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SUPPLEMENTARY APPENDIX
Legend
- Appendix table A1 Search terms
- Appendix table A2 Reason for exclusion.
- Appendix table A3 Study quality (NOS score)
- Appendix table A4 Detailed NOS score per study
- Appendix table A5 TP-IAT indication per study
- Appendix table A6 Pain results per study
- Appendix table A7 Endocrine outcomes per study
- Appendix figure A8 Forest plots of 30 day and 1 year mortality
- Appendix table A9 Mortality rates per study
- Appendix table A10 Quality of life per study
- Appendix table A11 Meta-regression analysis
- Appendix figure A12
A12A Funnel plots of publication bias for opioid free rates
A12B Funnel plots of publication bias for insulin free rates
- Contribution of authors
- Moose checklist
Table A1. Search terms
Chronic pancreatitis
AND
Pancreatectomy
Chronic pancreatitis[MeSH]
OR
Pancreatectomy[MeSH]
OR
Chronic pancreatitis[tiab]
OR
Chronic obstructive pancreatitis[tiab]
OR
Chronic calcifying pancreatitis[tiab]
Pancreatect*[tiab]
MeSH=medical subject headings; tiab=title and abstract
Table A2. Excluded articles based on full text
Reference Year Journal Exclusion reasonMorel et al 1994 Trans proc Case reportWhite et al 1999 Pancreas Case reportAlcolado et al 2010 Diabetic Medicine Conference abstractBellin et al 2015 Xeno trans Conference abstractBellin 2013 Pediatr Diab Conference abstractBellin et al 2011 Diabetes Conference abstractChinnakotla et al 2012 Am J Trans Conference abstractForlenza et al 2015 Xeno trans Conference abstractForlenza et al 2015 Diab Tech Ther Conference abstractFroschl et al 2014 Surg Infect Conference abstractGrigsby et al 2012 Am J Trans Conference abstractGuimaraes et al 2012 Cardio Interv Radio Conference abstractJohn et al 2014 Am J Gastro Conference abstractJohnston et al 2015 Diab Med Conference abstractJolissaint et al 2016 Am J Trans Conference abstractKalyani et al 2013 Diabetes Conference abstractKim et al 2014 Am J Trans Conference abstractLangman et al 2012 Am J Trans Conference abstractMakary et al 2014 S End Int Tech Conference abstractNazirudding et al 2013 Am J Trans Conference abstractPatel et al 2012 Lab Invest Conference abstractPokorney et al 2013 Surg Infect Conference abstractPokorney et al 2013 Ped Pulm Conference abstractQuinn et al 2012 Am J Trans Conference abstractSallemi et al 2015 Cardio Interv Radio Conference abstractSavari et al 2015 Xeno trans Conference abstractShahbazov et al 2016 Am J Trans Conference abstractShahbazov et al 2015 Xeno trans Conference abstractShahbazov et al 2016 Am J Trans Conference abstract
Takita et al 2012 Am J Trans Conference abstractTakita et al 2010 Am J Trans Conference abstractTakita et al 2013 Am J Trans Conference abstractTakita et al 2015 Xeno trans Conference abstractTekin et al 2015 Acta Diab Conference abstractTiwari et al 2013 Am J Trans Conference abstractTiwari et al 2012 Transplantation Conference abstractUflacker et al 2010 Cardio Interv Radio Conference abstractVega-Peralta et al 2011 Am J Gastro Conference abstractWagar et al 2016 Am J Trans Conference abstractWilhelm et al 2015 Xeno trans Conference abstractWilhelm et al 2015 Xeno trans Conference abstractYoshimatsu et al 2016 Am J Trans Conference abstractYoshimatsu et al 2016 Am J Trans Conference abstractBachmann et al 2012 G Chir EditorialArias-Diaz et al 1994 Trans proc Less than 5 patientsBalzano et al 2016 Am J Trans Less than 5 patientsBalzano et al 2013 Ann Surg Less than 5 patientsBuhler et al 1995 Trans proc Less than 5 patientsCasadei et al 2010 Updates surg Less than 5 patientsClark et al 2013 J Gastroint Surg Less than 5 patientsFarley et al 1996 Br J Surg Less than 5 patientsJohnson et al 1999 J Mol Med Less than 5 patientsMassucco et al 2001 Pancreas Less than 5 patientsPedrazzoli et al 2008 J Gastroint Surg Less than 5 patientsProca et al 2001 Arch path Lab Med Less than 5 patientsPuchalski et al 1996 Rocz Akad Less than 5 patientsPyzdrowski et al 1992 N Eng J Med Less than 5 patientsRossi et al 1990 Am J Surg Less than 5 patientsTrede et al 1990 Ann Surg Less than 5 patientsVenturini et al 2016 Br J Radio Less than 5 patientsBuchler et al 2007 Lang Arch Surg Letter to editorMullhaupt et al 2010 Pancreas Letter to editorAlexakis et al 2003 Br J Surg No IATBehrman et al 2006 Am Surg No IATBeltran et al 2014 J Diab Sci Tech No IATEaster et al 1991 Ann Surg No IATFleming et al 1995 Br J Surg No IATSakorafas et al 2000 Int J Pancr No IATThirlby et al 1994 Gastroent No IATWhite et al 2000 Am J Surg No IATWinny et al 2014 Surgery No IATWittel et al 2015 World J Surg Onc No IATDesai et al 2011 J Am Coll Surg No long term follow-upGalvani et al 2014 J Am Coll Surg No long term follow-up
Ahmad et al 2005 J Am Coll Surg No separate analysis for TP for
CPAlexakis et al 2004 Surgery No separate analysis for TP for
CPAlexakis et al 2004 Br J Surg No separate analysis for TP for
CPAlmond et al 2015 HPB No separate analysis for TP for
CPAnazawa et al 2009 Am J Trans No separate analysis for TP for
CPBalcom et al 2001 Arch surg No separate analysis for TP for
CPBelyaev et al 2013 Lang Arch Surg No separate analysis for TP for
CPBhayani et al 2014 HPB No separate analysis for TP for
CPBliss et al 2015 HPB No separate analysis for TP for
CPCalasan et al 2009 Zentralbl Chir No separate analysis for TP for
CPClayton et al 2003 Tranplantation No separate analysis for TP for
CPColling et al 2015 Surg Infect No separate analysis for TP for
CPCrosby et al 2015 Pancreas No separate analysis for TP for
CPCunningham et al 1998 Int J Pancr No separate analysis for TP for
CPDi Sebastiano et
al
2011 Lang Arch Surg No separate analysis for TP for
CPDunderale et al 2013 J Am Coll Surg No separate analysis for TP for
CPEvans et al 1997 Br J Surg No separate analysis for TP for
CPFarney et al 1991 Surgery No separate analysis for TP for
CPFazlalizadeh et al 2016 Word J Trans No separate analysis for TP for
CPFernandez-del
Castillo et al
1995 Arch surg No separate analysis for TP for
CPHerzog et al 2014 J Invest Surg No separate analysis for TP for
CPJanot et al 2010 HPB Surg No separate analysis for TP for
CPJethwa et al 2006 Dig Liv Dis No separate analysis for TP for
CPJohnston et al 2015 J Clin End Meta No separate analysis for TP for
CPKesseli et al 2017 Pancreas No separate analysis for TP for
CPKobayashi et al 2011 Pancreas No separate analysis for TP for
CPKoukoutsis et al 2007 World J Surg Onc No separate analysis for TP for
CPMacHado et al 2016 J Lap Adv Surg Tech No separate analysis for TP for
CPMorgan et al 2012 J Gastroint Surg No separate analysis for TP for
CPMuller et al 2007 Ann Surg No separate analysis for TP for
CPOberholzer et al 2000 Transplantation No separate analysis for TP for
CPOliveira-Cunha et
al
2013 HPB No separate analysis for TP for
CPRiall et al 2008 Surgery No separate analysis for TP for
CPRilo et
al/Robertson
2003 J Gastroint Surg No separate analysis for TP for
CPSuszynski et al 2014 Transplantation No separate analysis for TP for
CPUhl et al 2010 HPB Surg No separate analysis for TP for
CPWhite et al 2001 Ann Surg No separate analysis for TP for
CPWhite et al 2000 Cell Trans No separate analysis for TP for
CPYang et al 2015 Pancreas No separate analysis for TP for
CPZakaria et al 2016 World J Gastr No separate analysis for TP for
CPBuhler et al 1999 Hepatogastro No TPHoward et al 2008 J Gastroint Surg No TPKatuchova et al 2011 Wien Klin Woch No TPLiao et al 2003 Hep Pancr Dis Int No TPMontorsi et al 1995 Surgery No TP
van Hee et al 1998 Acta Chir Belg No TPStroescu et al 2010 Chirurgia Not availableBellin et al 2018 Pancreatology Not enough dataBogachus et al 2018 J Clin End Metabol Not enough dataDesai et al 2013 Dig Dis Sci Not enough dataGardner et al 2018 Am J Gastroenterol Not enough dataJohn et al 2015 J Gastroint Surg Not enough dataJohn et al 2017 J Gastroint Surg Not enough dataKizigul et al 2018 J Diabetes Not enough dataLin et al 2016 J Clin End Meta Not enough dataParikh et al 2010 HPB Not enough dataLundberg et al 2013 Am J Trans Not enough dataPaul Robertson et
al
2001 Diabetes Not enough dataRobertson et al 2015 Diabetes Not enough dataShabazov et al 2017 Pancreas Not enough dataWebb et al 2013 Cell Trans Not enough dataWilhelm et al 2013 Am J Trans Not enough dataGruessner et al 2004 J Am Coll Surg Not enough dataBellin et al 2016 Clin gastr hep Other diseaseBellin et al 2013 Pancreas OverlapBellin et al 2016 Am J Trans OverlapBellin et al 2018 Pancreas OverlapChinnakotla et al 2014 J Am Coll Surg OverlapColling et al 2018 Pancreas OverlapDorlon et al 2013 Am Surg OverlapForlenza et al 2016 Am J Trans OverlapGarcea et al 2009 Pancreas OverlapKesseli et al 2017 Am J Gastro OverlapLane et al 2018 Clin Transplant OverlapManciu et al 1999 J Clin Anesth OverlapMatsumoto et al 2012 Cell Trans OverlapMoran et al 2017 Pancreatology OverlapMorgan et al 2012 Am Surg OverlapMorgan et al 2015 J Am Coll Surg OverlapNazirudding et al 2012 Cell Trans OverlapOng et al 2008 Transplantation OverlapRabkin et al 1999 Am J Surg OverlapSavari et al 2015 Am Surg OverlapSutherland et al 2012 J Am Coll Surg OverlapSutton et al 2010 Surgery OverlapTakita et al 2011 Pancreas OverlapTakita et al 2011 Cell Trans OverlapWahoff et al 1995 Ann Surg OverlapWang et al 2013 Transpl OverlapWebb et al 2008 Pancreas Overlap
Wilson et al 2015 J Gastroint Surg OverlapWilson et al 2015 HPB OverlapWilson et al 2015 Surgery OverlapYoshimatsu et al 2016 J Hepato Pancreat Sci OverlapYoung et al 2016 Pancreas OverlapBellin et al 2008 J Ped Gastr Nutr Pediatric patientsBellin et al 2011 Clin gastr hep Pediatric patientsChinnakotla et al 2014 Ann Surg Pediatric patientsFarney et al 1992 Trans proc Pediatric patientsForlenza et al 2014 Diab Tech Ther Pediatric patientsHutchins et al 2016 Paediatr Anaesth Pediatric patientsJolissaint et al 2016 Clin Trans Pediatric PatientsBellin et al 2018 Am J Gastro ReviewNath et al 2004 J Am Coll Surg ReviewPezzilli et al 2011 Jop Reviewvan der Gaag et
al
2009 Ned Tijdsc Gnsk ReviewWitkowski et al 2014 ReviewWhite et al 2000 Dig Surg ReviewParsaik 2010 Clin End ReviewGumbs et al 2018 Surg Lap End Per Technical report
Table A3. Study quality (Newcastle-Ottawa quality assessment scale for cohort studies score)
Table A4. Detailed
Newcastle-Ottawa quality
assessment scale for cohort
studies scores per study
Study Selectio
n
Comparabili
ty
Outcom
e
Total
Argo et al 3 N/A 3 6
Chinnakotla
et al
2 N/A 2 4
Dixon et al 3 N/A 3 6
Fan et al 2 N/A 3 5
Garcea et al 2 N/A 1 3
Georgiev et al 3 N/A 2 5
Gruessner et
al
2 N/A 1 3
Mokadem et
al
2 N/A 3 5
Morgan et al 3 N/A 3 6Shahbazov et
al
2 N/A 3 5
Solomina et
al
3 N/A 2 5
Takita et al
(2015)
3 N/A 3 6
Takita et al
(2010)
3 N/A 2 5
Walsh et al 2 N/A 3 5
Wilson et al 2 N/A 3 5
Selection OutcomeReference: 1 2 3 4 1 2 3Argo et al a c a a a a aChinnakotla a c a b c a bDixon et al b c a a a a bFan et al b c a b a a aGarcea et al a c a b c a cGruessner b c d a d a dMokadem et a c a b a a bMorgan et a c a a b a aShahbazov b c a b a a aSolomina et a c a a b a cTakita et al, a c a a a a aTakita et al a c a a d a aWalsh et al a c a b a a aWilson et al a c a b a a a
Table A5. TP-IAT indication per study
Study Surgical indication
Argo et al Abdominal pain refractory to narcotic pain medication, endoscopic
procedures, and/or celiac neurolysis
Chinnakotla et
al
CP/RAP with abdominal pain requiring routine narcotics (>3 months)
unresponsive to maximal medical/endoscopic therapy
Dixon et al Pain
Fan et al RAP, painful CP, eliminating risk of pancreatic cancer in high-risk CP
patients
Garcea et al Painful CP, refractory to all other treatment modalities. Small duct gland
disease predominates
Georgiev
et al N/A
Gruessner N/A
et al
Mokadem
et al
Before consideration TP-IAT, patients with persistent evidence of
increased duct pressure underwent surgical or endoscopic decompression
procedures
Morgan et al Chronic pancreatitis
Shahbazov
et al
Indications were intractable pain despite medication, pancreatic duct stent
insertion, or celiac nerve block. Previous gastric or pancreatic surgery were
excluded
Solomina et al Based on refractory nature of the pancreatic pain and the lack of
appropriate alternative medical, endoscopic, or other surgical options.
Those with active alcohol addiction or without sufficient support to follow
the complex postoperative regimen were excluded.
Takita et al
(2015) N/A
Takita et al
(2010) Prescriptions of narcotics and prior endoscopic interventions
Walsh et al Presence of pain that failed to respond to previous medical, endoscopic, or
surgical treatments
Wilson et al All patients: intractable pain + 1 of following: despite previous medical and
surgical intervention, relapsing recurrent acute pancreatitis, genetically
linked pancreatitis, or CP in the absence of demonstrable main duct
pathology
CP=chronic pancreatitis; RAP=recurrent acute pancreatitis; N/A=not applicable
Table A6. Pain results per study
Study Duratio
n of
follow-
up
(months
)
No. of
patie
nts
Preoperati
ve opioid
use (ME)
Postope
rative
opioid
use
(ME)
Preoper
ative
opioid
free (%)
Postoper
ative
opioid
free (%)
Pain
relief
(%)
VAS
preoper
ative
VAS
postopera
tive
Chinnakotl
a et al
at 12 452
N/A N/A 0 80 93 N/A N/A
Dixon et al at 12 5 N/A N/A 0 0 N/A N/A N/A
Fan et al 6** 20 N/A N/A 0 60 90 41* 15*
Garcea et
al
138** 60
180* 10* 5 45 N/A 100** 20**
Gruessner
et al
at 12 55
N/A N/A 0 71 N/A N/A N/A
Mokadem
et al
36** 27
316* 104* N/A 33 N/A 80* 27*
Morgan et
al
at 12 195
214 ** 60 ** N/A N/A N/A N/A N/A
Shahbazov
et al
at 6 73
163* 87.8* N/A N/A N/A 72* 19*
at 12 73 163* 49* N/A 49 N/A 72* 21*
Solomina
et al
at 12 15
56.3** 0** 15 74 N/A N/A N/A
Takita et
al (2010)
7.3* 17
293* 81* 0 35 N/A N/A N/A
Walsh et al 12** 20 89* 78* 0 30 100 74* 20*
Wilson et
al
at 12 57
119* 74.1* 0 55 N/A N/A N/A
at 60 56 119* 21.2* 0 73 N/A N/A N/A
*= Mean; **= Median; No.=number; ME=morphine-equivalent; VAS=visual analogue scale; N/A=not applicable
Table A7. Endocrine outcomes per study
Study Follo
w-up
(mont
hs)
No. of
patien
ts
Insulin
free rate
preoper
atively
(%)
Insuli
n free
rate
posto
perati
vely
(%)
Units/
day
preoper
ative
Units/
day at
follow-
up
C-
peptide
preoper
ative
(ng/ml)
C-peptide
at follow-
up
(ng/ml)
HbA1c
preoper
ative
(%)
HbA1
c at
follow
-up
(%)
Argo et al 6.7* 21 95.2 0 N/A N/A 2.8* N/A 5.9* N/A
Chinnakotl
a et al
at 12 378
N/A 18.3 N/A N/A N/A N/A
N/A
N/A
Dixon et al at 12 5 100 20 N/A N/A N/A N/A N/A N/A
Fan et al 12.5* 20 N/A 25 N/A 10** N/A N/A N/A 7.4*
*
Garcea et
al
138** 60
N/A 18.6 0 22** N/A N/A N/A N/A
Mokadem
et al
36** 27
100 15 0 25* N/A N/A N/A 7.4*
Morgan et
al
at 12 195
N/A 29 N/A N/A N/A N/A N/A N/A
Solomina
et al
at 12 15
90 53 N/A N/A N/A N/A 6 6
Takita et
al (2015)
23.7* 51
89.5 41 N/A N/A N/A N/A N/A N/A
Walsh et al 12** 20 100 20 0 12** N/A 0.4** 6.0* 7.7*
Wilson et
al
at 12 60
97.3 38 1* 11.4*
2.9**
1**
5.9**
7,8**
at 60 56 97.3 27 1* 10* 2.9** 0,6** 5.9** 7,1**
*= Mean; **= Median; No.=number; N/A=not applicable
Figure A8. Forest plots of mortality
A. 30-day mortality; B. 1-year mortality
Table A9. Mortality rates per study
Study 30-day
mortali
ty (%)
Mortality
at 1 year
follow-up
(%)
Argo et al 0 N/A
Chinnakotla
et al
0·8 4·5
Dixon et al 0 14
Fan et al 0 0
Garcea et al 1·7 N/A
Gruessner
et al
0 N/A
Mokadem et
al
10 N/A
Morgan et
al
0 N/A
Solomina et
al
0 0
Walsh et al 0 0
Wilson et al 0 1·8
Table A10. Quality of life per study
Study Follow-
up
(month
s)
No. of
patie
nts
QoL
measure
ment
QoL
preoperat
ive
QoL at
follow-up
(scores)
QoL
improvemen
t (%)
Significan
ce
(scores)
Chinnakotla
et al
at 12 83 SF-36 PCS 30*
MCS 39*
PCS 42*
MCS 47*
PCS 12%
MCS 8%
N/A
Georgiev et
al
at 6 28 SF-36 PCS 32*
MCS 38*
PCS 44*
MCS 45*
PCS 12%
MCS 7%
PCS:
P<0·001
MCS:
P<0·05
at 12 18 SF-36 PCS 32*
MCS 38*
PCS 49*
MCS 46*
PCS 17%
MCS 8%
PCS:
P<0·001
MCS:
P<0·05
Morgan et
al
at 12 195 SF-12 PCS 29*
MCS 39*
PCS 36*
MCS 44*
PCS 7%
MCS 5%
PCS: P<
0·05
MCS: P<
0·05
at 24 195 SF-12 PCS 29*
MCS 39*
PCS 34*
MCS 42*
PCS 5%
MCS 3%
PCS: P<
0·05
MCS: P<
0·05
at 60 195 SF-12 PCS 29*
MCS 39*
PCS 33*
MCS 42*
PCS 4%
MCS 3%
PCS: P<
0·05
MCS: P<
0·05
Solomina et at 12 15 SF-36 PCS 27** PCS 52** PCS 25% PCS:
al
MCS 41**
MCS 68**
MCS 27%
P<0·05
MCS: P<
0·05
Walsh et al 12** 20 DASS and
PDI
DASS depression:
improvement 6.5**
DASS anxiety:
improvement 1.5**
PDI: improvement of 4.5**
DASS:
P<0·05
PDI:
P<0·05
Wilson et al at 12 24 SF-36 PCS 16.5*
MCS
28.5*
PCS 56.9*
MCS 71.6*
PCS 40.4%
MCS 43.1%
N/A
> 60 34 SF-36 PCS 16.5*
MCS
28.5*
PCS 59.6*
MCS 74.1*
PCS 43.1%
MCS 45.6%
N/A
*= Mean; **= Median, No.=number; QoL=quality of life; SF=short form health survey;
DASS=depression anxiety stress scale; PDI=pain disability index; PCS=physical health composite scale;
MCS=mental health composite scale; N/A=not applicable
Table A11. Meta-
regression analysis
Opioid free at last registered follow-up
Variable Coefficien
t
95% CIs p-value
Preoperative opioid-free 0·0068 [-0·0418 –
0·0554]
0·7836
Alcoholic etiology -0·0085 [-0·0095 –
0·0100]
0·3663
Previous surgery for CP -0·0057 [-0·0130 –
0·0016]
0·1261
Insulin-free at last registered follow-up
Variable Coefficien
t
95% CIs p-value
Preoperative insulin-free -0·0136 [-0·0324 –
0·0053]
0·1574
IEQ/kg 0·0000 [-0·0001 –
0·0001]
0·8225
Alcoholic etiology -0·0054 [-0·0079 – -
0·0029]
0·0053
Previous surgery for CP 0·0015 [-0·0028 –
0·0057]
0·4949
Figure A12. Funnel plots of publication bias
A Opioid free rates
-2,0 -1,5 -1,0 -0,5 0,0 0,5 1,0 1,5 2,0
0,0
0,1
0,2
0,3
0,4
Stan
dard
Err
or
Rate
Funnel Plot of Standard Error by Rate
B Insulin free rates
-2,0 -1,5 -1,0 -0,5 0,0 0,5 1,0 1,5 2,0
0,0
0,1
0,2
0,3
0,4
Stan
dard
Err
or
Rate
Funnel Plot of Standard Error by Rate
Explanation: Every dot in a funnel plot represents an included study. A symmetric funnel
including all studies shows that publication bias is unlikely. Deviation from this shape can
indicate publication bias. The above showed asymmetric funnel plots indicate a relationship
between treatment effect estimate and study precision.
Contribution of authors
Manuscript title
Efficacy of total pancreatectomy with islet autotransplantation on opioid and insulin requirement
in chronic pancreatitis: a systematic review and meta-analysis
Authors and contributions
M.A. Kempeneers
- Acquisition of data
- Analysis and interpretation of data
- Concept and design study
- Drafting article
- Final approval
Lianne Scholten
- Acquisition of data
- Analysis and interpretation of data
- Concept and design study
- Drafting article
- Final approval
Charissa R. Verkade
- Acquisition of data
- Drafting article
- Final approval
Jeanin E. van Hooft
- Revising critically
- Final approval
Hjalmar C. van Santvoort
- Revising critically
- Final approval
Olivier R. Busch
- Revising critically
- Final approval
J. Hans de Vries
- Concept and design study
- Revising critically
- Final approval
Yama Issa
- Revising critically
- Final approval
Ashley Dennison
- Revising critically
- Final approval
Marc G. Besselink
Principal investigator
- Concept and design study
- Revising critically
- Final approval
Marja A. Boermeester
Principal investigator
- Concept and design study
- Revising critically
- Final approval
