1.
膵・消化管神経内分泌腫瘍 (NEN) 診療ガイドライン2019年第 2 版
2.
Rossi RE, Burroughs AK, Caplin ME:Liver transplantation for unresectable
neuroendocrine tumor liver metastases. Ann Surg Oncol 21; 2398―2405:2014
3.
Kim SJ, Kim JW, Han SW, et al. Biological characteristics and treatment
outcomes of metastatic or recurrent neuroendocrine tumors: tumor grade and
metastatic site are important for treatment strategy. BMC Cancer. 2010; 10: 448.
4.
Capurso G, Bettini R, Rinzivillo M, Boninsegna L, Delle Fave G, Falconi M. Role
of resection of the primary pancreatic neuroendocrine tumour only in patients with
unresectable metastatic liver disease: a systematic review. Neuroendocrinology.
2011;93(4):223-9. doi: 10.1159/000324770. Epub 2011 Feb 25. PMID: 21358176.
5.
Cho CS, Labow DM, Tang L, Klimstra DS, Loeffler AG, Leverson GE, Fong Y,
Jarnagin WR, D'Angelica MI, Weber SM, Blumgart LH, Dematteo RP. Histologic
grade is correlated with outcome after resection of hepatic neuroendocrine
neoplasms. Cancer. 2008 Jul 1;113(1):126-34. doi: 10.1002/cncr.23523. PMID:
18457323.
6.
Sarmiento JM, Heywood G, Rubin J, Ilstrup DM, Nagorney DM, Que FG.
Surgical treatment of neuroendocrine metastases to the liver: a plea for resection
to increase survival. J Am Coll Surg. 2003 Jul;197(1):29-37. doi: 10.1016/S10727515(03)00230-8. PMID: 12831921.
7.
Scigliano S, Lebtahi R, Maire F, Stievenart JL, Kianmanesh R, Sauvanet A,
Vullierme MP, Couvelard A, Belghiti J, Ruszniewski P, Le Guludec D. Clinical
and imaging follow-up after exhaustive liver resection of endocrine metastases: a
15-year monocentric experience. Endocr Relat Cancer. 2009 Sep;16(3):977-90.
doi: 10.1677/ERC-08-0247. Epub 2009 May 26. PMID: 19470616.
8.
Mayo SC, de Jong MC, Pulitano C, Clary BM, Reddy SK, Gamblin TC, Celinksi
SA, Kooby DA, Staley CA, Stokes JB, Chu CK, Ferrero A, Schulick RD, Choti
MA, Mentha G, Strub J, Bauer TW, Adams RB, Aldrighetti L, Capussotti L,
Pawlik TM. Surgical management of hepatic neuroendocrine tumor metastasis:
results from an international multi-institutional analysis. Ann Surg Oncol. 2010
Dec;17(12):3129-36. doi: 10.1245/s10434-010-1154-5. Epub 2010 Jun 29. PMID:
20585879.
84
9.
Saxena A, Chua TC, Sarkar A, Chu F, Liauw W, Zhao J, Morris DL. Progression
and survival results after radical hepatic metastasectomy of indolent advanced
neuroendocrine neoplasms (NENs) supports an aggressive surgical approach.
Surgery. 2011 Feb;149(2):209-20. doi: 10.1016/j.surg.2010.06.008. Epub 2010
Aug 2. PMID: 20674950.
10.
Jiao Y, Shi C, Edil BH, de Wilde RF, Klimstra DS, Maitra A, Schulick RD, Tang
LH, Wolfgang CL, Choti MA, Velculescu VE, Diaz LA Jr, Vogelstein B, Kinzler
KW, Hruban RH, Papadopoulos N. DAXX/ATRX, MEN1, and mTOR pathway
genes are frequently altered in pancreatic neuroendocrine tumors. Science. 2011
Mar 4;331(6021):1199-203. doi: 10.1126/science.1200609. Epub 2011 Jan 20.
PMID: 21252315; PMCID: PMC3144496.
11. Vandamme T, Beyens M, Boons G, Schepers A, Kamp K, Biermann K, Pauwels P,
De Herder WW, Hofland LJ, Peeters M, Van Camp G, Op de Beeck K. Hotspot
DAXX, PTCH2 and CYFIP2 mutations in pancreatic neuroendocrine neoplasms.
Endocr Relat Cancer. 2019 Jan 1;26(1):1-12. doi: 10.1530/ERC-18-0120. PMID:
30021865.
12. Sato S, Tsuchikawa T, Nakamura T, Sato N, Tamoto E, Okamura K, Shichinohe T,
Hirano S. Impact of the tumor microenvironment in predicting postoperative
hepatic recurrence of pancreatic neuroendocrine tumors. Oncol Rep. 2014
Dec;32(6):2753-9. doi: 10.3892/or.2014.3530. Epub 2014 Oct 6. PMID: 25310565.
13.
Sabatini DM. mTOR and cancer: insights into a complex relationship. Nat Rev
Cancer. 2006 Sep;6(9):729-34. doi: 10.1038/nrc1974. Epub 2006 Aug 17. PMID:
16915295.
14.
Hay N, Sonenberg N. Upstream and downstream of mTOR. Genes Dev. 2004 Aug
15;18(16):1926-45. doi: 10.1101/gad.1212704. PMID: 15314020.
15.
Yao JC, Shah MH, Ito T, Bohas CL, Wolin EM, Van Cutsem E, Hobday TJ,
Okusaka T, Capdevila J, de Vries EG, Tomassetti P, Pavel ME, Hoosen S, Haas T,
Lincy J, Lebwohl D, Öberg K; RAD001 in Advanced Neuroendocrine Tumors,
Third Trial (RADIANT-3) Study Group. Everolimus for advanced pancreatic
neuroendocrine tumors. N Engl J Med. 2011 Feb 10;364(6):514-23. doi:
10.1056/NEJMoa1009290. PMID: 21306238; PMCID: PMC4208619.
16.
Pavel ME, Hainsworth JD, Baudin E, Peeters M, Hörsch D, Winkler RE,
85
Klimovsky J, Lebwohl D, Jehl V, Wolin EM, Öberg K, Van Cutsem E, Yao JC;
RADIANT-2 Study Group. Everolimus plus octreotide long-acting repeatable for
the treatment of advanced neuroendocrine tumours associated with carcinoid
syndrome (RADIANT-2): a randomised, placebo-controlled, phase 3 study.
Lancet. 2011 Dec 10;378(9808):2005-2012. doi: 10.1016/S0140-6736(11)61742X. Epub 2011 Nov 25. PMID: 22119496.
17.
Qian ZR, Ter-Minassian M, Chan JA, Imamura Y, Hooshmand SM, Kuchiba A,
Morikawa T, Brais LK, Daskalova A, Heafield R, Lin X, Christiani DC, Fuchs CS,
Ogino S, Kulke MH. Prognostic significance of MTOR pathway component
expression in neuroendocrine tumors. J Clin Oncol. 2013 Sep 20;31(27):3418-25.
doi:10.1200/JCO.2012.46.6946. Epub 2013 Aug 26. PMID: 23980085; PMCID:
PMC3770868.
18.
Kasajima A, Pavel M, Darb-Esfahani S, Noske A, Stenzinger A, Sasano H, Dietel
M, Denkert C, Röcken C, Wiedenmann B, Weichert W. mTOR expression and
activity patterns in gastroenteropancreatic neuroendocrine tumours. Endocr Relat
Cancer. 2011 Jan 13;18(1):181-92. doi: 10.1677/ERC-10-0126. PMID: 21159731.
19.
Arita J, Ono Y, Takahashi M, Inoue Y, Takahashi Y, Saiura A. Usefulness of
contrast-enhanced intraoperative ultrasound in identifying disappearing liver
metastases from colorectal carcinoma after chemotherapy. Ann Surg Oncol. 2014
Jun;21 Suppl 3:S390-7. doi: 10.1245/s10434-014-3576-y. Epub 2014 Feb 26.
PMID: 24570378.
20. Arita J, Ono Y, Takahashi M, Inoue Y, Takahashi Y, Matsueda K, Saiura A. Routine
Preoperative Liver-specific Magnetic Resonance Imaging Does Not Exclude the
Necessity of Contrast-enhanced Intraoperative Ultrasound in Hepatic Resection
for Colorectal Liver Metastasis. Ann Surg. 2015 Dec;262(6):1086-91. doi:
10.1097/SLA.0000000000001085. PMID: 26010441.
21.
Takahashi M, Hasegawa K, Arita J, Hata S, Aoki T, Sakamoto Y, Sugawara Y,
Kokudo N. Contrast-enhanced intraoperative ultrasonography using
perfluorobutane microbubbles for the enumeration of colorectal liver metastases.
Br J Surg. 2012 Sep;99(9):1271-7. doi: 10.1002/bjs.8844. Epub 2012 Jul 24.
PMID: 22829436.
22.
The Japan society of ultrasonics in medicine 50th anniversary book, [ 超音波医学
86
会50周年記念誌出版事業委員会編 ] 東京 : 日本超音波医学会 , 2013.323. Kiyoshi Maekawa, Masatoshi Kudo, Uezuri Toshinori, 超音波検査による質的診
断 , Medical journal of Kinki University. 35(1), 47-53, 2010-03-01
24.
Chung WS, Kim MJ, Chung YE, Kim YE, Park MS, Choi JY, Kim KW.
Comparison of gadoxetic acid-enhanced dynamic imaging and diffusion-weighted
imaging for the preoperative evaluation of colorectal liver metastases. J Magn
Reson Imaging. 2011 Aug;34(2):345-53. doi: 10.1002/jmri.22671. Epub 2011 Jun
23. PMID: 21702068.
25.
Donati OF, Hany TF, Reiner CS, von Schulthess GK, Marincek B, Seifert B,
Weishaupt D. Value of retrospective fusion of PET and MR images in detection of
hepatic metastases: comparison with 18F-FDG PET/CT and Gd-EOB-DTPAenhanced MRI. J Nucl Med. 2010 May;51(5):692-9. doi:
10.2967/jnumed.109.068510. Epub 2010 Apr 15. PMID: 20395324.
26.
Löwenthal D, Zeile M, Lim WY, Wybranski C, Fischbach F, Wieners G, Pech M,
Kropf S, Ricke J, Dudeck O. Detection and characterisation of focal liver lesions
in colorectal carcinoma patients: comparison of diffusion-weighted and Gd-EOBDTPA enhanced MR imaging. Eur Radiol. 2011 Apr;21(4):832-40. doi:
10.1007/s00330-010-1977-2. Epub 2010 Oct 2. PMID: 20886339.
27.
Niekel MC, Bipat S, Stoker J. Diagnostic imaging of colorectal liver metastases
with CT, MR imaging, FDG PET, and/or FDG PET/CT: a meta-analysis of
prospective studies including patients who have not previously undergone
treatment. Radiology. 2010 Dec;257(3):674-84. doi: 10.1148/radiol.10100729.
Epub 2010 Sep 9. PMID: 20829538.
28. Makuuchi M, Hasegawa H, Yamazaki S. Ultrasonically guided subsegmentectomy.
Surg Gynecol Obstet. 1985 Oct;161(4):346-50. PMID: 2996162.
29. Capurso G, Rinzivillo M, Bettini R, Boninsegna L, Delle Fave G, Falconi M.
Systematic review of resection of primary midgut carcinoid tumour in patients
with unresectable liver metastases. Br J Surg. 2012 Nov;99(11):1480-6. doi:
10.1002/bjs.8842. Epub 2012 Sep 13. PMID: 22972490.
30.
Zhou B, Zhan C, Ding Y, Yan S, Zheng S. Role of palliative resection of the
primary pancreatic neuroendocrine tumor in patients with unresectable metastatic
liver disease: a systematic review and meta-analysis. Onco Targets Ther. 2018
87
Feb 23;11:975-982. doi: 10.2147/OTT.S158171. PMID: 29503572; PMCID:
PMC5827741.
31.
Partelli S, Cirocchi R, Rancoita PMV, Muffatti F, Andreasi V, Crippa S,
Tamburrino D, Falconi M. A Systematic review and meta-analysis on the role of
palliative primary resection for pancreatic neuroendocrine neoplasm with liver
metastases. HPB (Oxford). 2018 Mar;20(3):197-203. doi:
10.1016/j.hpb.2017.10.014. Epub 2017 Nov 29. PMID: 29196022.
32.
Guo J, Zhang Q, Bi X, Zhou J, Li Z, Huang Z, Zhang Y, Li M, Chen X, Hu X,
Yihebali C, Liang J, Liu J, Zhao J, Cai J, Zhao H. Systematic review of resecting
primary tumor in MNETs patients with unresectable liver metastases. Oncotarget.
2017 Mar 7;8(10):17396-17405. doi: 10.18632/oncotarget.14156. PMID:
28030811; PMCID: PMC5370049.
33. Mörk H, Ignee A, Schuessler G, Ott M, Dietrich CF. Analysis of neuroendocrine
tumour metastases in the liver using contrast enhanced ultrasonography. Scand J
Gastroenterol. 2007 May;42(5):652-62. doi: 10.1080/00365520601021765.
PMID: 17454888.
34.
Hoeffel, C., Job, L., Ladam-Marcus, V. et al. Detection of Hepatic Metastases
from Carcinoid Tumor: Prospective Evaluation of Contrast-Enhanced
Ultrasonography. Dig Dis Sci 54, 2040–2046 (2009).
https://doi.org/10.1007/s10620-008-0570-x
35.
Dogeas E, Chong CCN, Weiss MJ, Ahuja N, Choti MA. Can echogenic
appearance of neuroendocrine liver metastases on intraoperative ultrasonography
predict tumor biology and prognosis? HPB (Oxford). 2018 Mar;20(3):237-243.
doi:10.1016/j.hpb.2017.08.029. Epub 2017 Nov 2. PMID: 29103839.
36.
DeOliveira ML, Pawlik TM, Gleisner AL, Assumpcaom L, Lopes-Filho GJ, Choti
MA. Echogenic appearance of colorectal liver metastases on intraoperative
ultrasonography is associated with survival after hepatic resection. J Gastrointest
Surg. 2007 Aug;11(8):970-6; discussion 976. doi: 10.1007/s11605-007-0093-3.
PMID: 17623266.
37. Tampellini M, Longo M, Cappia S, Bacillo E, Alabiso I, Volante M, Dogliotti L,
Papotti M. Co-expression of EGF receptor, TGFalpha and S6 kinase is
significantly associated with colorectal carcinomas with distant metastases at
88
diagnosis. Virchows Arch. 2007 Mar;450(3):321-8. doi: 10.1007/s00428-0070370-2. Epub 2007 Jan 30. PMID: 17265080.
38.
Anagnostou VK, Bepler G, Syrigos KN, Tanoue L, Gettinger S, Homer RJ, Boffa
D, Detterbeck F, Rimm DL. High expression of mammalian target of rapamycin is
associated with better outcome for patients with early stage lung adenocarcinoma.
Clin Cancer Res. 2009 Jun 15;15(12):4157-64. doi: 10.1158/1078-0432.CCR-090099. Epub 2009 Jun 9. PMID: 19509151.
39. Campbell L, Jasani B, Edwards K, Gumbleton M, Griffiths DF. Combined
expression of caveolin-1 and an activated AKT/mTOR pathway predicts reduced
disease-free survival in clinically confined renal cell carcinoma. Br J Cancer. 2008
Mar 11;98(5):931-40. doi: 10.1038/sj.bjc.6604243. Epub 2008 Feb 19. PMID:
18283322; PMCID: PMC2266860.
40.
Zhou X, Tan M, Stone Hawthorne V, Klos KS, Lan KH, Yang Y, Yang W, Smith
TL, Shi D, Yu D. Activation of the Akt/mammalian target of rapamycin/4E-BP1
pathway by ErbB2 overexpression predicts tumor progression in breast cancers.
Clin Cancer Res. 2004 Oct 15;10(20):6779-88. doi: 10.1158/1078-0432.CCR-040112. PMID: 15501954.
41.
Plöckinger U, Wiedenmann B. Treatment of gastroenteropancreatic
neuroendocrine tumors. Virchows Arch. 2007 Aug;451 Suppl 1:S71-80. doi:
10.1007/s00428-007-0446-z. Epub 2007 Aug 8. PMID: 17684765.
42.
Rindi G, Klöppel G, Couvelard A, Komminoth P, Körner M, Lopes JM, McNicol
AM, Nilsson O, Perren A, Scarpa A, Scoazec JY, Wiedenmann B. TNM staging of
midgut and hindgut (neuro) endocrine tumors: a consensus proposal including a
grading system. Virchows Arch. 2007 Oct;451(4):757-62. doi: 10.1007/s00428007-0452-1. Epub 2007 Aug 3. PMID: 17674042.
43. Komori Y, Yada K, Ohta M, Uchida H, Iwashita Y, Fukuzawa K, Kashima K,
Yokoyama S, Inomata M, Kitano S. Mammalian target of rapamycin signaling
activation patterns in pancreatic neuroendocrine tumors. J Hepatobiliary Pancreat
Sci. 2014 Apr;21(4):288-95. doi: 10.1002/jhbp.26. Epub 2013 Sep 3. PMID:
24002888.
44. Zhou CF, Ji J, Yuan F, Shi M, Zhang J, Liu BY, Zhu ZG. mTOR activation in well
differentiated pancreatic neuroendocrine tumors: a retrospective study on 34 cases.
89
Hepatogastroenterology. 2011 Nov-Dec;58(112):2140-3. doi: 10.5754/hge11212.
PMID: 22024086.
45. Kononen J, Bubendorf L, Kallioniemi A, Bärlund M, Schraml P, Leighton S,
Torhorst J, Mihatsch MJ, Sauter G, Kallioniemi OP. Tissue microarrays for highthroughput molecular profiling of tumor specimens. Nat Med. 1998 Jul;4(7):844-7.
doi: 10.1038/nm0798-844. PMID: 9662379.
46. Darb-Esfahani S, Faggad A, Noske A, Weichert W, Buckendahl AC, Müller B,
Budczies J, Röske A, Dietel M, Denkert C. Phospho-mTOR and phospho-4EBP1
in endometrial adenocarcinoma: association with stage and grade in vivo and link
with response to rapamycin treatment in vitro. J Cancer Res Clin Oncol. 2009
Jul;135(7):933-41. doi: 10.1007/s00432-008-0529-5. Epub 2008 Dec 24. PMID:
19107520.
47.
Zen Y, Heaton N. Elevated Ki-67 labeling index in 'synchronous liver metastases'
of well differentiated enteropancreatic neuroendocrine tumor. Pathol Int. 2013
Nov;63(11):532-8. doi: 10.1111/pin.12108. PMID: 24274715.
48. Richards-Taylor S, Tilley C, Jaynes E, Hu H, Armstrong T, Pearce NW, Plant R,
Cave J. Clinically Significant Differences in Ki-67 Proliferation Index Between
Primary and Metastases in Resected Pancreatic Neuroendocrine Tumors. Pancreas.
2017 Nov/Dec;46(10):1354-1358. doi: 10.1097/MPA.0000000000000933. PMID:
28984786.
49. Shi C, Gonzalez RS, Zhao Z, Koyama T, Cornish TC, Hande KR, Walker R,
Sandler M, Berlin J, Liu EH. Liver metastases of small intestine neuroendocrine
tumors: Ki-67 heterogeneity and World Health Organization grade discordance
with primary tumors. Am J Clin Pathol. 2015 Mar;143(3):398-404. doi:
10.1309/AJCPQ55SKOCYFZHN. PMID: 25696798; PMCID: PMC4354931.
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8 ．謝辞
今回研究を遂行する機会および御指導、御鞭撻を賜りました、東京大学大学院
医学系研究科肝胆膵外科学
長谷川
教授に厚く御礼申し上げます。
また本研究の遂行および論文作成において、直接御指導をいただいた東京大学
医学部肝胆膵外科
有田
淳一
准教授、稲垣
善則先生に深く感謝申し上げ
ます。
以下の先生方にも多大なご協力を賜りましたことを記し、謹んで感謝申し上げ
ます。
東京大学医学部附属病院病理部
田中
麻理子先生、国保旭中央病院遠隔病理
診断センター，東京大学名誉教授（前人体病理学・病理診断学分野教授）深山
正久先生、獨協医科大学第二外科
ター肝胆膵外科
別宮
青木
琢教授、埼玉医科大学総合医療セン
好文教授、その他様々な面でご協力、ご助言頂きまし
た、東京大学医学部肝胆膵外科の先生方に感謝申し上げます。
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