Individual Follow-up After Rectal Cancer - Focus on the Needs of the Patient
Phase: NA
Conditions: Rectal Neoplasms
Sponsor: Aarhus University Hospital

Individualised follow-up afee eeetal eaneee – foeus on the needs of the patent
Cover page
Title: 
Individual Follow-up afee  eetal Caneee - Foeus on the Needs 
of the Patent (FU CA)
[NCT-number not assigned yet]
Date: 07 February 2016
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Individualised follow-up afee eeetal eaneee – foeus on the needs of the patent
Study protocol – February 2016
Content
1 Introducton.............................................................................................................................1
1.1 Objecties.........................................................................................................................2
2 Hypotheses..............................................................................................................................2
3 Material and methods.............................................................................................................2
3.1 Patents.............................................................................................................................3
3.2 Inclusion...........................................................................................................................3
3.3 Randomisaton..................................................................................................................3
3.4 Data..................................................................................................................................5
3.5 Patent reported outcome measures PROM’s..................................................................5
4 Organisaton and tme schedule..............................................................................................6
5 Funding....................................................................................................................................6
6 Ethics.......................................................................................................................................6
7 Publishing strategy..................................................................................................................7
8 Perspecties.............................................................................................................................7
9 Literature list...........................................................................................................................8
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Individualised follow-up afee eeetal eaneee – foeus on the needs of the patent
Study protocol – February 2016
1 Inteodueton
Colorectal cancer is the third most common cancer worldwide. Rectal cancer amounts for 
about one third of colorectal cancers, with a small male predominance (1,2). A total of 1674 
new rectal cancer patents (62 ,1 % males) were diagnosed in Denmark in 2014 (3). The 
oierall 5-year suriiial rate is 62 %, although mortality is decreasing due to improiement in 
treatment (3).
Among the patents undergoing treatment with a curatie intent, the standard treatment is
surgery. The two predominant resectonal techniques in Europe are abdomino-perineal
resecton (APR) and low anterior resecton (LAR). APR leaies the patent with a
permanent stoma, while LAR is a sphincter-sparing procedure that restores bowel
contnuity. 
Surgery is in some cases combined with pre- and/or postoperatie chemo-radiotherapy (4,5).  
The risk of local recurrence afer rectal cancer has been estmated to 7-9 % and possibly
lowers with the additon of preoperatie radiotherapy and improied surgery techniques. 
Local recurrence is a seiere conditon, and markedly increases mortality (6,7). It is therefore 
crucial to identfy these indiiiduals at a iery early stage. Most local recurrenses occur within 
the frst three years past diagnosis, and 65-70 % of the cases will present clinical symptoms 
(rectal bleeding, pain, sudden change in bowel functon, weight loss). In other cases, the 
recurrence is asymptomatc (8-10).
A large proporton of rectal cancer patents sufer from seiere physical and psychological 
adierse efects from treatment .
Recent studies haie shown that almost half of the LAR patents sufer from seiere bowel
dysfuncton one year afer their operaton (11,12). The symptoms consist of fecal/gas 
incontnence, fecal urgency, frequent bowel moiements and fragmentaton/clustering of 
stools, which collectiely is referred to as “the low anterior resecton syndrome” – or LARS .
Other physical adierse efects from the treatment can be urinary dysfuncton, sexual 
dysfuncton, pain and fatgue   (13-15). Psychological distress and fear of recurrence are 
known psychological adierse efects following treatment for rectal cancer (8,16). All of which, 
can infuence negatiely on the patents’ symptom burden, eieryday functoning and quality 
of life (17,18).
The follow-up regimen currently ofered to Danish rectal cancer patents is rigidly
constructed with standardised controls in the outpatent clinic, has a low leiel of patent
inioliement and is based on a poor leiel of eiidence.
The primary focus is detecton of local recurrence and methastases. The follow-up regimen 
consists of rectoscopy and clinical control 6,12,18,24 and 36 months afer surgery (APR-
patents receiie less clinical controls and no rectoscopies). Furthermore, a CT-scan of the 
thorax and abdomen is performed one and three years  postoperatiely and a colonoscopy is 
ofered eiery ffh year untl the age of 75 (19).
There is some eiidence that frequent follow-up to detect distant methastases reduces 
mortality, but eiidence on the efect from frequent routne controls and endoscopies on 
detectng local recurrences, and the general methodology of follow up programmes is scarce 
(20,21). Thus, a large number of Danish patents are each year enrolled in comprehensiie 
follow up programs based on dubious leiels of eiidence. 
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Individualised follow-up afee eeetal eaneee – foeus on the needs of the patent
Study protocol – February 2016
Based on seieral years of clinical experience we know that the specifc needs afer rectal
cancer surgery difer substantally from patent to patent. Patents and clinicians request 
more patent-centred follow up, also focusing on physiological and psychological aspects – in 
combinaton with monitoring potental recurrence of the cancer (20,22). 
The Danish Health Authorites recommend a more indiiidualised follow-up, in order to detect 
both recurring cancers and to treat the adierse efects of rectal cancer surgery (20). 
As a new alternatie we propose a patent-led follow-up program with a higher degree of 
patent inioliement. 
The patent-led follow-up programme is based on a standardized educaton program in order 
to enforce the patents’ ability to assess and respond sufciently to symptoms and health 
problems, by consultng a health professional for adequate assistance and interienton.
Patent educaton, supportng the patents’ self-efcacy and health literacy, together with 
standardised and eiidence based response algorithms to self-referrals form the basis for 
patent-led follow-up program. 
1.1 Objeetves 
This project aims at improiing the follow-up program afer rectal cancer by:
1. Deieloping and implementng a new patent led follow-up program, based on patent 
educaton and inioliement, and self-referral by direct access to project nurse 
2. Examining the efect of the new follow-up program on symptom burden and health related 
quality of life
3. Examining the efect of the new follow-up program on specifc physiological and 
psychological symptoms and late adierse efects from treatment, eient-free suriiial, patent 
experienced satsfacton, informaton and inioliement
4. Eialuatng cost-efectieness of the new follow-up program
2 Hypotheses
We hypothesize, that early identfcaton and treatment of late adierse efects afer rectal 
cancer surgery, and earlier detecton of local recurrence is possible if the patents are 
empowered to actiely play a role in their own care pathway. This, by means of the new 
patent-led follow-up programme, based on standardised educaton and thorough patent 
informaton regarding releiant symptoms, patents’ access to direct self-referral to an 
afliated nurse, and standardised response algorithms to patent reported data.
We belieie that this will reduce the symptom burden from physical and psychological 
symptoms and greatly improie the quality of life of each indiiidual patent. And that this new 
follow-up program will improie other patent-reported outcomes such as patent satsfacton, 
patent inioliement and informaton. 
Furthermore, we hypothesise that the patent led follow-up program will lead to earlier 
detecton and treatment of local recurrences, although no efect on oierall suriiial is 
expected. We expect that the new program will optmise the use of economic resources.
3 Mateeial and methods
The study will be designed as a multcentre randomized controlled trial, with follow-up in 
three years (see Figure 1)
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Individualised follow-up afee eeetal eaneee – foeus on the needs of the patent
Study protocol – February 2016
3.1 Patents
Colorectal surgical departments in Aarhus, Randers, Herning and Aalborg will be iniited to 
partcipate. These centres coier one third of all Danish rectal cancer patents (556 out of 1675 
rectal cancers in 2014= 33 %) (3). 
Inclusion criteria:
Adult patents operated for a primary adenocarcinoma in the rectum (0-15 cm from the anal 
ierge), with pathology results showing R0/R1 resecton – thus treatment with curatie intent.
The patents must be able to read, speak and understand the Danish language and must not 
sufer from mental dementa or other mental disorders afectng cognitie functons. 
Moreoier, writen informed consent is required from all partcipants.
Patents treated with local excision of the tumour (without resecton of the rectum) are 
excluded, and likewise if the pathology shows non-radical resecton (R2) or known malignant 
methastases. 
Residual life expectancy less than two years and synchronous cancer will lead to exclusion, as 
will concurrent partcipaton in other research studies with contacts in the follow up periode. 
Loss to follow-up will be registered as ierifed recurrence, death, emigraton from the 
partcipatng regions or if a patent requests to interrupt partcipaton. 
The three partcipatng centres operate about 550 rectal cancer patents each year and taking 
the in- and exclusion in regard, this leaies about 330 eligible patents each year. 
An estmaton of samplesize shows, that a total of 334 partcipants are needed in order to 
obtain statstcally signifcant results (p0.0.05). 
3.2 Inelusion 
Patents will be approached at the postoperatie iisit in the outpatent clinic where they are 
presented for the pathology results from the surgery, approximately 2 weeks afer the 
operaton. The doctor will proiide short oral informaton about the study and hand out 
writen informaton. 
A research nurse will contact the patent by telephone a few days later, to help the patent 
deciding whether or not to partcipate. If the patent agrees to partcipate, the research nurse 
will collect informed writen consent and baseline informaton from the partcipants before 
randomisaton. 
Patents, receiiing postoperatie chemotherapy, will be contacted by the research nurse afer 
ended treatment.
3.3  andomisaton
Partcipants are randomised into A) an interienton group, where patents will receiie 
standardised educaton, and are encouraged to contact the assigned project nurse if they 
experience symptoms of adierse efects or cancer recurrence a control group, and B) 
following the current FU-programme with routne check-ups. Follow-up tme in both groups is 
3 years.
Non-partcipants are asked to complete a baseline questonnaire similar to the one 
partcipants fll in. 
The block-randomizaton is set op to stratfy by centre, sex and treatment type (+/- 
postoperatie oncological treatment and +/- temporary illeal stoma) 
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Individualised follow-up afee eeetal eaneee – foeus on the needs of the patent
Study protocol – February 2016
Figure 1: randomisation
Geoup A:
The interienton groups, following the patent-led follow-up programme will not atend 
regular iisits in the outpatent clinic.  
They will receiie structured educaton by a nurse regarding early signs of recurrence of the 
cancer and symptoms of adierse efects, and how to respond adequately. 
The educaton will be performed by the afliated research nurse, and based on a protocolled 
manual. The educaton is supported by a website proiiding more detailed informaton on the 
symptoms and adierse efects. The website is exclusiie for the patents in the interienton 
group. Methods and content for the patent educaton is deieloped by the group of afliated 
research nurses. Patents are iniolied in the process, by means of two focus group 
interiiews. 
Partcipants will be instructed to approach the research nurse in case of symptoms and are 
informed of the necessity of contactng the research nurse immediately in case of pre-defned 
alarm symptoms (self-referral).
The research nurse will respond to patent’s self-referral according to a pre-defned, 
standardised response-algorithm. The algorithm is deieloped in close cooperaton between 
partcipatng health professionals, and representaties from other specialites and the primary 
sector.
Patents can contact the research nurse by telephone and e-mail on a daily basis. 
The patents will haie a CT scan afer 12 and 36 months, and a colonoscopy with fie years 
interial untl the age of 75.
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Individualised follow-up afee eeetal eaneee – foeus on the needs of the patent
Study protocol – February 2016
Geoup B:
The control group will follow regular iisits with a doctor in the outpatent clinic (+ rectoscopy) 
at 6, 12, 18, 24 and 36 months postoperatiely, haie a CEA-test and a CT scan afer 12 and 36 
months, and a colonoscopy with fie years interial untl the age of 75.
3.4 Data
Outcomes
A Symptom burden and health related quality of life, together with late adierse efects from 
rectal cancer surgery: bowel dysfuncton, urinary and sexual dysfuncton, pain, fatgue, fear of 
recurrence, anxiety and depression
B Self-efcacy and patent actiaton, patentnioliement, and patent’s experience of 
informaton and sense of security.
C QALY’s 
D Time to recurrence, 3- year suriiial
Most data will be collected using patent reported outcome measures (PROM’s).
Patents are asked to complete a questonnaire at baseline (tme of inclusion), 12 and 36 
months postoperatiely. The questonnaire will focus on symptom burden and quality of life, 
specifc symptoms, patent actiaton and self-efcacy, patent inioliement and informaton, 
needs in the follow-up period and how they haie been handled. 
Data regarding recurrence of cancer, mortality and socioeconomic factors will be extracted 
from natonal registers. While data on comorbidity is extracted from the natonal clinical 
database for colorectal cancer surgery.
Data on health care utlisaton in the follow-up period will be collected from natonal 
registers, in combinaton with informaton from patent records (limited access).
3.5 Patent eepoeted outeome measuees P OM’s 
1.
Symptom bueden: ’Functonal Assessment of Cancer Treatment – Colorectal’ (FACT-C).  
36 items
2.
Bowel funeton: Patents without a stoma: ‘Low Anterior Resecton Syndrome Score’ 
(LARS) and Bristol Stool Scale (together 7 items). Patents with a stoma: The Colostomy 
bother score.  8 items
3.
Ueinaey funeton: ‘Male/Female Lower Urinary Tract Symptoms’ (ICIQ-MFLUTS/ICIQ-
FLUTS). 12 and 13 items respectiely
4.
Sexual funeton, female: ‘The sexual functon – Vaginal Changes Questonnaire’ (SVQ). 27 
items/17 items (shortorm)
Sexual funeton, male: ‘Internatonal Index for Erectle Functon’ (IIEF). 15 items/5 items 
(shortorm)
5.
Pain: ‘Brief Pain Inientory Short Form’ (BPI). 15 items
6.
Fatgue: The Multdimensional Fatgue Inientory (MFI). 20 items 
7.
Feae of  eeueeenee: ’Fear of Cancer Recurrence Inientory’ (FCRI). 43 items
8.
Psyehologieal disteess: ’Hospital Anxiety and Depression Scale’ (HADS). 14 items. 
9.
Quality of Life: ‘EuroQol 5-dimensional health state measure’ (EQ-5D). 5 items (+ VAS) 
10. Self-effieaey: ‘Patent Actiaton Measure’ (PAM). 13 items 
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Individualised follow-up afee eeetal eaneee – foeus on the needs of the patent
Study protocol – February 2016
11. Patent involvement, infoematon and sense of seeueity: Combinaton of two Danish 
questonnaires. 11 items 
12. Peesonality: ’Life orientaton test-reiised’ (LOT-R). 10 items 
4 Oeganisaton and tme sehedule
The head doctors in four surgical departments in two Danish regions haie agreed to 
partcipate in the study:

Mogens Rørbæk Madsen, Head of Surgical Department, Hospitalsenheden Vest,
Regionshospitalet Herning.

Inge Bernstein, Head of Surgical Department, FBE Kirurgi Syd, Aalborg
Uniiersitetshospital.

Knud Thygesen, Head of Surgical Department P, Aarhus Uniiersity Hospital. 

Lars Maagaard Andersen, Head of Surgical Department, Regionshospitalet Randers.
The partcipatng centres haie outstanding research eniironments and a long research 
traditon. The collaboraton between the centres has in preiious studies and projects proien 
to be irreproachable. 
The research group in Aarhus will coordinate the project, and the Ph.D.-student will act as 
daily project-manager and fll the role as research nurse in the centres Aarhus and Randers. 
All iniestgators are responsible for inclusion and the executon of the research project 
locally. 
Time sehedule
Yeae 1
Yeae 2
Yeae 3
Yeae 4
Yeae 5
Fall 
2015
Spring 
2016
Fall 
2016
Spring 
2017
Fall
2017
Spring 
2018
Fall 
2018
Spring 
2019
Fall 
2019
Spring 
2020
Deielopment and pilot-testng of 
the interienton
Systematc literature reiiew
Instructon of research nurses
Inclusion RCT
Follow-up RCT
Data analysis, publicatons and 
completon of  Ph.D.-dissertaton
5 Funding
The study is initated by researchers and clinicians from the partcipatng centres, and thus 
partally funded from the centres.
Most funding, though, comes from the Danish Cancer Society (3 mio. Dkr).
Funding coiers salary for Ph.D.-student, research nurses and consultng statstcian, required 
electronic equipment and other material and resources. 
None of the partcipatng iniestgators haie concurrent fnancial interests in the research 
study. 
6 Ethies
The risks and ethical concerns related to the project are limited. The risk of missing a locally 
recurrent cancer is minimal, as most recurrences are symptomatc. A local quality report from 
one of the partcipatng centres showed that out of 33 ierifed local recurrences oier a tme 
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Individualised follow-up afee eeetal eaneee – foeus on the needs of the patent
Study protocol – February 2016
period of six years, only two were detected in connecton with a clinical control. The 
remaining were detected either by patents’ self-referral due to symptoms or by CT or MR-
scans (unpublished data). 
Answering the questonnaire may remind the partcipant of their disease and therefore to 
some persons be unpleasant and a stress factor. 
The study will empower the partcipants in the interienton group to be more iniolied in own 
health care, desirable to some and the opposite to others. Patents acceptng to partcipate 
should feel secure whateier group they are randomised to follow. We aim to ensure patents 
of this by thorough and explicit informaton by the tme of inclusion.
All partcipants will be asked to proiide writen informed consent. Data will be handled and
stored according to natonal law and only anonymised results will be published. The study
is reported and approied by the Danish Data Protecton Agency and The Natonal Commitee 
on Health Research Ethics as required. 
7 Publishing steategy
Negatie as well as positie results will be published in internatonal peer-reiiewed
scientfc journals. The project will result in at least fie scientfc publicatons, and all
sources of funding will be acknowledged in the manuscript. 
The Ph.d.-student afliated to the project will draf the manuscripts in collaboraton with the 
superiisors. The iniestgators from the four centres will besides deliiering partcipants to the 
study also partcipate in data management and preparaton of manuscripts as co-authors.
First author will be the one drafing the inital manuscript, last author will be prof. Søren 
Laurberg. Other authors will be listed alphabetcally.
8 Peespeetves
Results from the study will contribute to strengthen the eiidence base for RC follow-up, and 
may impact the future follow-up of RC patents in Denmark and internatonally.
If the new follow-up program proies successful, it will be readily implementable in daily
clinical practce at a natonal leiel. Also, it may atract internatonal atenton due to the
huge number of afected patents and the high leiel of costs all oier the Western world.
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Individualised follow-up afee eeetal eaneee – foeus on the needs of the patent
Study protocol – February 2016
9  efeeenee list
(1) Haggar FA, Boushey RP. Colorectal cancer epidemiology: incidence, mortality, suriiial, and 
risk factors. Clin Colon Rectal Surg 2009 Noi;22(4):191-197. 
(2) Brethauer M, Kalager M. Colonoscopy as a Triage Screening Test. N Engl J Med 2012 
02/23; 2015/02;366(8):759-760. 
(3) DCCG. Landsdækkende database for kræf i tyk- og endetarm (DCCG). Natonal  rsrapport 
for 2014. 2015. 
(4) Roikjær O. Anatomi og mesorektal ekscision - DCCG's natonale retningslinjer for 
diagnostk og behandling af kolorektal cancer. 2014. 
(5) Sundhedsstyrelsen. Pakkeforløb for Kræf i Tyk- og Endetarm. 2012. 
(6) M. B. Nielsen. Outcome following intended curatie treatment of locally recurrent rectal 
cancer Health Aarhus Uniiersity, Department of Colorectal Surgery, Aarhus Uniiersity 
Hospital; 2012. 
(7) Wiig N, Søreide O. Locoregional recurrence of rectal cancer. In: Holzheimer RG, Mannick 
JA, editors. Surgical Treatment: Eiidence-Based and Problem-Oriented Munich: 
Zuckschwerdt-Verlag; 2001. 
(8) Engel J, Kerr J, Schlesinger-Raab A, Eckel R, Sauer H, Holzel D. Quality of life in rectal cancer 
patents: a four-year prospectie study. Ann Surg 2003 Aug;238(2):203-213. 
(9) Emmertsen K. Funktonelle forstyrrelser efer rectumresekton - DCCG's natonale 
retningslinjer for diagnostk og behandling af kolorektal cancer. 
(10) Nielsen MB, Laurberg S, Holm T. Current management of locally recurrent rectal cancer. 
Colorectal Dis 2011 Jul;13(7):732-742. 
(11) Emmertsen KJ, Laurberg S. Bowel dysfuncton afer treatment for rectal cancer. Acta 
Oncol 2008;47(6):994-1003. 
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Individualised follow-up afee eeetal eaneee – foeus on the needs of the patent
Study protocol – February 2016
(12) Chen TY, Emmertsen KJ, Laurberg S. Bowel dysfuncton afer rectal cancer treatment: a 
study comparing the specialist's iersus patent's perspectie. BMJ Open 2014 Jan 
21;4(1):e003374-2013-003374. 
(13) Bregendahl S, Emmertsen KJ, Lindegaard JC, Laurberg S. Urinary and sexual dysfuncton 
in women afer resecton with and without preoperatie radiotherapy for rectal cancer: a 
populaton-based cross-sectonal study. Colorectal Dis 2015 Jan;17(1):26-37. 
(14) Lange MM, ian de Velde CJ. Urinary and sexual dysfuncton afer rectal cancer 
treatment. Nat Rei Urol 2011 Jan;8(1):51-57. 
(15) Johansen C. Kræf - Senfølger og Rehabilitering. 1st ed. Københain: Hans Reitzels Forlag; 
2013. 
(16) Simard S, Thewes B, Humphris G, Dixon M, Hayden C, Mireskandari S, et al. Fear of 
cancer recurrence in adult cancer suriiiors: a systematc reiiew of quanttatie studies. J 
Cancer Suriii 2013 Sep;7(3):300-322. 
(17) Denlinger CS, Barseiick AM. The challenges of colorectal cancer suriiiorship. J Natl 
Compr Canc Netw 2009 Sep;7(8):883-93; quiz 894. 
(18) Marientano S, Forjaz M, Grosso G, Mistreta A, Giorgianni G, Platania A, et al. Health 
related quality of life in colorectal cancer patents: state of the art. BMC Surg 2013;13 Suppl 
2:S15-2482-13-S2-S15. Epub 2013 Oct 8. 
(19) Postoperati kontrol - DCCG's natonale retningslinjer for diagnostk og behandling af 
kolorektal cancer. 2012. 
(20) Sundhedsstyrelsen. Opfølgningsprogram for tyk- og endetarmskræf. 2015. 
(21) Jefery M, Hickey BE, Hider PN. Follow-up strategies for patents treated for non-
metastatc colorectal cancer. Cochrane Database Syst Rei 2007 Jan 24;(1)(1):CD002200. 
(22) Williamson S, Chalmers K, Beaier K. Patent experiences of nurse-led telephone follow-
up following treatment for colorectal cancer. Eur J Oncol Nurs 2014 Dec 16. 
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Individualised follow-up afee eeetal eaneee – foeus on the needs of the patent
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Addendum foe the sample size estmaton foe the FU CA-teial
Date: June 06, 2018
An inital estmaton of sample size showed, that a total of 334 partcipants were needed in 
order to obtain statstcally signifcant results (alpha 0.05, beta 0.20, SD 13, minimally 
important diference 4 points on the TOI-score). 
As the end of inclusion draws nearer, a confrmatie updated sample size analysis has been 
performed. The reason for this was mainly that the assumed standard deiiaton (SD) used for 
the inital estmaton was subject to considerable uncertainty, as it was based on studies 
where setng and populatons difered substantally from ours. 
Therefore, an interim analysis of the main-outcome (Trial Outcome Index - TOI) has been 
performed in order to determine a more precise SD. In the updated sample size estmaton, 
the following preconditons are listed: 10.4 SD, 0.05 alpha-ialue, 0.20 beta-ialue, an expected 
diference of 4 points on the TOI-scale and an expected total drop-out of 30%. Furthermore, 
additonally 15% are added to the sample size, due to the assumpton that the outcome data 
will be non-parametric. Thus the conclusion from the updated sample size estmaton is that a 
total of 324 partcipants are needed in order to obtain statstcally signifcant results.
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