with oral equivalent doses of prednisolone. Other adverse effects include exacerbation or reappearance of extraintestinal manifestations when switching treatment from systemically acting glucocorticosteroids. Legal category: POM. UK NHS Cost: (granules) packs of 60 sachets £135; (capsules) packs of 100 capsules £75.05. Ireland cost (PtW): (granules) packs of 60 sachets: €165.80; (capsules) packs of 100 capsules: €78.96. Product licence holder: Dr Falk Pharma GmbH, Leinenweberstr.5, D-79108 Freiburg, Germany. Product licence number: (granules) PL08637/0020 (UK) PA573/2/3 (IE) (capsules) PL08637/0002 (UK) PA573/2/1 (IE). Date of preparation: May 2015.

Further information is available on request.

Adverse events should be reported. Reporting forms and information can be found at www.mhra.gov.uk/yellowcard (UK residents) or at http://www.hpra.ie/homepage/about-us/report-an-issue (residents of the Republic of Ireland). Adverse events should also be reported to Dr Falk Pharma UK Ltd. References: 1. McDermott E et al. Inflamm Bowel Dis 2015; 21(2): 353-60. 2. De Cassan C et al. Dig Des 2012; 30(4): 368-75. 3. Bar-Meir S et al. Gastroenterol 1998; 115(4): 835-40. 4. Data on file, Dr Falk Pharma.

5. Möllman HW et al. In: Möllman HW, May B. Glucocortcoid Therapy in Chronic Inflammatory Bowel Disease.

Dordrecht: Kluwer 1996. 6. He Y et al. Cell Res 2014; 24(6): 713-26.

Date of preparation: December 2015

DrF15/143

FEATURE Results

This process enables rapid decisions for cases in which PEG is clearly indicated. In more complex cases, areas of concern or uncertainty can be highlighted by any member of the MDT, usually by replying to the group email. Where concerns cannot be resolved virtually, appropriate specialist review (e.g. gastroenterology, palliative care, gerontology, neuropsychiatry, speech and language therapy) is instigated. In some complex cases, virtual assessments are continued over a period of days or sometimes weeks, allowing updates to be fed back to the team and responded to. Once a final decision is made this is documented in the medical notes by a member of the PEG team (usually the gastroenterology registrar).

The patient is listed for PEG insertion and the gastroenterology/ endoscopy team instruct the ward team regarding pre-endoscopy preparation.

Out of 179 patients referred for PEG in total 93 patients underwent the procedure and were eligible for inclusion into the study with 43 in the conventional group and 50 in the virtual group. Overall the median age was 58 (IQR 45-72) and 46% were women (Table 1). The median time to PEG insertion from referral was 10 days (IQR 6-21).

Factors associated with all-cause mortality The overall probability of all-cause mortality was 38% (95% CI: 0.280.50) at 12 months from PEG insertion (Figure 2a). Kaplan Meier analysis demonstrated no significant difference between overall mortality between the conventional and virtual group (log rank p=0.74) (Figure 2b). Cox regression was used to demonstrate factors associated

Statistical analysis

with all-cause mortality within 12 months of PEG insertion in the whole cohort comprising 93 patients (Table 2). Multivariate regression

Statistical analysis was performed using STATA version 11. Cox

demonstrated there was no significant difference in risk of mortality

regression was used to assess factors associated with mortality which

between the conventional versus virtual method (HR 0.83; CI: 0.41-

included age, gender, indication for PEG and conventional versus virtual

1.70). There was no difference between gender (HR0.96; CI: 0.47-1.96).

method. We presented means or medians (range) in the case of any

The 12 month mortality was higher in the elderly defined by â&#x2030;Ľ65 vs. < 65

non-Gaussian distributions for continuous variables and categorical

(HR 2.34; CI: 1.11-4.90). Evaluation by indication for PEG revealed no

variables are expressed as percentages. Two tailed p- values of <0.05

significant difference compared to stroke: Neurodegenerative vs. stroke

were considered significant and 95% confidence interval (CI) was

(HR 0.90; CI: 0.39-2.05), disease related malnutrition vs. stroke (HR

calculated for each statistic to provide an estimate of uncertainty.

0.97; CI: 0.34-2.77) and head injury vs. stroke (HR 0.30; CI: 0.04-1.69).

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15

FEATURE Discussion Main findings

thereafter would not have been captured. We had no recorded PEG exit

This study has demonstrated that the virtual pathway was as safe and

Clinical implications

effective compared to the conventional method. There were no serious complications such as major bleeding requiring blood transfusion, endoscopic, radiological or surgical intervention. There were two cases of bleeding from the abdominal puncture site occurring during the procedure but were controlled with compression in the conventional group. There were no cases of perforation in either group.

Multivariate Cox regression evaluated factors associated with all-cause mortality including era of PEG, age group and gender. We found the elderly defined by an age that was more than 65 years old according to the World Health Organisation had a two-fold higher mortality than those less than 65. There was no difference in mortality with regard to gender and indication and the virtual and conventional methodology. The increased mortality in the elderly group reflects increased morbidity.

In relation to the literature There are no comparative studies evaluating a virtual PEG service that we could find in the published literature since to our knowledge this is a novel methodology. A national survey[3] evaluated PEG service provision in the UK and found that most centres were performing between 26-50 PEGs a year and 33% (70/216) inserting more than 75 new PEGs a year.

The number of new PEGs performed at our centre annually were similar to what most units are reporting in this survey whereby we performed 43 and 50 procedures in 2011 and 2012 respectively.

The difference in mortality compared to national estimates may reflect variation in patient selection which has previously been shown by a report released by the recent National Confidential Enquiry into Patient Outcome and Death (NCEPOD)[4]. Their evaluation reported a 30-day mortality rate in a cohort of 16,648 patients of 6% and of those that died 48% did within 1 week of the procedure. Our 30-day mortality rate was similar at 9%. It may be that differences in practice and patient selection

missed since GP consultations were not captured.

This study has shown that a virtual PEG assessment service can be as safe and effective as the conventional PEG service which is widely practised in the UK. Adoption and further evaluation of this strategy in other centres is required before this can be advocated more widely. Advantages of virtual methods include assessment of each referral by all members of the team, and reductions in time and resources allocated to PEG assessments.

The advantages of a virtual PEG assessment pathway include i) Ensuring each patient has access to assessment from all members of the multi-disciplinary team. A virtual service can improve MDT member participation by enabling each specialist to contribute to assessments at their convenience, and to follow and respond to new information shared within the group as it emerges. ii) Improving the efficiency of MDT assessment in patients referred for consideration of PEG insertion. In cases where PEG is obviously indicated a decision to list for PEG insertion can be made very quickly by the PEG MDT. In other cases, missing information or assessments can be identified earlier and addressed. We have found that the MDT permits broader MDT membership, including medical specialties (gerontology, palliative care) who might otherwise find it difficult to commit time to PEG assessments.

Conclusions This study demonstrates that a virtual PEG service was as safe and effective as the conventional method. This service should be encouraged to impact on increasing work load on gastroenterological services. In addition we found being elderly was an independent risk factor associated with increased 12 month mortality after PEG insertion.

may be a factor.

Summary Box

There are clear guidelines from the British Society of Gastroenterology

• PEG services require significant time investment by multiple

which define optimal pathways required for trusts providing a PEG GASTROENTEROLOGY TODAY - SUMMER 2016

16

site infections within 30 days of the procedure but these may have been

disciplines of the nutrition team.

service[5] to improve quality of care.

• We have demonstrated that elderly age was an independent risk factor

At our centre there are comprehensive PEG guidelines and a clear after

• Our study shows a virtual PEG referral service can be used as a safe

PEG pathway which has been endorsed by The National Patient Safety

and effective method of referral to improve the workload placed upon

Agency (NPSA) report to ensure optimal identification and subsequent

the gastroenterological.

associated with increased 12 months mortality after PEG insertion.

management of PEG related complications including perforation, haemorrhage and buried bumper syndrome[6].

Contributorship Statement

Strengths and limitations

Sukhdev Chatu: designed study, performed statistical analysis and participated in write-up of study

This was a retrospective study at a single centre which has its inherent

Deepika Reddy: performed data collection, participated in write-up of

limitations; however, the data was collected prospectively. The cohort

study, submitted study

size is limited and more studies evaluating this service are required

Louise Bensaid: performed prospective database collection

before results can be generalised. To evaluate factors associated with

Bu Hayee: Supervising Consultant

all-cause mortality we used Cox regression to impact on bias. Patients

Patrick Dubois: Lead supervising Consultant

were only followed up for 12 months from PEG insertion and events

No funding required for study, and no competing interests identified.

FEATURE Figure 1: ‘virtual’ PEG referral form

Urgency

**Important** all in-patient referrals must be received before 1700 Monday to be considered for addition to list.

Submission before the deadline does not guarantee PEG insertion for the following week

Timing of procedure Date to be considered □

Consent form 4 Source of referral

For Nasojejunal tube insertion please use EPR form 'OGD- additional procedures'

Procedure required

For PEG replacement/ removal?

□

Is the current site infected

□

Please note a new PEG tube cannot be inserted if the old site is currently infected.

Please discuss with endoscopy if uncertain

Does the PEG tube advance centrally and rotated 360 degrees?

□

Has the patient been reviewed and PEG insertion recommended by…

□

Dietetics

□

SAL therapist

□

MND Nurse?

□

Parkinson's Nurse?

□

Who are the above individuals?

please insert name and contact number if known please insert name and contact number if known please insert name and contact number if known

Tracheostomy?

□

Please note all patients with tracheostomy must be accompanied by an airway- trained member of staff throughout the procedure

Indication 1: Indication 2:

Clinical details

please state duration of symptoms

Method of transport Does the patients have diabetes?

Malignancy?

□

Renal impairment?

□

Respiratory disease?

□

Ischaemic Heart Disease?

□

Coagulation Disorder?

□

Other serious illness?

□

If yes to above, please specify (including medication if appropriate)

Current medication:

Aspirin

□

Relevant medication (please specify):

Name for contact for discussion:

Contact/ bleep number:

Warfarin

□

Clopidogrel

□

GASTROENTEROLOGY TODAY - SUMMER 2016

Valvular Heart Disease?

□

17

FEATURE

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Pathway Management of Referral to Discharge - eReferrals, Waiting Lists, Triage & Scheduling covering all areas of gastroenterology Reporting and Image Capture across the full range of Endoscopy Procedures National JAG and NED requirements Mobile Devices for clinicians, patients, and access across the community High capability for local configuration Integration with other Trust systems – HL7, XML, ITK, Inter-Trust Messaging Audit and research CIMS’ help desk provides high quality support

FEATURE Table 1: Baseline characteristics and PEG related outcomes: conventional vs.virtual Variable Number Women n (%)

Conventional 43 20 (47%)

Virtual 50 23 (46%)

P value

Median age (IQR)

55 (42-71)

63 (49-74)

NS

11(26) 16(36) 8(19)

11(22) 21(42) 10(20)

NS NS NS

8(19)

8(16)

NS

Outcome Within 30 days:

Conventional

Virtual

p

Mortality Wound infection Bleeding Perforation

5 0 2 0

3 0 1 0

NS

Buried bumper syndrome Re-siting Proceeded PEG-J extension PEG removed

3 2 7 3

1 2 5 2

NS NS NS NS

PEG inappropriate n

40

46

NS

19(56) 9(35) 15(46)

15(44) 17(65) 18(54)

NS <0.05 NS

Indication n(%): Stroke Neurodegenerative disease Disease related malnutrition Head injury

NS

NS

Late: (>30 days-12 months)

Waiting time (days from referral to insertion) n(%): 0-7 8-14 15-21

Variable Conventional vs. virtual

HR 0.89

Univariate 95% CI 0.44-1.79

Multivariate p HR 95% CI 0.74 0.83 0.41-1.70

p 0.61

female vs. male

1.04

0.52-2.10

0.90 0.96

0.47-1.96

0.90

Age < 65 vs. â&#x2030;Ľ65

2.61

1.28-5.31

<0.01 2.34

1.11- 4.90

0.03

Indication: Neurodegenerative vs. stroke Disease related mal. vs. stroke Head injury vs. stroke

0.82 0.73 0.24

0.37- 1.85 0.27- 2.01 0.05-1.09

0.64 0.90 0.54 0.97 0.07 0.33

0.39- 2.05 0.34- 2.77 0.41-1.69

0.80 0.96 0.61

GASTROENTEROLOGY TODAY - SUMMER 2016

Table 2: Cox regression showing the hazard ratio (HR) of factors associated with all- cause mortality within 12 months of PEG insertion (n=93).

19

FEATURE

GASTROENTEROLOGY TODAY - SUMMER 2016

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FEATURE Figure 2a: Kaplan Meier analysis demonstrating all-cause mortality within 12 months of PEG insertion was 38% (95% CI: 28 - 50%).

Reference List 1. Sacks BA, Vine HS, Palestrant AM, et al. A nonoperative technique for establishment of a gastrostomy in the dog. Invest Radiol 1983;18:485-7.

2. Sanders DS, Carter MJ, Dâ&#x20AC;&#x2122;Silva J, et al. Percutaneous endoscopic gastrostomy: a prospective audit of the impact of guidelines in two district general hospitals in the United Kingdom. Am J Gastroenterol 2002;97:2239-45.

3. Kurien M, Westaby D, Romaya C, et al. National survey evaluating service provision for percutaneous endoscopic gastrostomy within the UK. Scand J Gastroenterol 2011;46:1519-24.

4. National Confidential Enquiry into Patient Outcome and Death 2005.

Figure 2b: Kaplan Meier curve showing no significant difference in cumulative mortality between conventional and virtual group (log rank p= 0.74).

5. Westaby D, Young A, Oâ&#x20AC;&#x2122;Toole P, et al. The provision of a percutaneously placed enteral tube feeding service. Gut 2010;59:1592-605.

GASTROENTEROLOGY TODAY - SUMMER 2016

6. Healey F, Sanders DS, Lamont T, et al. Early detection of complications after gastrostomy: summary of a safety report from the National Patient Safety Agency. BMJ 2010;340:c2160.

21

NEWS Pancreatic cancer: TUM researchers develop a new therapy concept New cancer therapy concept based on epigenetic mechanisms Pancreatic cancer is one of the most aggressive forms of cancer and one of the most difficult to treat. Its high resistance to treatment is a major problem, particularly in the advanced stages. Researchers at Klinikum rechts der Isar University Hospital of the Technical University of Munich (TUM) have joined forces with a team from Stanford University to investigate a conceptually new approach to therapy which primarily takes epigenetic mechanisms into consideration. The impact of this approach in both pancreatic and lung cancer was demonstrated in animal experiments. The results have now been published in Nature Medicine.

Pancreatic cancer is a highly aggressive tumor for which there have been few successful ScheBo_GastroToday_Orange therapy approaches until now. One of the

GASTROENTEROLOGY TODAY - SUMMER 2016

22

reasons for this is its extremely high resistance to chemotherapy or radiation therapy of any kind. Recent studies on genetic changes in the tumor cells indicate that it is not just a question of mutations in known cancer genes such as RAS und MYC; epigenetic factors that modify chromosomes and DNA and, as a result, affect the activity of genes without changing the DNA sequence are also increasingly being identified as key hubs for a number of tumor properties also in pancreatic cancer.

Important role of epigenetic mechanisms In the study just published, a team of scientists from several clinics and institutes from Klinikum rechts der Isar University Hospital and Stanford University headed by Prof. Dr. Jens Siveke from Medical Clinic II and Pawel Mazur and Julien Sage from Stanford University conducted research on a particular protein by the name of BRD4 in relation to pancreatic cancer. This protein regulates the so-called histone code of cells which determines which areas of the DNA are read. The scientists were keen to find out whether BRD4 is a target structure for therapies in pancreatic cancer.

As a first step, the researchers were able to show that BRD4 is upregulated in pancreatic cancer, before going on to test whether a therapy aimed at combating BRD4 with the API JQ1 can have a therapeutic effect. The scientists used both cell culture studies and various animal experiment model systems to do this, examining tumors using noninvasive methods including imaging systems that they had developed jointly in the “Collaborative Research Center 824”.

Although JQ1 therapy demonstrated an effect on the growth in size of the tumors, there was no clear indication of any survival effect as a result of it.

Combined therapy produces results In a second step, the scientists examined whether the therapy aimed

at combating BRD4 can potentially be more effectively combined with chemotherapy or other targeted therapies using drug screens.

Surprisingly, it was found that a combination of JQ1 and another epigenetic therapy principle – preventing histone deacetylation using socalled HDAC inhibitors – produced an increase in the programmed cell death of cancer cells. Combining the two created improved effectiveness and a clear survival advantage.

Since pancreatic cancer is almost always caused by a mutation in the RAS gene for which there is currently no specific treatment, the team asked themselves the question of whether this combined therapy could also be effective with other types of cancer driven by the RAS gene. It also showed activity against lung cancer caused by RAS. The next goals – higher accuracy and fewer side-effects “The hope is that these results will help to further evaluate this therapy principle as quickly as possible in clinical studies,” explains Jens Siveke, who tends to large numbers of patients in oncological studies. “Unfortunately, until now we have had little in the way of effective means of treating advanced stages of the disease. So for our patients, a rapid translation to clinical studies and a better understanding of the action mechanisms for even more carefully-targeted therapies are our main concern.”

With this in mind, the scientists are keen to among other things make further improvements in the substances for greater accuracy in inhibiting proteins and reducing side-effects. The research team is also planning to use so-called biomarkers to better identify patients who will benefit from this type of therapy. In their work, the authors were able to identify the first candidates, such as the apoptosis gene p57, using a new method based on so-called CRISPR technology.

Publication Mazur PK*, Herner A*, Mello SS, Wirth M, Hausmann S, Sanchez-Rivera FJ, Lofgren SM, Kuschma T, Hahn SA, Vangala D, Trajkovic-Arsic M, Gupta A, Heid I, Noel PB, Braren R, Erkan M, Kleeff J, Sipos B, Sayles LC, Heikenwalder M, Hessmann E, Ellenrieder V, Esposito I, Jacks T, Bradner JE, Khatri P, Sweet-Cordero EA, Attardi LD, Schmid RM, Schneider G, Sage J, Siveke JT, Combined inhibition of BET family proteins and histone deacetylases as a potential epigenetics-based therapy for pancreatic ductal adenocarcinoma, Nature Medicine, 2015.

DOI:10.1038/nm.3952 http://www.nature.com/nm/journal/vaop/ncurrent/ full/nm.3952.html

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23

NEWS Cancer treatment success nearly doubles when equipping patients with info about their disease, new study finds

Dr Kamau investigated the relationship between

secondary analysis of survey data from the

the frequency patients received information that

wider sample of 6,700 patients (irrespective of

increased their understanding of their condition,

their current employment status). Similarly, this

its treatment and side effects, and the likely

showed that preparing patients produces nearly

impact on their work life and education.

twice better odds of successful cancer treatment.

The results showed that:

Interpreting the results, Dr Kamau said: “There are two main reasons why preparing patients

Providing cancer patients with information

• patients who receive information about the

seems to produce nearly twice better odds of

about their disease, its treatment and its

impact of cancer on work life or education

successful cancer treatment. One is that patient

impact on work life and education, nearly

are 1.72 times more likely to have a

education lowers uncertainty and the stress

doubles their chances of a positive treatment

positive treatment outcome (defined as

that comes with not knowing what to expect.

outcome, a new study from Birkbeck,

completion of treatment with no further signs

Uncertainty is a known stressor that interferes

University of London has found.

or symptoms of cancer)

with health therefore reducing it will improve the odds of successful cancer treatment.

The research, published Monday 14 Sept in BMJ

• patients who receive information about the

Supportive and Palliative Care, indicates that

type of cancer are 1.99 times more likely to

“The second reason is that preparation equips

educating cancer patients helps lower uncertainty

have a positive treatment outcome

working cancer patients with knowledge about

and stress, while also equipping working patients with coping strategies during treatment.

good coping strategies, including how to cope • patients who receive information before a cancer-related operation are 1.90 times more

The study was carried out by Dr Caroline

Commenting on why providing patients with • conversely, patients who receive information

survey data from nearly 3,500 British cancer

about the side effects had worse odds of a

patients in employment. The data was drawn

positive treatment outcome (0.65 to 1) The results were then corroborated with a

info@healthtemps.co.uk +44 (0) 1908 355800

GASTROENTEROLOGY TODAY - SUMMER 2016

24

information on side effects worsens the odds of successful treatment, she added: “Informing patients about potential side effects

from the UK Department of Health’s National Cancer Patient Experience Survey, 2013-2014.

through adjusting work load.”

likely to have a positive treatment outcome

Kamau of Birkbeck’s Department of Organizational Psychology, who analysed

with the fatigue that comes with treatment

can trigger unnecessary stress and increase

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NEWS rather than decrease uncertainty. It can trigger unnecessary doubt about the treatment process and make them worry about factors beyond their control. This can give rise to negative coping behaviours that interfere with recovery.”

Looking ahead, Dr Kamau noted some areas of further research which could develop on this study’s findings.

She said: “The results showed good practice in cancer care but we need to ensure that working patients with other potentially life-limiting illnesses are receiving similar support.”

The report, titled Preparing patients with cancer who work and treatment responsiveness was published Monday 14 September in BMJ Supportive and Palliative Care.

Cause of acute liver failure in young children discovered Mutations in patients disrupt cellular transport Acute liver failure is a rare yet life-threatening disease for young children. It often occurs extremely rapidly, for example, when a child has a fever. Yet in around 50 percent of cases it is unclear as to why this happens. Now, a team of researchers working on an international research project headed by Technische Universität München (TUM), the Helmholtz Zentrum Munich and Heidelberg University Hospital have discovered a link between the disease and mutations in a specific gene. The researchers used whole genome sequencing to uncover the mutations, which affect transport processes in cells.

at the Institute for Human Genetics at TUM and the Helmholtz Zentrum Munich have been examining four children suffering from recurrent, fever-dependent liver failure in a bid to identify a genetic cause.

“In our study, we initially focused on the genetic similarities in these children to determine a possible cause for their disease,” explains Haack.

The researchers used exome sequencing to do this, a process that involves sequencing all subsets of a patient’s DNA that contain information on creating protein. They also examined the DNA of close family members. In multiple instances, they discovered mutations in one specific gene. “We identified mutations in the NBAS gene in a total of 11 patients. This is the first time that we have been able to establish a link between this gene and liver disease. This discovery could also be interesting for other illnesses,” summarizes Prokisch.

Mutations disrupt transport processes However, the researchers were keen to find out exactly how these mutations affect cellular processes. To do this, they carried out a number of molecular biology experiments. These revealed that when the mutations were present in the NBAS

Professor Georg Hoffmann at the pediatric hospital in Heidelberg has spent 20 years caring for several patients who have suffered from recurrent acute liver failure since childhood. The similarities in the progression of the disease led him to suspect that there might be a common cause. Dr. Tobias Haack and Dr. Holger Prokisch

The researchers’ primary aim is to improve the diagnosis of rare diseases such as acute liver failure in childhood and pave the way for targeted

According to the European Union, a disease such as acute liver failure is classified as rare if it affects less than five in 10,000 people. Yet despite low patient numbers, research into rare diseases has been on the rise in recent years. The reason for this is that many of these illnesses have a genetic cause that researchers can pinpoint. The findings could also provide important insights into metabolic processes in healthy people or serve as a model for other diseases.

“Diagnosis already triggers a specific therapeutic path,” adds Hoffmann. “Over the years, we have been able to empirically develop a therapy that uses specific drugs as well as sugar and fat infusions. These can be immediately administered once a patient is diagnosed. We can now use the latest findings to further improve our therapeutic approach.”

Original publication T. B. Haack, C. Staufner, M. G. Köpke, B. K. Straub, S. Kölker, C. Thiel, P. Freisinger, I. Baric, P. J. McKiernan, N. Dikow, I. Harting, F. Beisse, P. Burgard, U. Kotzaeridou, J. Kühr, U. Himbert, R. W. Taylor, F. Distelmaier, J. Vockley, L. GhaloulGonzalez, J. Zschocke, L. S. Kremer, E. Graf, T. Schwarzmayr, D. M. Bader, J. Gagneur, T. Wieland, C. Terrile, T. M. Strom, T. Meitinger, G. F. Hoffmann und H. Prokisch, Biallelic Mutations in NBAS Cause Recurrent Acute Liver Failure with Onset in Infancy, American Journal of Human Genetics, June 2015.

DOI: 10.1016/j.ajhg.2015.05.009 (http://www.cell. com/ajhg/abstract/S0002-9297%2815%2900195-0)

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GASTROENTEROLOGY TODAY - SUMMER 2016

Using sequence analyses to identify genetic defects

gene, only small amounts of the NBAS protein were created.

NBAS is involved in cell transport processes that pack proteins in vesicles and transport them from one cell compartment to another. “We were able to show that the faulty protein is more susceptible to heat.

This means that when an individual has a fever, there are fewer proteins available for coordinating the transport processes.

This, in turn, can have a negative impact on metabolic processes in the liver in an acute situation,” elaborates Prokisch.

treatment. Haack believes that the results give them an important starting point: “When a child suffers from liver failure triggered by fever, we can now specifically investigate the NBAS gene.”

25 Gastro-Today_Quart-Ad-Jun16_FINAL_17May16.indd 1

17/05/2016 16:26:46

NEWS Coeliac UK Coeliac UK, the national charity for people with coeliac disease has launched its first television advert to raise awareness of the symptoms of coeliac disease and to encourage people experiencing symptoms to take steps towards a diagnosis.

Coeliac disease is an autoimmune condition associated with chronic inflammation of the small intestine which can lead to malabsorption and nutritional deficiencies.

In people with coeliac disease, gluten, a protein found in wheat, barley and rye elicits an abnormal immune response.

The only treatment for coeliac disease is lifelong strict adherence to the gluten-free diet and undiagnosed coeliac disease can result in long term complications including osteoporosis, unfavourable pregnancy outcomes and a small increased risk of intestinal malignancy.

One in 100 people in the UK has coeliac disease [1], however the latest statistics show that only 24% of those with the condition are diagnosed [2]. Rates of diagnosis are also known to vary by socio-economic status, with children living in more socioeconomically deprived areas in the UK less likely to be diagnosed with coeliac disease [3].

With only 24% of people with coeliac disease currently diagnosed, there are around half a million people in the UK who are living with undiagnosed coeliac disease.

For many people, securing a diagnosis can take many years, with most people securing a diagnosis in their 50s or 60s [2]. Research shows that on average, it takes 13 years from the initial symptoms to diagnosis [4] and 1 in 4 people with coeliac disease receive treatment for irritable bowel syndrome prior to their diagnosis with coeliac disease [5].

To reach people currently living with undiagnosed coeliac disease in the UK, in May this year Coeliac UK launched a new two year campaign, ‘Is it coeliac disease?’.

The campaign aims to raise awareness of the symptoms of coeliac disease and encourage people experiencing the symptoms to seek a diagnosis.

The campaign has seen the launch of a TV advert which highlights three commonly reported symptoms of coeliac disease; abdominal pain and cramping, diarrhoea and fatigue. The advert is narrated by TV actress Caroline Quentin who is Coeliac UK’s Charity Patron and has recently completed her own coeliac disease diagnosis journey. As most people are diagnosed with coeliac disease later in life, and as one aim of the campaign is to reduce the length of time to diagnosis, the advert

was created to be directed at the target audience of people aged 25 – 45 years old.

The advert was first broadcast on Monday 7 September and can be watched online. The advert directs people who are experiencing symptoms to the campaign website www.isitcoeliacdisease.org.uk which features an online assessment to help people undiagnosed with coeliac disease to decide whether they need to seek further medical advice about a diagnosis of coeliac disease. The online assessment is based on NICE (2009) guidelines for the recognition and assessment of coeliac disease [6]. As such, people with symptoms, a first degree family member with coeliac disease or those diagnosed with an associated condition are recommended to continue eating a normal, gluten containing diet and visit their GP for serological testing.

The online assessment has been adopted to reduce the impact of the campaign on primary care services, ensuring that only those recommended by NICE are referred for testing.

For more information about the campaign, including healthcare professional resources visit www.isitcoeliacdisease.org.uk. A specific section has been created on the website for healthcare professionals, which includes links free online training tools and campaign resources.

GASTROENTEROLOGY TODAY - SUMMER 2016

26

References

[1] Bingley PJ, Williams AJ, Norcross AJ et al (2004) Undiagnosed coeliac disease at age seven: population based prospective birth cohort study. BMJ 328(7435): 322–3. doi:http://dx.doi. org/10.1136/bmj.328.7435.322 [2] West J, Fleming KM, Tata LJ et al (2013) Incidence and Prevalence of Celiac Disease and Dermatitis Herpetiformis in the UK Over Two Decades: Population-Based Study. Am J Gastroenterol 2014;109:757-768 [3] Zingone F, West J, Crooks CJ et al (2014) Socioeconomic variation in the incidence of childhood coeliac disease in the UK. Arch Dis Child;0:1–8. doi:10.1136/archdischild-2014-307105 [4] Gray AM & Papanicolas IN (2010) Impact of symptoms on quality of life before and after diagnosis of coeliac disease: results from a UK population survey. BMC Health Serv Res 10: 105. doi:10.1186/1472-6963-10-105 [5] Card TR, Siffledeen J, West J et al (2013) An excess of prior irritable bowel syndrome diagnoses or treatments in Celiac disease: evidence of diagnostic delay. Scand J Gastroenterol 48(7): 801–7. doi: 10.3109/00365521.2013.786130 [6] National Institute for Health and Clinical Excellence (2009) Coeliac disease: recognition and assessment of coeliac disease. http://www.nice.org.uk/guidance/cg86 (accessed 21.09.2015)

NEWS Latest UK IBD audit report shows further improvement for patients following treatment with biological therapies The UK inflammatory bowel disease (IBD) clinical audit report reveals today that the majority of patients (80% adult and 77% paediatric) with Crohn’s disease saw an improvement following biological therapies.

The results clearly demonstrate biological therapies for IBD are effective and safe treatments. Patterns of prescribing are also changing with earlier use in patients with less severe disease which suggests doctors have become more familiar with the treatment.

The audit is commissioned by the Healthcare Quality Improvement Partnership (HQIP),*as part of the National Clinical Audit Programme (NCA). The UK IBD audit is carried out by the Royal College of Physicians on behalf of the IBD programme steering group.

‘Biological therapies’ is the collective term

for two particular drugs – Infliximab (IFX) and Adalimumab (ADA). These are strong antiinflammatory drugs that are used to treat patients with severe Crohn’s disease (CD). The National Institute of Health and Care Excellence (NICE) recommend that these drugs are used for treatment of patients who have not responded to conventional therapy, such as immunosuppressive or corticosteroid treatment.

Participation in the biological therapies audit has been excellent with 152 out of 159 (96%) adult trusts and health boards, and 23 out of the 25 (92%) specialist paediatric sites providing data.

However, a minority of cases are being entered at some adult sites and follow up data remains incomplete for both adult and paediatric sites.

Further improvement is needed to ensure that complete data is entered on all eligible patients.

Dr Ian Arnott, associate clinical director, UK IBD audit said: This audit demonstrates that biological therapies continue to be safe and effective treatments for IBD. It is interesting to see that patterns of use have changed over the course of this audit suggesting more appropriate prescribing. It is important that further audits continue to address the issue of long term safety and also collect data on biosimilars* and newer biological treatments.

Dr Richard Russell, consultant paediatric gastroenterologist, The Royal Hospital for Sick Children, Glasgow said: It is very encouraging to see more than half of all children that are receiving these therapies in the UK are participating in this audit, so we can be confident that the results produced are likely to apply to all children across the UK. With the imminent introduction of a wider range of these medicines this will allow us to closely monitor any changes in their effectiveness or safety profile.

Ulcerative colitis and Crohn’s disease are the two main forms of IBD and they are lifelong, chronic conditions. It is estimated that over 300,000[1] people are likely to be affected in the UK. IBD is a debilitating condition for both adults and children. It causes bouts of watery and bloody diarrhoea but also stomach pain, weight loss and lethargy and severely affects the way these people live their lives. Left untreated it can be a life-threatening disease.

Biological therapies have been available since the 1990s. This audit is one element of the wider UK IBD audit and strives to provide a much better understanding of the role of biological therapies in the overall treatment of IBD as currently undertaken in the UK.

NICE NG12 - How Does This Impact Your Clinical Practice?

The new NICE NG12 guideline on the patient pathway for suspected Lower GI cancer, recommending FOBT, has resulted in considerable debate about what test should be offered.

The questions raised about FIT:

■ Where in the patient pathways should such tests be

STAND NO.9

implemented?

■ How would this impact patient referrals?

■ How would this affect the NHS 2 week wait guidelines?

■ What impact would this have on patient outcomes?

To find out more about how FIT could improve your patient pathway, visit Alpha Laboratories at BSG 2016, Liverpool ACC June 21st -23rd, stand no. 9, where you can also see the automated FIT technology HM-JACKarc.

Alternatively visit www.alphalabs.co.uk/FIT for more information and to view videos of recent expert discussions on the use of FIT in the patient pathway.

Gastro-Today_Half-Ad-Jun16_FINAL_17May16.indd 1

Faecal Immunochemical Testing (FIT)

GASTROENTEROLOGY TODAY - SUMMER 2016

NICE are now reviewing the latest literature on quantitative Faecal Immunochemical Tests (FIT) with a view to publishing new guidelines on how FIT should be used.

Tel: +44 (0)23 8048 3000 | Web: www.alphalabs.co.uk 17/05/2016 16:21:38

27

POSTERS Are megamitochondria a cellular survival strategy for ethanol-induced liver toxicity?

Elena Palma*, Antonio Riva*, Roger Williams*, Azzura Greco*, Satvinder Mudan#, Nikolai Manyakin#, Shilpa Chokshi* *Foundation for Liver Research, Institute of Hepatology, London, UK; #The London Clinic, London, UK.

Human Precision Cut Liver Slices

0 .0 c trl

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P t# 0 0 7 P t# 0 0 8

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th r e s h o ld o f v ia b ility

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72h treatment EtOH 50mM

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15

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Drp-1 activation Drp-1

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o f v ia b ility

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(loading control)

Panel A: Impairment of cellular proliferation was observed in the cells treated with EtOH at 100mM. (mean ± S.E.M; n=12, *P<0.05).

Panel B: Rate of cell death (apoptosis) was assessed in the final 3 days in culture and found increased (Annexin-V positive cells; mean ± S.E.M; n=7, *P<0.05), while the necrotic levels were not significantly different from the control (n.s. P>0.05).

Panel C: Mitochondrial respiration was slightly impaired, but without significant changes in the spare respiratory capacity and the coupling efficiency (mean ± S.E.M; n=3, n.s. P>0.05).

Panels D: The viability in the PCLS was estimated by measuring the ATP levels, and only a slightly decrease (not significant, P>0.05) was observed both after 24 and 72 hours of treatment with the indicated doses of EtOH. Panel E: Increased cell death at 72 hours, with fragmented nuclei, chromatin disintegration and prominent cytoplasmic vacuolation was revealed by electron microscopy.

Figure 2. EtOH exposure perturbs mitochondrial dynamics and induces megamitochondria formation in VL-17A cells and human PCLS A

A’ over-fragmented

A’’ mixed network

D

Modified from de Graaf IA, et al. Nat Protoc 2010,(9):1540-1551.

α-PDK1

007 55

F F

Cauc Asian

24.4

none

26.7

none

focal nodular no steatosis hyperplasia

6

53

16

mCRC

F

Cauc

19.9

<5

42

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mCRC

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M

Cauc

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Cauc

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012 52

F

Cauc

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n/a

48

12

n/a no evident fibrosis, minimal steatosis minor degree of steatosis

metastatic ductal BC, mild steatosis diabetes type 2 no steatosis, mCRC no fibrosis

*All patients received chemotherapy prior to resection.

Cauc= caucasian; BMI=body mass index; mCRC= metastatic colorectal adenocarcinoma; BC= breast adenocarcinoma

Results Figure 1. EtOH exposure causes moderate toxicity in VL-17A cells and human PCLS A B *

1 .5

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g r o w t h r a t e ( f o ld /d a y )

GASTROENTEROLOGY TODAY - SUMMER 2016

005 33

Alcohol ALT Bilirubin Pathological Background Ethnicity BMI (weekly n (IU/L) (µmol/L) conditions liver histology units)

d a y3 - 7

d a y7 - 1 1

A p o p t o t ic

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N e c r o t ic

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d a y3 - 7

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Pt#011

E

*

*

*

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* *

100mM *

Pt#010

MM

250mM

Pt#012

* *

*

*

m ega

*

2 .5

*

*

*

Panel A: Cells were blindly classified accordingly to their mitochondrial phenotype into three groups: A’ hyperfragmented, when more than 50% of the organelles were separate and spherical entities; A’’ mixed network, when the mitochondria were a continuous and interconnected net, as well as a mix of fragmented (less than 50% of the total) and elongated; A’’’ mega, when the organelles presented an hyperinterconnected structure with some abnormal enlargements, which could be seen also as separate oversized entities.

Panel B: The distribution among these three categories was significantly different (100 cells counted per condition, *P<0.05) between control and EtOH-treated cells, with ̴30% of cells showing megamitochondria vs 8% in the ctrl.

Panel C, D: Megamitochondria (MM or *) were detected by electron microscopy both in the VL-17A cells and in the PCLS from different patients treated for 24h or 72h at the indicated doses of EtOH.

*

0 .8

2 .0 1 .5 1 .0 0 .5 0 .0

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50

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*

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Table 1. Baseline characteristics of liver donors for PCLS. Pt Age Sex ID

α-VDAC-1

(loading control)

B 10 µm

0

24h

EtOH

α-Drp-1

Figure 4. Chronic double hit with ethanol and fatty acids induces high toxicity but not megamitochondria formation in the VL-17A cells

m ega

D

c h r o n ic

ctrl

α-Drp-1

Et O H

CTRL

c trl

Panel A: Mechanism of action of Drp-1, after a stimulus occurs Drp-1 translocates from the cytosol to the mitochondria and induces fragmentation. This translocation was found impaired by EtOH treatment.

Panel B, C: representative western blots of Drp-1 on isolated mitochondria and the quantitative densitometric analysis of the Drp-1 bands normalised against the loading control (VDAC-1) and expressed as ratio of the chronic EtOH sample vs the untreated (mean ± S.E.M, n=6, *P<0.05).

Panel D: representative western blots showing the reduction of Drp-1 on mitochondria isolated from 3 slices of PT#010 or PT#012 after 24 or 72 hours of treatment with 250mM EtOH. The mitochondrial proteins PDK1 or VDAC-1 are used as loading controls.

m ix e d n e tw o rk

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(loading control)

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Isolated mitochondria

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C e lls ( % o f t o t a l )

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15

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1 .5

Fragmentation

A

PCLS represent an ideal model to study the pathogenesis of liver injury, due to the preservation of the intact liver architecture with the characteristic heterogeneity of the cell types and the conservation of physiological metabolic pathways.

PCLS were treated for 24 or 72 hours with EtOH at 50, 100, 250mM.

chronic Et

α-Drp-1

EtOH 250mM

Pt#012

C

Isolated mitochondria

Drp-1

th r e s h o ld

50m M 100m M 250m M

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d e n s it o m e tr y D r p - 1 /V D A C -1

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( r e la tiv e r a t io n o r m a liz e d f o r t h e c t r l)

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c o u p lin g e ffic ie n c y

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α-TUBULIN

1 .5

c o u p lin g e ffic ie n c y

Human hepatoma cell line (HepG2) was stable transfected with murine alcohol dehydrogenase (ADH) and human cytochrome P450 2E1. Cells were treated with EtOH at 100mM for 14 days in order to mimic chronic abuse of alcohol.

α-CYP2E1 α-ADH

2 .0

7 2 h tre a tm e n t

2 4 h tre a tm e n t

n .s .

0 .8

s p a r e r e s p ir a t o r y c a p a c ity

Experimental models VL-17A cell line

Figure 3. EtOH exposure causes a reduction in the activation of Drp-1 in VL-17A cells and human PCLS

D n .s .

2 .5

g r o w t h r a t e ( f o ld /d a y )

Aim of the project

To investigate the impact of alcohol on mitochondrial architecture and the potential role of mitochondria-shaping proteins in the pathogenesis of ALD.

C s p a r e r e s p ir a t o r y c a p a c ity

Background

Mitochondria are essential hubs for the organism and they can promptly modify their shape to actively respond to the changing needs of the cell. These adjustments in morphology are mediated through cycles of fusion (binding of mitochondria) and fission (mitochondrial-fragmentation) and the balance between these processes determines the shape of these organelles and thus their functionality. Fusion and fission are driven primarily through the activity of multiple “mitochondria-shaping proteins” (MSP) which act together to maintain a balance between these two antagonistic events.

One of the best characterised MSP is Dynamin-related protein1 (Drp-1), a cytosolic protein which after activation can translocate to mitochondria where it fragments the organelle.

Several studies have shown that one of the earliest consequences of chronic alcohol consumption is an alteration of mitochondrial structure in the liver where the organelle is enlarged and misshapen and contains disrupted cristae (megamitochondria). However, the molecular mechanisms involved in the megamitochondria development and their significance in the context of ALD remain elusive.

c trl

c h r o n ic E tO H + F A

Panel A: Cell death was quantified in the final 3 days in culture (after 14d in presence/absence of EtOH 100mM and oleic+linoleic acids 0.1mM) and levels of apoptosis found considerably higher in the EtOH+FA samples compared to the control (mean ± S.E.M, n=7, *P<0.05).

Panel B: A lack of cell proliferation was observed during the culture in presence of EtOH+FA (mean ± S.E.M of 12 experiments, *P<0.05).

Panel C: At least 40 cells per condition were classified into three mitochondrial phenotype categories and the difference in the distribution was statistically significant (*P<0.05), with a high level of hyper-fragmented organelles and a reduced number of megamitochondria in the EtOH+FA samples.

Panel D: electron micrographs showing examples of small mitochondria, and the striking fat accumulation (dark grey droplets).

Panel E: Mitochondrial respiration resulted impaired with decreased spare respiratory capacity and coupling efficiency in EtOH+FA cells (mean ± S.E.M; n=3, *P<0.05).

Conclusions

• The equilibrium between mitochondrial fusion and fission is profoundly perturbed by alcohol and this induces significant alterations in mitochondrial morphology.

• The appearance of megamitochondria during chronic alcohol exposure is associated with a moderate cellular toxicity.

• The mitochondria-shaping protein Drp-1 is intimately associated with megamitochondria development in the presence of chronic alcohol.

• Drp-1 represents a unique therapeutic target and may be modulated to induce megamitochondria in order to slow down the progression of liver injury and disease.

POSTERS CAN SCREENING FOR POOR PROGNOSIS IMPROVE CARE FOR PATIENTS WITH END STAGE LIVER DISEASE? B. Hudson 1 , K. Ameneshoa 1 , P. Collins 1 , J. Portal 1 , F. Gordon 1, J. Verne 2 , A. McCune 1

University Hospitals Bristol NHS Trust 1 & Public Health England 2 Introduction • Liver disease is the 3rd commonest cause of premature death in the UK. • The end of life care strategy (Department Of Health, 2008) noted many patients do not die in a place of their choosing • Patients included on palliative care registers, such as the Gold Standards Framework, have been shown to receive better coordinated care at the end of life.

• The General Medical Council (GMC) define people to be ‘approaching the end of life’ when they are likely to die within the next 12 months.

• Data from the Royal Free hospital demonstrated that only 19% of patients assessed unsuitable for liver transplantation were referred to palliative care services, a median of 4 days before death.

• Across the United Kingdom between 2007-2011 81% of patients with alcoholic liver disease died in hospital, compared to 48% with cancer (Office of National Statistics).

• We aimed to design and validate a tool to identify inpatients with liver disease who stand to benefit from palliative care assessment and advanced care planning, and to create a model of care for such patients.

Methods • The department of health document ‘Getting it Right: improving end of life care for people living with liver disease’ and the NHS North East document ‘Framework for supportive care in advanced liver disease’ identify evidence based factors which are predictive of death in liver disease.

• Five of these factors (Childs Pugh C, >2 admissions within last 6 months, continued use of alcohol, unsuitable for liver transplantation, pre-admission WHO performance status >2) were assimilated into a screening tool.

• The tool was retrospectively applied to all patients admitted to the Bristol Royal Infirmary with a diagnosis of cirrhosis over 90 consecutive days from 1st July 2013 (n=54).

• Based on the GMC definition of ‘approaching end of life’ mortality 1 year post initial admission was calculated.

Results • Of 54 index cases 7 were not analysed due to incompleteness of data or loss to follow up • Sensitivity and specificity for predicting one year mortality when 2, 3 or 4 poor prognostic criteria were positive were analysed (see table).

• On this basis, an admission score of 3 or more criteria was considered a “positive” poor prognosis screen (see figure 1)

Figure 1 – Accuracy of tool at varying ‘thresholds’ for predicting mortality at 1 year Threshold for Positive predictive positive screen (no value (death at 1 of positive criteria at year in pts over index admission) (n) threshold) % <2 (10) 0 ≥2 (16) 57 ≥ 3 (18) 81 ≥ 4 (3) 67

Conclusions and further work

Negative predictive value (survival at 1 year in pts under threshold) % 100 100 85 57

(death at 1 year) %

Sensitivity

Specificity (death at 1 year) %

100 81 10

62 81 96

Figure 2 – Poor Prognosis Screening Tool

• The tool has been trialed and audited locally over the past year.

• Assuming MDT agreement this triggers a consultant led prognosis discussion with the patient, a poor prognosis letter to the GP, and involvement of the palliative medicine team • To support the hepatology team in having poor prognosis conversations, communication skills training has been delivered to consultants and junior staff by the palliative medicine team • Identifying patients who stand to benefit from advanced care planning will become increasingly important as deaths from liver disease continue to increase.

• Patients assessed as unfit for transplantation represent a group in whom early interventions could be targeted and validated for a wider population References 1. Tackling liver disease in the UK: A Lancet Commission. Lancet. 2014 Nov 29;384(9958):1902. doi: 10.1016/S0140-6736(14)62263-7.

2. End of Life Care Strategy: promoting high quality care for adults at the end of their life. Department of Health. 2008

GASTROENTEROLOGY TODAY - SUMMER 2016

• Patients who screen positive (score ≥ 3 criteria) are highlighted for discussion at a weekly hepatology MDT (see figure 2)

3. Phoolchund, Murray, Hogan & O’Beirne, Survival of patients assessed unfit for liver transplant. BSG. 2014 4. Office of National Statistics. Mortality. 2007-2011 5. The NHS Atlas of Variation in Healthcare for People with Liver Disease. Department of Health. 2014

29

POSTERS

An Innovative Model To Increase Uptake of Hepatitis C Testing In The Pakistani Population in Reading, England D.linzey1, S Shahin, O Macleod1, A Evans1 J. Booth1 1Department of Gastroenterology and Hepatology, Royal Berkshire Hospital NHS Foundation Trust, Reading, U.K.

Introduction:

Results:

● Chronic Hepatitis C affects over 170 million people worldwide.

•

In 18 months the volunteers performed 300 oral tests.

• 8 tests (2.6%) were reactive for Hepatitis C. ● Hepatitis C virus (H.C.V.) genotype 3 is common in S.E. Asia, particularly Pakistan, and in Europe represents up to 45% of newly diagnosed infections. ● In this project we evaluated the use of nonmedical volunteers to lead community based testing for Hepatitis C in the Pakistani population in Reading, Berkshire, England. ● Berkshire is a county bordering Greater London with one of the largest Pakistani populations in the UK after London and Birmingham. The Royal Berkshire Hospital serves a population of around 600,000 people.

Methods: GASTROENTEROLOGY TODAY - SUMMER 2016

30

● Four female volunteers from the local Pakistani community were trained to deliver point of care testing for Hepatitis C using oral swabs. They operated within a strict protocol with clear governance, support and training. Individuals for testing self-referred following community based awareness events. Reactive results were followed up with confirmatory PCR tests by the viral hepatitis Nurse Consultant and then treated in the Viral Hepatitis clinic at the Royal Berkshire Hospital.

• Of these 1 patient returned to Pakistan and was lost to follow up.

• 1 Patient spontaneously cleared the virus.

• 6 patients started antiviral treatment.

• At time of submission 4 patients had achieved sustained virologic response (SVR) and 2 were still to complete treatment. Since submission 1 further patient has achieved SVR.

Conclusion: •There is a recognized higher prevalence of Hepatitis C in the Pakistani population in the UK. •This group are often regarded as “hard to reach” resulting in late diagnosis and higher morbidity associated with this.

•This project demonstrated the value of community volunteers in identifying patients for treatment who would not normally have presented for testing.

POSTERS Radiofrequency Ablation of Symptomatic Cervical Inlet Patch using a 'Through the Scope' device – a pilot study Authors- 1,2Dunn JM, 1Sui G, 1Angiannsah A, 1Wong T. Institution- 1Department of Gastroenterology, Guy’s and St Thomas’s Hospital NHS Trust, 2Institue for Cancer Genetics and Informatics, Oslo University, Norway.

Introduction

The Cervical Inlet patch (CIP) is an area of heterotopic gastric mucosa at the proximal oesophagus, which can secrete both acid and mucus.

They are congenital and affect 5% of the population.

There is increased prevalence in patients with Barrett’s oesophagus (30%).

Attributable symptoms include chronic globus sensation and sore throat.

Previous studies have demonstrated improvement in symptoms following ablation with argon plasma coagulation 1,2.

The BarrxTM Channel device is a novel through the scope Radiofrequency Ablation (RFA) catheter that may be advantageous for this indication.

Oesophageal physiology Figure 2 Oesophageal pH study demonstrating isolated acid exposure from proximal oesophagus due to inlet patch, which resolved after successful ablation.

Normal pH proximal sensor

Drop in pH proximal sensor

Normal pH distal sensor

Normal pH distal sensor

Figure 1 (L to R) – Position of globus sensation, inlet patch under WLE, inlet patch under NBI, RFA Channel device

Images pre and post RFA

Figure 3a) (L to R) – i) Inlet patch at 11 o’clock position ii) immediately after first ablation iii) 3 months after first ablation iv) CR-IP after 2nd treatment

Aims

Figure 3b) (L to R) – i) Inlet patch at 8 o’clock position ii) immediately after first ablation iii) CR-IP 3 months after first ablation

To assess efficacy and safety of RFA for symptomatic CIP.

Methods

Ten patients with endoscopically and histologically proven CIP, and symptoms of globus or sore throat, were prospectively enrolled.

All had laryngoscopy, high resolution manometry and 24-hour dualchannel pH/impedance studies prior to treatment.

An ablation protocol of 3 ablations at 12J/cm2, without removal of coagulated tissue between ablations, was employed.

Patients were discharged on twice daily proton pump inhibitor (PPI) for 6 weeks, and a follow up endoscopy was undertaken at 3 months.

A maximum of 2 RFA sessions, 3 months apart, were allowed.

A visual analogue score (VAS; 0-100) was completed at baseline, then at 6 weeks (on PPI), 3 months (off PPI), 6 months and 12 months after treatment.

Wilcoxon test was used for statistical analysis.

Visual Analogue Score Visual Analogue Scale

1) Globus

Follow up oesophageal physiology studies, questionnaire and endoscopy at 3 months (off PPI 4/52)

2) Sore throat

Residual inlet patch with ongoing symptoms or positive pH test

No inlet patch patch with ongoing symptoms or positive pH test

5) Hoarseness

Severe

None

Severe

None

Severe

1.

2.

90 80

None

Severe

None

Severe

70 60

Globus

50

Sore throat Cough

40 30

Meining A, Bajbouj M, Preeg M et al. Argon plasma ablation of gastric inlet patches in the cervical esophagus may alleviate globus sensation: a pilot trial. Endoscopy 2006;38(6):566-70.

Bajbouj M, Becker V, Eckel F et al. Argon plasma coagulation of cervical heterotopic gastric mucosa as an alternative treatment for globus sensations. Gastroenterology. 2009;137:440–444.

70 60 Heartburn

50

Hoarseness

40 30 20

20

10

10

Endoscopy and repeat questionnaire at 1 year post ablation

References

100

90 80

3) Heartburn

4) Cough Maximum of one further rescue RFA

None

100

Visual Analogue Scores

Oesophageal physiology studies (if not already done as part of routine care) Baseline Questionnaire

RFA of Inlet patch PPI prescribed for 8 weeks.

Questionnaire at 6 weeks

Figure 4a) Graph showing VAS for chronic globus, sore throat and cough 4b) Graph showing VAS for hoarseness and heartburn

Visual Analogue Scores

Stop PPI therapy

The mean age was 56 years (+/- 3 years, SEM), 60% male, 80% Caucasian.

Barrett’s oesophagus was present in 50%.

Mean number of CIP was 2 (range, 1-4) with a median surface area of 2 cm2 (range, 0.5-14cm2).

After a median of 2 RFA sessions, 80% achieved complete endoscopic and histological resolution (CR-IP), with >90% visual resolution for remainder.

Globus, sore throat and cough were significantly improved from baseline (p<0.05) (see Figure 4 below).

There were no strictures or buried glands identified at follow up.

0

0 Baseline

6 weeks

3 Months

6 weeks after 2nd treatment

3 months after 2nd treatment

Baseline

Week 6

3 Months

Week 6 After 2nd treatment

3 months after 2nd treatment

Conclusion

This prospective pilot study demonstrates that RFA using the BarrxTM Channel Catheter is safe and effective for treating patients with symptoms of chronic globus sensation and sore throat, secondary to cervical inlet patch.

A randomized controlled trial is warranted.

GASTROENTEROLOGY TODAY - SUMMER 2016

Study Design

Results

Acknowledgements - This work was part funded by an educational grant from Covidien.

31

POSTERS Faecal calprotec/n iden/fies non responders to an/-­‐TNFα therapy when measured a<er induc/on in inflammatory Crohn’s disease.

Inflammatory Bowel Disease Service Department of Gastroenterology King’s College Hospital London SE5 9RS

Polychronis Pavlidis, Anna Cavazza, Nabil Siddique, Panos Stamoulos, Jaroslava Tumova, Lucy Metcalf, Guy Chung-­‐Faye, Patrick Dubois, Ingvar Bjarnason, Bu’Hussain Hayee ppavlidis@nhs.net

20 (77%) 6 (23%)

Other Immunosuppresants Azathioprine Prednisolone

10 (36%) 20 (77%)

Table 1. Pa.ent demographics

250 150 0

!me$0

post$induc!on

6$months

Figure 1. Fcal prior to first an.-­‐TNFα dose (.me 0), post induc.on and at 6 months a=er therapy commencement.

Sens%

95% CI

Spec%

95% CI

+LR

> 142.5

100

71.51% to 100.0%

87 59.54% to 98.34%

7.5

> 146.5

100

71.51% to 100.0%

93 68.05% to 99.83%

15.0

> 149.5

91

58.72% to 99.77%

93 68.05% to 99.83%

13.6

150

Figure 2/ Table 2. ROC curve analysis results (area under curve: 0.98, p<0.0001).

100

50

0

80

B1 (inflammatory) B2 (stricturing)

1000

10 0

1 (4%) 8 (31%) 17 (65%)

*

60

L1 (Ileal) L2 (colonic) L3 (ileo-­‐colonic)

*

2000

40

5 (19%) 20 (77%) 1 (4%)

Remission Active disease

3000

20

Montreal Classifica/on A1 (<16 yrs) A2 (17-­‐40 yrs) A3 (>40 yrs)

4000

Sensitivity%

GASTROENTEROLOGY TODAY - SUMMER 2016

32

32 (18, 59) 15:11 5 (1,8)

5000

0

Age Sex (f:m) Disease duraAon (years)

Results

We idenAfied 26 paAents (table 1) who started either infliximab (16) or adalimumab (10) and had serial fcal at the set Ame. PaAents on infliximab received 5mg/kg doses at 0,2,6 and then 8 weekly. Those on adalimumab had one dose of 160mg followed by 80mg ajer two weeks and then received 40mg doses fortnightly.

At 6 months, 15/26 (58%) paAents were in remission.

Fcal post inducAon in those in remission at 6 months was lower compared to those with persistently acAve disease [65 (38, 118) vs. 269 (161, 542)] (figure 1). Receiver operator characterisAc (ROC) curve analysis is presented in figure/ table 2.

FCAL (ug/g)

Introduc/on

Poor response to anA-­‐TNFα treatment in paAents with Crohn’s disease (CD) is not infrequent. As new biologic therapies targeAng other immune pathways of the intesAnal inflammaAon are becoming available in rouAne clinical pracAce early prognosAc markers of treatment failure are urgently needed.

Faecal calprotecAn (fcal) has been shown to be a useful prognosAc marker of relapse in CD1 correlaAng well with endoscopic acAvity scores2.

Furthermore, a recently published study3 idenAfied the two genes coding for the calprotecAn subunits (S100A8, S100A9) to be among the most highly expressed gene transcripts in anA-­‐TNFα non-­‐responders.

Methods

This is a retrospecAve observaAonal study of a prospecAvely kept database tesAng the hypothesis that a fcal measurement ajer anA-­‐TNFα inducAon (infliximab: 8-­‐12 weeks, adalimumab: 6-­‐8 weeks) reflects response to treatment. CD paAents, who commenced anA-­‐TNFα therapy for acAve, inflammatory disease and had serial fcal measurements before and ajer inducAon were idenAfied.

Remission was assessed at 6 months and defined as the composite of Harvey Bradshaw Index (HBI<5) and fcal<250μg/g. Fcal was measured using a commercially available ELISA kit provided by Bühlmann.

100% - Specificity%

Conclusion

Fcal measurement ajer anA-­‐TNFα inducAon predicts non-­‐ response, providing the opportunity to idenAfy those paAents who require further treatment tailoring early.

References 1. Tibble JA, Sigthorsson G, Bridger S, Fagerhol MK, Bjarnason I. Surrogate markers of intesAnal inflammaAon are predicAve of relapse in paAents with inflammatory bowel disease. Gastroenterology. 2000 Jul;119(1):15–22.

2. DʼHaens G, Ferrante M, Vermeire S, Baert F, Noman M, Moortgat L, et al. Fecal calprotecAn is a surrogate marker for endoscopic lesions in inflammatory bowel disease. Inflamm Bowel Dis. 2012 Dec;18(12):2218–24.

3. Leal RF, Planell N, Kajekar R, Lozano JJ, Ordás I, Do_ I, et al. IdenAficaAon of inflammatory mediators in paAents with Crohn's disease unresponsive to anA-­‐TNFα therapy. Gut. BMJ Publishing Group Ltd and BriAsh Society of Gastroenterology; 2015 Feb;64(2):233–42.

POSTERS Intra-abdominal adhesions: Identifying the "sticking point(s)" using novel cine-magnetic resonance image analysis. Pilot results D Randall1, C Strik3, H Van Goor3, F Joosten3, R Gillott2, P Spencer2, J W Fenner1, K D Bardhan2

of Sheffield, Sheffield, UK

2Rotherham

Hospital, The Rotherham NHS Foundation Trust, Rotherham, UK

Summary

University Medical Centre, Nijmegen, Netherlands

Results: ‘Sheargram’ Validation

• Aim: Develop technique for non-invasive detection of abdominal adhesions • Novel approach analyses sliding of abdominal contents against abdominal wall • Adhesions identified by disruption of movement pattern – here, ‘visceral slide’ • Principle: • • • •

3Radboud

Movement separated into regions (segmentation) Each region is ‘tracked’ (registration) Shear quantifies visceral slide Sticking points are visible as ‘cold spots’ in the cumulative ‘sheargram’

Validation test 1: Accuracy of shear measurement validated in highly idealised computer model.

Comparison of actual boundary shear to calculated shear at boundary of stretched region with and without separation of movement 2 1.8 1.6

Shear (pixels)

1University

Actual Shear

1.4 1.2 With segmentation left boundary

1 0.8 0.6

No segmentation left boundary

0.4 0.2 0 0

50

100

150

200

250

Spatial Position (along direction of sliding boundary, 0 = bottom of image)

Method: ‘Sheargram’ Generation Validation test 2: Syringe and sponge model. Sponge gradually compressed by plunger. ‘Adhesion’ alters the shear pattern.

Start: Sagittal dynamic MR slice Step 1: Separate motions of abdominal contents from wall (semiautomated) Step 2: Mask motion and create 2 sets of images Step 3: Register consecutive frames to extract deformation field

Syringe model

Frame 1

Frame 1

Frame 2

Frame 2

Clinical Application: Shear calculation as a diagnostic technique for adhesions. ‘Sheargram’ result correlates with surgically confirmed adhesion.

Adhesion (arrow)

No Adhesion Adhesion

Healthy Volunteers

Discussion

Step 4: Combine deformation fields

• New method measured shear accurately: 2.

Step 5: Calculate deformation gradient tensor Horizontal shear

Step 6: Calculate strain and shear relative to boundary and sum over ~3 respiratory cycles

Vertical shear

Horizontal strain

Vertical strain

Shear profile reproduced in highly idealised computer model Presence of syringe ‘adhesion’ detected

• Implication: Detectable reduction in shear infers adhesions • Clinical Application: Method can be used to detect adhesions

Future Work Boundary shear – ‘Sheargram’

Boundary strain

• 3D Analysis: Analyse abdominal movement in 3D for complete picture of movement • Visualisation: Optimal visualisation to aid data interpretation

Acknowledgements The authors would like to thank BRET for supporting this project

GASTROENTEROLOGY TODAY - SUMMER 2016

1.

Alternative ‘sheargram’ visualisation in a 3D surface plot

33

POSTERS Research design implications from a survey and focus group of IBS sufferers at a specialised patient conference K J Etherson1, J M Mason2, C Dower1, C Emmett1, Y Yiannakou1 of Surgery, County Durham and Darlington NHS Foundation Trust 2Durham Clinical Trials Unit, Wolfson Institute, Durham University

1Department

Introduction

Method

A large patient conference attended by >150 patients with IBS was hosted by County Durham and Darlington NHS Foundation Trust in July 2014. It aims were to educate, support and gain patients’ perspectives into their condition. A 45-minute session on “engaging with research” described current research and thinking into IBS, and then offered participants the opportunity to complete a survey and focus group discussion on the topic. This session was repeated three times during the conference.

Each of the 3 sessions followed a prescribed format. A survey sheet asked participants to complete 5 multiple choice questions on health research in IBS. The cohort were then split into two focus groups led separately by a professor and specialist in health research design (JM) or a research fellow who treats and recruits patients with IBS into clinical studies (KE). Survey data was analysed quantitatively after the conference. Qualitative data was shared between researchers after each session and emerging themes explored further in the subsequent focus groups for validation.

What do you think our research priority should be?

Developing diagnostic tests 18%

What motivates you to take part in a research trial?

Other non-drug treatments 5%

Investigation of the causes of IBS 54%

70%

Other 8%

60%

Percentage response

Investigation of psychological issues in IBS 3%

New drugs treatments 20%

How long is it acceptable to keep doing a symptom diary for?

50%

40%

30%

20%

10%

1 Week, 2%

2 Weeks, 10% 3 Weeks, 2%

0%

A new Altruism treatment for IBS

>4 Weeks, 85%

Other motivating factors

Validation of condition

Would you still willing to be involved if you may receive a sham/placebo treatment ?

Feeling empowered

Improved QOL

Research the causes of IBS

YES

How many visits to hospital are acceptable in a 6 month period for a research trial?

1-2 Visits 3-4 Visits

32%

4%

> 5 Visits

Pain is a priority symptom

32% 64%

General consensus was monthly visits on average

GASTROENTEROLOGY TODAY - SUMMER 2016

34

68%

Themes emerging from focus groups

Sense of gaining control

Validation of symptoms & experiences

Results 78 people attended and participated over 3 sessions. Response rates varied between survey items. Patients felt that research priorities should be; investigating the causes of IBS (54%), new drug treatments (20%), and developing diagnostic tests (18%). As research participants, 85% felt it was acceptable to keep a bowel diary for >4 weeks and 63% felt >5 visits in a 6 month period during a clinical trial were acceptable. Motivations to participate in clinical trials were due to; a new treatment for IBS (65%), altruism (37%) and other factors (11%). 68% were willing to participate in studies where they might receive a placebo or sham treatment as part of the study design.

Themes emerging from the focus groups emphasised the need to research the causes of IBS, particularly as a diagnosis was felt to validate their experiences and brought a sense of gaining control. The treatment of pain was felt to be “a first priority”, as was a wish for a side-effect free “magic pill”, but expectations of these were realistic. Most agreed that their IBS symptoms were highly variable and so longer diary exercises were acceptable and required.

Conclusion Methodologists and clinicians involved in the design of clinical trials of investigational medical products for IBS should consider our patients’ ideas and their acceptability. In particular: lengthening symptom diaries, monitoring pain as a priority symptom, and frequent monthly study visits. Recruitment is not hindered by placebo or sham treatment arm designs and most patients are motivated to participate by receiving a new treatment over altruism or honorariums.

POSTERS

The Management of Incidentally Diagnosed Pancreatic Neuroendocrine Lesions: A New Tool to Evaluate Risk of Malignancy L. Mills1, J.K. Ramage1,2, A. Prachalias1,3, P. Srinivasan1,3, K. Menon1,3, A. Quaglia 1,4, N. Heaton3, D. Sarker1, P. Ross1, R. Basuroy1, R. Srirajaskanthan1,5 1- ENETS Centre of Excellence, Institute of Liver Studies, King’s College Hospital 2- Department of Gastroenterology, Hampshire Hospitals NHS Trust 3- Hepatopancreatobiliary surgery, Institute of Liver Studies, King’s College Hospital

4- Department of Histopathology, Institute of Liver Studies, King’s College Hospital 5- Department of Gastroenterology, University Hospital Lewisham, London

Background:

Whilst most small, benign pancreatic neuroendocrine tumours (PNETs) are diagnosed following a presentation with the symptoms of a functional syndrome, such as insulinomas, the incidence of incidentally diagnosed PNETs is rising. It is widely accepted that surgical resection offers the only curative option for PNETs. However, many of these incidentally diagnosed tumours are small and are thought to have an indolent natural history, and the risks of pancreatic surgery are significant. As an alternative to surgery, surveillance strategies have been proposed for selected patients, the so called ‘watch and wait’ strategy.

Indeed there are three published cohorts of PNET patients for whom the surveillance strategy was successfully adopted.1,2,3 Ultimately the risks of surgery must be balanced against the risk of later malignancy, a difficult decision that presents a unique management dilemma.

Aims:

- To evaluate the experience of our single centre in managing PNETs, particularly with regards to small, incidental lesions - To investigate predictive variables of malignant features of tumours in order to aid selection of a ‘watch and wait’ cohort - To review the surgical outcomes of our centre, comparing enucleation to pancreatectomy

Methods:

The records of 233 patients with PNETs treated at King’s College Hospital between 2004 and 2013 were reviewed. Median follow-up of the 147 surviving patients was 42.3 months. Histopathology reports, surgical notes and radiology were reviewed to identify malignant features. Malignancy was defined as the presence of distant metastasis either synchronously or metachronously, nodal involvement, recurrence after resection or local invasion. Kaplan-Meier survival analysis and multivariate logistic regression were conducted in IBM’s SPSS.

Results: Treatment Outcomes of Surveillance

Of 134 patients without metastatic disease at presentation, the 100 who received primary resection had an increased survival compared to those receiving other treatments (5 year survival 92.1% vs. 81.2%, p=0.019).

Survival was significantly better for functional patients (p=0.026). Of the 34 not receiving surgery, 14 had comorbidities, 8 declined surgery, the reason was unknown in 4 and non-operative surveillance was adopted in 8 patients.

Patients with surgical contraindications had significantly worse 5 year survival than other patients not receiving resection (33% vs. 100%, p<0.003).

Results: Prediction of Malignant Features

All diagnostic variables were analysed with univariate logistic regression to identify significant predictors of malignancy. Presentation style, familial syndromes, diameter, elevated CgA, elevated 5HIAA and histological grade were all shown to be significant OR 95% CI p .001 predictors.

Two iterations of Presentation multivariate analysis revealed that only Asymptomatic 1 Symptomatic 4.780 2.058-11.105 diameter, CgA elevation and Unknown 3.484 1.229-9.876 presentation were independently Size (mm) 1.067 1.037-1.097 .000 significant. The odds ratios produced CgA High 3.484 1.229-9.876 .019 by this model can be used to Constant .068 graphically represent Probability the probability of of Malignancy Sympt & CgA malignancy. 1.0 CgA Symptomatic Baseline

Probability

0.8 0.6

Enucleation Morbidity Resection Morbidity

0.4 0.2 0.0

Results: Prevalence of Malignant Features

10

20

30

40

Diameter (mm)

50

60

Distal Mortality

Results: Surgical Outcomes

The mean tumour diameter did not significantly differ between the two comparison groups. Interestingly, standard resections were performed for 4 patients with tumours 1-10mm, whereas the smallest enucleation was 10mm.

Overall 90 day mortality did not significantly differ between enucleations and small resections (0% vs. 5.7%). All grade morbidity was not significantly higher in the enucleated cohort (54.5% vs. 50.9%) and neither was fistula formation significantly increased (9.0% vs. 5.7%). However, microscopic and macroscopic surgical margin involvement was significantly higher for enucleated patients (30% vs. 16.7%, p=0.032).

Treatment n Mean Diameter (range) 30 day mortality (%)

Whipple’s

Distal

All Resections Enucleation <31mm

Resect <31 vs.

Enuc

47

80

63

12

30.35 (4-85)

43.9 (4-180)

18.6 (4-30)

16.55 (10-51)

1 (2.1)

1 (1.3)

2 (3.2)

0

.295 .704

90 day mortality (%) Morbidity (%) Fistula (%)

4 (8.5) 21 (55) 4 (11)

2 (2.5) 23 (33) 1 (1.4)

5 (5.7) 27 (51) 3 (5.6)

0 6 (55) 1 (9.1)

.407 .546 .539

R0 Resection (%)

35 (83)

57 (84)

50 (83)

7 (70)

.032

Conclusions:

- Up to 40% of tumours <2cm in diameter demonstrate malignant features; 2cm cannot be used as a significant cut-off for malignancy - The probability of malignancy can be predicted using diameter, style of presentation and CgA levels - The risk of malignancy outweighs the risk of surgery for all tumour diameters; enucleation has a higher rate of involved margins than pancreatectomy References: 1Crippa et. al. Surgery (2014) 155, 145-153 2Gaujoux et. al. J. Clin. Endocrinol. Metab. (2013) 98 , 4784-9

3Lee

GASTROENTEROLOGY TODAY - SUMMER 2016

The presence of malignant features varied with tumour diameter. Malignant features were present in 28 (41%) of all tumours 2cm, and in 15 (27%) of 2cm without distant metastasis. Synchronous metastasis, vascular invasion and local invasion showed a linear correlation (r2>0.8). Vascular invasion and lymph node positivity plateau at diameters >4cm. This may be explained by the fact that many pathology reports do not explicitly mention these features for very large, invasive tumours leading to a reporter bias.

Whipple's Mortality 0

et. al. Surgery (2012) 152, 965-974

35

COMPANY NEWS

BSG 2016

ANNUAL MEETING

BRITISH SOCIETY OF GASTROENTEROLOGY

20 – 23 June 2016 ACC Liverpool, UK

Live endoscopy, cutting-edge sessions, interactive symposia, world renowned speakers, state-of-the-art lectures, prices held at 2014 rates, free paper sessions, conference app, gastroenterology masterclass, 24 CPD points’ available, clinical updates, Twitter sessions, moderated poster rounds, conference party, interactive programme, basic and clinical science symposia, industry exhibition and a bike ride!

This is not an ordinary annual meeting; this is a BSG annual meeting.

GASTROENTEROLOGY TODAY - SUMMER 2016

For more information

36

www.BSG2016.org.uk BSG2016@mci-group.com App: Search ‘BSG2016 App’ to download

#BSG2016 @BritSocGastro

COMPANY NEWS

PROBIOTICS INTERNATIONAL LTD (PROTEXIN) SCIENCE AND NATURE IN BALANCE AN INTRODUCTION… How many probiotic companies have their own strains of bacteria and manufacture their own products on site in the UK, whilst being able to show robust research evidence for their products by backing them with strong clinical research?

frequency, stool consistency, abdominal pain and faecal incontinence in children with chronic constipation.

In a different randomised controlled trial, published in the Journal of Paediatrics and Child Health, the seven bacterial strains were shown

This is something that Probiotics International Ltd (Protexin) can boast,

to significantly improve symptoms in infants suffering with colic. The

being a company dedicated to producing innovative, research-based

researchers added that the study supports the case for larger trials to

products under its brand name, Protexin.

see whether probiotics can prevent infant colic.

Within Protexin, there is both the Bio-Kult brand, which includes the

The probiotic strains found within the Bio-Kult range have over 10

popular and unique 14 strain live bacteria (probiotic) product, and Lepicol, a multi-fibre product with prebiotics and probiotics to help support healthy bowels.

Protexin boasts a purpose built, state-of the- art facility in Somerset, UK, affording it complete control over its production. The company manufacturers to pharmaceutical standards and has been awarded

clinical trials, are used within the NHS, and are manufactured to the highest possible quality standards.

Protexin is also a company that contains a vast amount of technical expertise; Janine Barlow Technical and New Product Development Manager, Peter Cartwright, Head of Research, who has a wealth of microbiota knowledge. Dr Ashton Harper, who is one of two Medical

cGMP (MHRA) and ISO 9001:2008 status.

Advisors. He is a fully registered doctor, who worked in the NHS for five

Their innovation and leadership in the probiotic market comes from

of gastrointestinal diseases. Among his responsibilities, Dr Harper

developing their own research driven probiotic strains (identified with the initials PXN after each strains name) which are individual to their

years, during which time he discovered a passion for the management writes medical articles and contributes to research and development projects. Also part of the team is Dr Alejandro Palacios, who has

company alone.

a B.Sc. degree in Food Engineering, a Ph.D. in Molecular and Cell

Research investment

fields of hostpathogen interactions, stem cell biology, oncology, and

As a business, Protexin works closely with leading universities, hospitals and research centres around the world on a range of ongoing research programmes, and this is one of the unique selling points of both Bio-Kult and Lepicol.

Protexin’s investment in research is significant, both in terms of finances working with the clinical research organisations, then going through ethics and then the actual study itself, but it is a process the company is dedicated to.

The most recent example of this was a double-blind, randomised controlled trial focusing on Lepicol and its effect on people suffering

cardiovascular diseases. He is responsible for providing medical and scientific support to the clinical community in the UK, particularly the primary and secondary care sectors. Finally there is Natalie Lamb and Claire Barnes who have extensive nutritional and product knowledge and complete the team as Protexin’s Technical Advisors.

Protexin has won the Queens Award for International Trade in 2016 and 2011 and most recently obtained a two star accreditation from Best Companies.

To speak to any of the Protexin experts in relation to any of their products and research please contact info@protexin.com or call +44 (0) 1460 243 230.

with constipation. The study found that there was an increase in bowel movements from week one.

Research has also been carried out to confirm the effectiveness of Bio-Kult Infantis, a product designed especially for babies and children.

The study looked at the effects of probiotics on childhood constipation.

The randomised controlled, double-blind clinical trial, published in the International Journal of Paediatrics, concluded that there was evidence that the seven strain probiotic mixture used can help to improve stool

Within Protexin, there is both the Bio-Kult brand, which includes the popular and unique 14 strain live bacteria (probiotic) product, and Lepicol, a multi-fibre product with prebiotics and probiotics to help support healthy bowels.

GASTROENTEROLOGY TODAY - SUMMER 2016

but also time; it is a long process, from setting up the study design, then

Biology, and nearly 20 years of biomedical research experience in the

37

COMPANY NEWS

FOCUS ON FIT CAN FAECAL IMMUNOCHEMICAL TESTING IMPROVE THE PATHWAY FOR PATIENTS WITH LOWER GI CANCERS? At the ACB Focus meeting in April 2016, Alpha Laboratories organised a panel of experts to discuss the ramifications of the new NICE NG12 Guideline – Suspected cancer: recognition and referral, in relation to bowel cancer.

Of these, 484 had successful colonoscopies, which identified 11 cancers, 19 higher-risk adenomas and 15 cases of inflammatory bowel disease, detection rates in keeping with other UK statistics.

The study categorised significant bowel disease as colorectal cancer, higher-risk adenomas and inflammatory bowel disease. Hyperplastic

Professor Callum Fraser, Senior Research Fellow, School of Medicine,

polyps, diverticular disease (DD), haemorrhoids and other less clinically

University of Dundee, opened the discussion with a reminder that over

important findings were considered as the non-diseased group. There

26,000 people die of bowel cancer annually, making it the second

were statistically significant differences in the f-Hb concentrations

most common cause of cancer deaths today. And, with over 40,000

between these two groups.

diagnosed each year, it remains a major clinical problem.

Dr. Godber concluded that there is firm evidence that f-Hb is related to Until 2015, NICE advised that patients with abdominal symptoms and

colorectal disease severity and future risk and that FIT is a good test

pain should only have abdominal and rectal examinations and a full

to rule-out significant bowel disease in patients with lower abdominal

blood count. In addition, the Scottish Intercollegiate Guidelines Network

symptoms. Using a cut off of 10 µg Hb/g faeces, FIT provided a high

stated that faecal occult blood testing is too insensitive to be used

negative predictive value (NPV) for significant bowel disease (96.2%).

in guiding investigations of symptomatic patients. Of course, at that

Measurement of f-Hb, in patients referred from primary care, could save

time, these recommendations concerned the traditional, low sensitivity

considerable endoscopy resources and enable fast tracking of those

guaiac-based faecal occult blood test.

with a high suspicion of neoplastic disease, patients with high f-Hb.

When NICE issued the suspected cancer recognition and referral,

Next to present was Mr Paul Skaife, Consultant Colorectal Surgeon,

guideline NG12, in June 2015, the situation changed, since it included

Aintree University Hospitals NHS Foundation Trust.

the re-introduction of tests for faecal occult blood (FOBT) in specific patient groups. However, this did not differentiate what type of FOBT

He explained that, in clinical care, practice is governed by time constraints

should be used. Professor Fraser provided additional background on

with the cancer referral two week wait rule. When the GP first refers a

the more advanced technologies now available and explained how

patient, secondary care has two weeks to see them and is financially

quantitative Faecal Immunochemical Tests (FIT) are very useful in

constrained if those targets are not met. A diagnosis is required within

assessment of patients with lower abdominal symptoms.

31 days. If a diagnosis is determined before 31 days, then the next 31 day timeline, for treatment, is initiated. Thus, there is a maximum target

GASTROENTEROLOGY TODAY - SUMMER 2016

38

He concluded by highlighting the growing body of evidence that FIT

here of 62 days from referral to treatment. This treatment may be with

could be used as a rule-out test for significant bowel pathology (cancer,

surgery, chemotherapy, radiotherapy or may be palliative care. There are

higher-risk adenoma or inflammatory bowel disease), and that NICE were

time constraints at each step of the clinical pathway. Introducing any new

in the process of reviewing the latest data on FIT, with a view to publishing

target, safety or quality mechanism must fit in with these time constraints.

new guidelines on its application in the triage of symptomatic patients.

Currently NICE have not included such considerations.

In the meantime, much debate exists amongst laboratory professionals, gastroenterologists, colorectal cancer surgeons and healthcare

Within those being referred within the two week wait rule, current literature

professionals about how to introduce FIT in routine clinical practice.

suggests between 9.4 and 16% of patients who meet the criteria for urgent referral will have cancer. More than 70% will go through the

Dr Ian Godber, Consultant Clinical Scientist, NHS Lanarkshire, then

diagnostic pathway but will not have cancer. Data from 2013/14 showed

outlined how he had introduced FIT into his Health Board trust. He

more than 200,000 fast track referrals did not lead to diagnosis of

reviewed the key information from his initial evaluation, now published

significant bowel disease. This has significant consequential impact and

in CCLM,1 which identified that FIT could be used as a rule-out test for

on the financial and human resources of our health care system.

patients with significant bowel disease.

A study using a qualitative Point of Care (POC) FIT in Aintree in 2012, The study was based on findings from 909 invited patients scheduled

looked at patients who were admitted, without rectal bleeding, through

for colonoscopy. Of these, 507 returned faecal samples which were

the fast track referral. Each patient had a FIT done at POC and was

analysed on the HM-JACKarc automated quantitative FIT system for

classed as positive or negative based on the cut-off of this FIT, which

faecal haemoglobin concentration (f-Hb).

was 8µg Hb / g faeces.

Godber IM, Todd LM, Fraser CG, MacDonald LR, Younes HB. Use of a faecal immunochemical test for haemoglobin can aid in the investigation of patients with lower abdominal symptoms. Clin Chem Lab Med 2016;54(4):595-602

1

COMPANY NEWS Out of 137 cases, there were 17 cancers in the FIT positive group, and none in the negative group. In essence, if the two week wait referral criteria were met, and a FIT positive was found, then there was a 60% chance of cancer being present. That seemed a reasonable end result, but more importantly, FIT provided a good rule-out test. The NPV, at least in this series of patients, was 100%. So if the two week wait criteria were met, but a patient had a negative FIT result, then cancer was not present.

The clinical impact of these data is that FIT is a good discriminatory test. A negative test result informs that cancer is not present. The result does not tell you what the patient has, but it does inform you of the absence of disease.

This information has the potential impact in deciding what sort of investigations patients are going to have. It may be the patients with FIT negative results have still got symptoms and will require a colonoscopy but, with the time constraints in current clinical practice, it means that they do not need that colonoscopy within 31 days of the diagnosis.

It is very important for clinicians to define which patients need to follow a time restrained clinical pathway, those which don’t, and more importantly, which require a colonoscopy straight away, within a couple of weeks or not at all. Symptoms can be re-assessed, further tests can be performed, perhaps for markers other than FIT. Perhaps a patient will go on to get colonic imaging anyway, but it just does not have to be within the constrained time frame.

Unanswered questions included the following. Does FIT belong in primary care? Is FIT discriminatory and can it define who should be referred? Does the patient actually need a two week wait referral in the first place?

Mr Skaife concluded that FIT is a good test and the available science supports its use. It is the applicability that is still under question. Where does this test belong? Qualitative FIT provides a quick assessment, however, quantitative FIT is more interesting. But there’s an inherent delay in getting a f-Hb result. If a sample is sent off, does the referral for colonoscopy go on hold, until the FIT result is available to decide if this patient is going to be referred or not? The further assessment under way by NICE will need to modify the patient pathway to decide where FIT is most useful. Does it fit in primary care? Does it fit in secondary care? Or both?

Videos of the entire presentations given at ACB Focus ‘The NICE NG12 Guideline: a FIT Outcome’, can be viewed at www.alphalabs.co.uk/ FIT#video including the question and answer session that followed.

GASTROENTEROLOGY TODAY - SUMMER 2016

Following these presentations, there was an interactive question and answer session between the audience and the panellists. There were some excellent points raised including: could other biomarkers be useful in identifying colorectal cancers, who should make the decision on the results from the FIT and what path should the patient follow?

39

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