Difference between pages "Neuroendocrine neoplasms" and "TRK fusions"

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[[Image:Small intestine neuroendocrine tumour high mag.jpg|thumb|right|200px|Micrograph of a neuroendocrine tumour of the small bowel. [[H&E stain]].]]
'''TRK fusions''' are seen in many solid tumours of children and adults and have targeted drugs.<ref name=pmid29466156>{{Cite journal  | last1 = Drilon | first1 = A. | last2 = Laetsch | first2 = TW. | last3 = Kummar | first3 = S. | last4 = DuBois | first4 = SG. | last5 = Lassen | first5 = UN. | last6 = Demetri | first6 = GD. | last7 = Nathenson | first7 = M. | last8 = Doebele | first8 = RC. | last9 = Farago | first9 = AF. | title = Efficacy of Larotrectinib in TRK Fusion-Positive Cancers in Adults and Children. | journal = N Engl J Med | volume = 378 | issue = 8 | pages = 731-739 | month = 02 | year = 2018 | doi = 10.1056/NEJMoa1714448 | PMID = 29466156 }}</ref>
'''Neuroendocrine neoplasms''', also '''neuroendocrine tumours''', are a group of tumours whose behaviour varies from benign to malignant and are found in may different sites. ''Neuroendocrine tumour'' is commonly abbreviated '''NET'''.  


These tumours arise from epithelium; thus, malignant tumours in this group are referred to as '''neuroendocrine carcinomas'''.
==General==
Genes:<ref name=pmid27843590>{{cite journal |authors=Amatu A, Sartore-Bianchi A, Siena S |title=NTRK gene fusions as novel targets of cancer therapy across multiple tumour types |journal=ESMO Open |volume=1 |issue=2 |pages=e000023 |date=2016 |pmid=27843590 |pmc=5070277 |doi=10.1136/esmoopen-2015-000023 |url=https://www.ncbi.nlm.nih.gov/pubmed/27843590}}</ref>
*NTRK1.
*NTRK2.
*NTRK3.


=Use of the term ''carcinoid''=
Notes:
Use of the term ''carcinoid'' is discouraged (in pathology reports), in the context of ''[[gastrointestinal pathology]]''.<ref name=pmid18414708>{{Cite journal  | last1 = Chetty | first1 = R. | title = Requiem for the term 'carcinoid tumour' in the gastrointestinal tract? | journal = Can J Gastroenterol | volume = 22 | issue = 4 | pages = 357-8 | month = Apr | year = 2008 | doi =  | PMID = 18414708 }}
*The TRK genes are tropomyosine kinase receptors.
</ref><ref name=pmid15153416>{{Cite journal  | last1 = Klöppel | first1 = G. | last2 = Perren | first2 = A. | last3 = Heitz | first3 = PU. | title = The gastroenteropancreatic neuroendocrine cell system and its tumors: the WHO classification. | journal = Ann N Y Acad Sci | volume = 1014 | issue =  | pages = 13-27 | month = Apr | year = 2004 | doi =  | PMID = 15153416 }}
*Multiple fusion partners for each gene.
</ref><ref name=pmid14513276>{{cite journal |author=Klöppel G |title=[Neuroendocrine tumors of the gastrointestinal tract] |language=German |journal=Pathologe |volume=24 |issue=4 |pages=287–96 |year=2003 |month=July |pmid=14513276 |doi=10.1007/s00292-003-0636-7 |url=}}</ref>
 
The term is still used for neuroendocrine tumours of the lung - see [[carcinoid tumours]].
 
=Carcinoid syndrome=
===Pathophysiology===
*Neuroendocrine tumour -> hormone secretion (5-hydroxytryptamine + others).<ref name=pmid19444261>{{Cite journal  | last1 = Druce | first1 = M. | last2 = Rockall | first2 = A. | last3 = Grossman | first3 = AB. | title = Fibrosis and carcinoid syndrome: from causation to future therapy. | journal = Nat Rev Endocrinol | volume = 5 | issue = 5 | pages = 276-83 | month = May | year = 2009 | doi = 10.1038/nrendo.2009.51 | PMID = 19444261 }}</ref>
*In GI NETs ''carcinoid syndrome'' usually only arises in the context of liver metastases.
**GI NETs without liver mets do not develop the syndrome due to ''first pass effect'' of the liver.
**Exceptions to the rule -- carcinoid syndrome without liver mets: ovarian NETs, testicular NETs, bronchial NETs.<ref name=pmid1574032>{{Cite journal  | last1 = Haq | first1 = AU. | last2 = Yook | first2 = CR. | last3 = Hiremath | first3 = V. | last4 = Kasimis | first4 = BS. | title = Carcinoid syndrome in the absence of liver metastasis: a case report and review of literature. | journal = Med Pediatr Oncol | volume = 20 | issue = 3 | pages = 221-3 | month =  | year = 1992 | doi =  | PMID = 1574032 }}</ref>
 
===Clinical===
Features:<ref name=pmid19444261/>
*Diarrhea, flushing and wheezing.
 
===Pathologic findings===
Classic pathologic finding:<ref name=pmid19444261/>
*Fibrosis of cardiac valves (tricuspid and pulmonary).
**Result ''TIPS'' = '''t'''ricuspid '''i'''nsufficiency '''p'''ulmonary '''s'''tenosis.
 
=Microscopic - generic=
Features:
*Nests of cells - with fibrous stroma in between.
**May have a [[trabecular]] architecture.
*Stippled chromatin [[AKA]] salt-and-pepper chromatin, coarse chromatin.
*Classically subepithelial/mural.
 
DDx:
*[[Paraganglioma]].
*Neoplasm with neuroendocrine differentiation (<30% neuroendocrine component<ref name=pmid26556999>{{Cite journal  | last1 = Kleist | first1 = B. | last2 = Poetsch | first2 = M. | title = Neuroendocrine differentiation: The mysterious fellow of colorectal cancer. | journal = World J Gastroenterol | volume = 21 | issue = 41 | pages = 11740-7 | month = Nov | year = 2015 | doi = 10.3748/wjg.v21.i41.11740 | PMID = 26556999 }}</ref>).
 
==Images==
<gallery>
Image:Small_intestine_neuroendocrine_tumour_low_mag.jpg | Neuroendocrine tumour - low mag. (WC/Nephron)
Image:Small_intestine_neuroendocrine_tumour_intermed_mag.jpg | Neuroendocrine tumour - intermed. mag. (WC/Nephron)
Image:Small_intestine_neuroendocrine_tumour_high_mag.jpg | Neuroendocrine tumour - high mag. (WC/Nephron)
</gallery>
www:
*[http://path.upmc.edu/cases/case7/images/micro3.jpg NET met to liver (upmc.edu)].<ref>URL: [http://path.upmc.edu/cases/case7.html http://path.upmc.edu/cases/case7.html}. Accessed on: 17 December 2011.</ref>
 
=IHC - generic=
Key stains:<ref name=pmid17204019>{{Cite journal  | last1 = Williams | first1 = GT. | title = Endocrine tumours of the gastrointestinal tract-selected topics. | journal = Histopathology | volume = 50 | issue = 1 | pages = 30-41 | month = Jan | year = 2007 | doi = 10.1111/j.1365-2559.2006.02570.x | PMID = 17204019 }}</ref>
*Chromogranin A +ve.
**Considered the most specific neuroendocrine stain.<ref name=pmid20182342>{{Cite journal  | last1 = McCluggage | first1 = WG. | last2 = Kennedy | first2 = K. | last3 = Busam | first3 = KJ. | title = An immunohistochemical study of cervical neuroendocrine carcinomas: Neoplasms that are commonly TTF1 positive and which may express CK20 and P63. | journal = Am J Surg Pathol | volume = 34 | issue = 4 | pages = 525-32 | month = Apr | year = 2010 | doi = 10.1097/PAS.0b013e3181d1d457 | PMID = 20182342 }}</ref>
*Synaptophysin +ve.
 
Others:
*NSE +ve.
*[[CD56]] +ve.
*[[Ki-67]] - useful for grading.
*PGP9.5.<ref name=pmid20182342/>
*[[CDX2]] -ve/+ve.
**+ve suggests ileum, appendix or colon origin.<ref name=pmid22180832>{{Cite journal  | last1 = Saad | first1 = RS. | last2 = Ghorab | first2 = Z. | last3 = Khalifa | first3 = MA. | last4 = Xu | first4 = M. | title = CDX2 as a marker for intestinal differentiation: Its utility and limitations. | journal = World J Gastrointest Surg | volume = 3 | issue = 11 | pages = 159-66 | month = Nov | year = 2011 | doi = 10.4240/wjgs.v3.i11.159 | PMID = 22180832 }}</ref>
 
Hormone products:
*Glucagon +ve/-ve.
*Gastrin +ve/-ve.
*Somatostatin +ve/-ve.
 
=Site specific=
==Lung==
{{Main|Lung_tumours#Neuroendocrine_tumours}}
 
==Genitourinary pathology==
{{Main|Small cell carcinoma of the prostate gland}}
{{Main|Small cell carcinoma of the urinary bladder}}
 
==Gastrointestinal tract==
===WHO classification for digestive NET===
Subtypes:<ref name=pmid21601112>{{Cite journal  | last1 = Scoazec | first1 = JY. | last2 = Couvelard | first2 = A. | title = [The new WHO classification of digestive neuroendocrine tumors]. | journal = Ann Pathol | volume = 31 | issue = 2 | pages = 88-92 | month = Apr | year = 2011 | doi = 10.1016/j.annpat.2011.01.001 | PMID = 21601112 }}</ref>
#Neuroendocrine tumour G1.
#Neuroendocrine tumour G2.
#Neuroendocrine carcinoma, small cell type.
#Neuroendocrine carcinoma, large cell type.
#Mixed adenoneuroendocrine carcinoma.
 
====Grading====
Grading of NETs:<ref name=pmid21344263>{{Cite journal  | last1 = Volante | first1 = M. | last2 = Righi | first2 = L. | last3 = Berruti | first3 = A. | last4 = Rindi | first4 = G. | last5 = Papotti | first5 = M. | title = The pathological diagnosis of neuroendocrine tumors: common questions and tentative answers. | journal = Virchows Arch | volume = 458 | issue = 4 | pages = 393-402 | month = Apr | year = 2011 | doi = 10.1007/s00428-011-1060-7 | PMID = 21344263 }}</ref>
*Grade 1 (G1): < 2 mitoses/2 mm^2 ''or'' < 3% Ki-67.
*Grade 2 (G2): > 2 mitoses/2 mm^2 ''or'' > 3% Ki-67 '''and''' < 20 mitoses/2 mm^2 ''or'' < 20% Ki-67.
*Grade 3 (G3): > 20 mitoses/2 mm^2 ''or'' > 20% Ki-67.


Notes:
Testing:  
*Neuroendocrine carcinomas are G3 by definition.
*RNA-based next generation sequencing.
*[[Immunohistochemistry]]<ref name=pmid28719467>{{Cite journal  | last1 = Hechtman | first1 = JF. | last2 = Benayed | first2 = R. | last3 = Hyman | first3 = DM. | last4 = Drilon | first4 = A. | last5 = Zehir | first5 = A. | last6 = Frosina | first6 = D. | last7 = Arcila | first7 = ME. | last8 = Dogan | first8 = S. | last9 = Klimstra | first9 = DS. | title = Pan-Trk Immunohistochemistry Is an Efficient and Reliable Screen for the Detection of NTRK Fusions. | journal = Am J Surg Pathol | volume = 41 | issue = 11 | pages = 1547-1551 | month = Nov | year = 2017 | doi = 10.1097/PAS.0000000000000911 | PMID = 28719467 }}</ref> - limited sensitivity for leiomyosarcoma, neural differentiation tumours.
*FISH breakapart probes.
*DNA NGS<ref>{{Cite journal  | last1 = Cocco | first1 = E. | last2 = Scaltriti | first2 = M. | last3 = Drilon | first3 = A. | title = NTRK fusion-positive cancers and TRK inhibitor therapy. | journal = Nat Rev Clin Oncol | volume = 15 | issue = 12 | pages = 731-747 | month = Dec | year = 2018 | doi = 10.1038/s41571-018-0113-0 | PMID = 30333516 }}
</ref> - sensitivity low for fusions.


===Stomach===
==Associations==
{{Main|Gastric neuroendocrine tumour}}
===Classic===


===Duodenum===
*[[Secretory carcinoma of the salivary gland]] (previously ''mammary analogue secretory carcinoma'') - ETV6-NTRK3.<ref name=pmid22127547>{{Cite journal  | last1 = Lei | first1 = Y. | last2 = Chiosea | first2 = SI. | title = Re-evaluating historic cohort of salivary acinic cell carcinoma with new diagnostic tools. | journal = Head Neck Pathol | volume = 6 | issue = 2 | pages = 166-70 | month = Jun | year = 2012 | doi = 10.1007/s12105-011-0312-9 | PMID = 22127547 }}</ref>
{{Main|Duodenal neuroendocrine tumour}}
*[[Secretory breast carcinoma]] - ETV6-NTRK3.<ref name=pmid22129193>{{Cite journal  | last1 = Vasudev | first1 = P. | last2 = Onuma | first2 = K. | title = Secretory breast carcinoma: unique, triple-negative carcinoma with a favorable prognosis and characteristic molecular expression. | journal = Arch Pathol Lab Med | volume = 135 | issue = 12 | pages = 1606-10 | month = Dec | year = 2011 | doi = 10.5858/arpa.2010-0351-RS | PMID = 22129193 }}</ref>


===Pancreatic===
===Others===
{{Main|Pancreatic neuroendocrine tumour}}
*[[Congenital-infantile fibrosarcoma]].<ref name=pmid11242790 >{{Cite journal  | last1 = Sheng | first1 = WQ. | last2 = Hisaoka | first2 = M. | last3 = Okamoto | first3 = S. | last4 = Tanaka | first4 = A. | last5 = Meis-Kindblom | first5 = JM. | last6 = Kindblom | first6 = LG. | last7 = Ishida | first7 = T. | last8 = Nojima | first8 = T. | last9 = Hashimoto | first9 = H. | title = Congenital-infantile fibrosarcoma. A clinicopathologic study of 10 cases and molecular detection of the ETV6-NTRK3 fusion transcripts using paraffin-embedded tissues. | journal = Am J Clin Pathol | volume = 115 | issue = 3 | pages = 348-55 | month = Mar | year = 2001 | doi = 10.1309/3H24-E7T7-V37G-AKKQ | PMID = 11242790 }}</ref>
*Cellular [[mesoblastic nephroma]].<ref name=pmid29893456>{{Cite journal  | last1 = Halalsheh | first1 = H. | last2 = McCarville | first2 = MB. | last3 = Neel | first3 = M. | last4 = Reynolds | first4 = M. | last5 = Cox | first5 = MC. | last6 = Pappo | first6 = AS. | title = Dramatic bone remodeling following larotrectinib administration for bone metastasis in a patient with TRK fusion congenital mesoblastic nephroma. | journal = Pediatr Blood Cancer | volume = 65 | issue = 10 | pages = e27271 | month = Oct | year = 2018 | doi = 10.1002/pbc.27271 | PMID = 29893456 }}</ref><ref name=pmid29683818>{{Cite journal  | last1 = Rudzinski | first1 = ER. | last2 = Lockwood | first2 = CM. | last3 = Stohr | first3 = BA. | last4 = Vargas | first4 = SO. | last5 = Sheridan | first5 = R. | last6 = Black | first6 = JO. | last7 = Rajaram | first7 = V. | last8 = Laetsch | first8 = TW. | last9 = Davis | first9 = JL. | title = Pan-Trk Immunohistochemistry Identifies NTRK Rearrangements in Pediatric Mesenchymal Tumors. | journal = Am J Surg Pathol | volume = 42 | issue = 7 | pages = 927-935 | month = Jul | year = 2018 | doi = 10.1097/PAS.0000000000001062 | PMID = 29683818 }}</ref>
*NTRK1 fusions occasionally in [[Glioblastoma]] (1-2%).<ref>{{Cite journal  | last1 = Xu | first1 = T. | last2 = Wang | first2 = H. | last3 = Huang | first3 = X. | last4 = Li | first4 = W. | last5 = Huang | first5 = Q. | last6 = Yan | first6 = Y. | last7 = Chen | first7 = J. | title = Gene Fusion in Malignant Glioma: An Emerging Target for Next-Generation Personalized Treatment. | journal = Transl Oncol | volume = 11 | issue = 3 | pages = 609-618 | month = Jun | year = 2018 | doi = 10.1016/j.tranon.2018.02.020 | PMID = 29571074 }}</ref>
*SQSTM1-NTRK1 non-small cell carcinoma (~0.1%).<ref>{{Cite journal  | last1 = Agaimy | first1 = A. | last2 = Hartmann | first2 = A. | last3 = Antonescu | first3 = CR. | last4 = Chiosea | first4 = SI. | last5 = El-Mofty | first5 = SK. | last6 = Geddert | first6 = H. | last7 = Iro | first7 = H. | last8 = Lewis | first8 = JS. | last9 = Märkl | first9 = B. | title = SMARCB1 (INI-1)-deficient Sinonasal Carcinoma: A Series of 39 Cases Expanding the Morphologic and Clinicopathologic Spectrum of a Recently Described Entity. | journal = Am J Surg Pathol | volume = 41 | issue = 4 | pages = 458-471 | month = Apr | year = 2017 | doi = 10.1097/PAS.0000000000000797 | PMID = 28291122 }}</ref>


===Vermiform appendix===
==Drugs==
{{Main|Appendiceal neuroendocrine tumour}}
*Merestinib.
*Larotrectinib.<ref name=pmid29466156>{{Cite journal  | last1 = Drilon | first1 = A. | last2 = Laetsch | first2 = TW. | last3 = Kummar | first3 = S. | last4 = DuBois | first4 = SG. | last5 = Lassen | first5 = UN. | last6 = Demetri | first6 = GD. | last7 = Nathenson | first7 = M. | last8 = Doebele | first8 = RC. | last9 = Farago | first9 = AF. | title = Efficacy of Larotrectinib in TRK Fusion-Positive Cancers in Adults and Children. | journal = N Engl J Med | volume = 378 | issue = 8 | pages = 731-739 | month = 02 | year = 2018 | doi = 10.1056/NEJMoa1714448 | PMID = 29466156 }}</ref>
*Entrectinib.<ref name=pmid26565381>{{Cite journal  | last1 = Farago | first1 = AF. | last2 = Le | first2 = LP. | last3 = Zheng | first3 = Z. | last4 = Muzikansky | first4 = A. | last5 = Drilon | first5 = A. | last6 = Patel | first6 = M. | last7 = Bauer | first7 = TM. | last8 = Liu | first8 = SV. | last9 = Ou | first9 = SH. | title = Durable Clinical Response to Entrectinib in NTRK1-Rearranged Non-Small Cell Lung Cancer. | journal = J Thorac Oncol | volume = 10 | issue = 12 | pages = 1670-4 | month = Dec | year = 2015 | doi = 10.1097/01.JTO.0000473485.38553.f0 | PMID = 26565381 }}</ref>
*Others.


=See also=
==See also==
*[[Basics]].
*[[Molecular pathology]]
*[[Goblet cell carcinoid]].
*[[Mixed neuroendocrine-nonneuroendocrine neoplasm]] (MiNEN).


=References=
==References==
{{Reflist|2}}
{{Reflist|2}}


[[Category:Basics]]
[[Category:Molecular pathology]]

Revision as of 20:29, 24 May 2020

TRK fusions are seen in many solid tumours of children and adults and have targeted drugs.[1]

General

Genes:[2]

  • NTRK1.
  • NTRK2.
  • NTRK3.

Notes:

  • The TRK genes are tropomyosine kinase receptors.
  • Multiple fusion partners for each gene.

Testing:

  • RNA-based next generation sequencing.
  • Immunohistochemistry[3] - limited sensitivity for leiomyosarcoma, neural differentiation tumours.
  • FISH breakapart probes.
  • DNA NGS[4] - sensitivity low for fusions.

Associations

Classic

Others

Drugs

  • Merestinib.
  • Larotrectinib.[1]
  • Entrectinib.[12]
  • Others.

See also

References

  1. ↑ 1.0 1.1 Drilon, A.; Laetsch, TW.; Kummar, S.; DuBois, SG.; Lassen, UN.; Demetri, GD.; Nathenson, M.; Doebele, RC. et al. (02 2018). "Efficacy of Larotrectinib in TRK Fusion-Positive Cancers in Adults and Children.". N Engl J Med 378 (8): 731-739. doi:10.1056/NEJMoa1714448. PMID 29466156.
  2. ↑ Amatu A, Sartore-Bianchi A, Siena S (2016). "NTRK gene fusions as novel targets of cancer therapy across multiple tumour types". ESMO Open 1 (2): e000023. doi:10.1136/esmoopen-2015-000023. PMC 5070277. PMID 27843590. https://www.ncbi.nlm.nih.gov/pubmed/27843590.
  3. ↑ Hechtman, JF.; Benayed, R.; Hyman, DM.; Drilon, A.; Zehir, A.; Frosina, D.; Arcila, ME.; Dogan, S. et al. (Nov 2017). "Pan-Trk Immunohistochemistry Is an Efficient and Reliable Screen for the Detection of NTRK Fusions.". Am J Surg Pathol 41 (11): 1547-1551. doi:10.1097/PAS.0000000000000911. PMID 28719467.
  4. ↑ Cocco, E.; Scaltriti, M.; Drilon, A. (Dec 2018). "NTRK fusion-positive cancers and TRK inhibitor therapy.". Nat Rev Clin Oncol 15 (12): 731-747. doi:10.1038/s41571-018-0113-0. PMID 30333516.
  5. ↑ Lei, Y.; Chiosea, SI. (Jun 2012). "Re-evaluating historic cohort of salivary acinic cell carcinoma with new diagnostic tools.". Head Neck Pathol 6 (2): 166-70. doi:10.1007/s12105-011-0312-9. PMID 22127547.
  6. ↑ Vasudev, P.; Onuma, K. (Dec 2011). "Secretory breast carcinoma: unique, triple-negative carcinoma with a favorable prognosis and characteristic molecular expression.". Arch Pathol Lab Med 135 (12): 1606-10. doi:10.5858/arpa.2010-0351-RS. PMID 22129193.
  7. ↑ Sheng, WQ.; Hisaoka, M.; Okamoto, S.; Tanaka, A.; Meis-Kindblom, JM.; Kindblom, LG.; Ishida, T.; Nojima, T. et al. (Mar 2001). "Congenital-infantile fibrosarcoma. A clinicopathologic study of 10 cases and molecular detection of the ETV6-NTRK3 fusion transcripts using paraffin-embedded tissues.". Am J Clin Pathol 115 (3): 348-55. doi:10.1309/3H24-E7T7-V37G-AKKQ. PMID 11242790.
  8. ↑ Halalsheh, H.; McCarville, MB.; Neel, M.; Reynolds, M.; Cox, MC.; Pappo, AS. (Oct 2018). "Dramatic bone remodeling following larotrectinib administration for bone metastasis in a patient with TRK fusion congenital mesoblastic nephroma.". Pediatr Blood Cancer 65 (10): e27271. doi:10.1002/pbc.27271. PMID 29893456.
  9. ↑ Rudzinski, ER.; Lockwood, CM.; Stohr, BA.; Vargas, SO.; Sheridan, R.; Black, JO.; Rajaram, V.; Laetsch, TW. et al. (Jul 2018). "Pan-Trk Immunohistochemistry Identifies NTRK Rearrangements in Pediatric Mesenchymal Tumors.". Am J Surg Pathol 42 (7): 927-935. doi:10.1097/PAS.0000000000001062. PMID 29683818.
  10. ↑ Xu, T.; Wang, H.; Huang, X.; Li, W.; Huang, Q.; Yan, Y.; Chen, J. (Jun 2018). "Gene Fusion in Malignant Glioma: An Emerging Target for Next-Generation Personalized Treatment.". Transl Oncol 11 (3): 609-618. doi:10.1016/j.tranon.2018.02.020. PMID 29571074.
  11. ↑ Agaimy, A.; Hartmann, A.; Antonescu, CR.; Chiosea, SI.; El-Mofty, SK.; Geddert, H.; Iro, H.; Lewis, JS. et al. (Apr 2017). "SMARCB1 (INI-1)-deficient Sinonasal Carcinoma: A Series of 39 Cases Expanding the Morphologic and Clinicopathologic Spectrum of a Recently Described Entity.". Am J Surg Pathol 41 (4): 458-471. doi:10.1097/PAS.0000000000000797. PMID 28291122.
  12. ↑ Farago, AF.; Le, LP.; Zheng, Z.; Muzikansky, A.; Drilon, A.; Patel, M.; Bauer, TM.; Liu, SV. et al. (Dec 2015). "Durable Clinical Response to Entrectinib in NTRK1-Rearranged Non-Small Cell Lung Cancer.". J Thorac Oncol 10 (12): 1670-4. doi:10.1097/01.JTO.0000473485.38553.f0. PMID 26565381.
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