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__NOTOC__ | |||
{{Carcinoid syndrome}} | {{Carcinoid syndrome}} | ||
{{CMG}} | {{CMG}}{{AE}}{{PSD}} | ||
==Overview== | ==Overview== | ||
[[Surgery]] is the mainstay of treatment for [[Carcinoid tumor|carcinoid tumor.]] The feasibility of [[surgery]] depends on the [[Cancer staging|stage]] of [[carcinoid tumor]] at [[Diagnosis|diagnosis.]] | |||
==Surgery== | ==Surgery== | ||
[[Surgery]], if feasible, is the only curative therapy. If the | [[Surgery]], if feasible, is the only curative therapy. If the [[tumor]] has [[metastasized]] (most commonly, to the [[liver]]), the [[tumor]] may be ineligible for [[surgery]] (unresectable), though there are many promising treatment modalities, such as radiolabeled [[octreotide]], that are very effective in arresting the [[growth]] of the [[tumors]] and prolonging [[Survival rate|survival]] in patients with [[Liver (2)|liver]] [[metastases]]. | ||
===Gastric Carcinoids=== | |||
* Type I [[gastric]] [[Carcinoid tumours|carcinoids]]: smaller than 1 cm can be removed with [[endoscopic]] [[Mucosal|mucosal resection]]. Local [[Surgery operation|surgical excision]] may be performed for larger [[Tumors|tumors.]]<ref name="surgery">Treatment Option Overview for gastrointestinal Carcinoid Tumors.<nowiki><ref name="pmid12972355"></nowiki>{{cite journal |vauthors=Kulke MH |title=Neuroendocrine tumours: clinical presentation and management of localized disease |journal=Cancer Treat. Rev. |volume=29 |issue=5 |pages=363–70 |date=October 2003 |pmid=12972355 |doi= |url=}} | |||
*Type II carcinoids,the surgery is focused on removing the source of hypergastrinemia, typically by excision of duodenal gastrinomas via duodenotomy with resection of lymph node metastases.<nowiki><ref name="pmid9298884"></nowiki>{{cite journal |vauthors=Bordi C, Falchetti A, Azzoni C, D'Adda T, Canavese G, Guariglia A, Santini D, Tomassetti P, Brandi ML |title=Aggressive forms of gastric neuroendocrine tumors in multiple endocrine neoplasia type I |journal=Am. J. Surg. Pathol. |volume=21 |issue=9 |pages=1075–82 |date=September 1997 |pmid=9298884 |doi= |url=}}</ref><ref name="pmid28763328">{{cite journal |vauthors=Callahan AF, White M, Ituarte P, Gagandeep S, Woo Y, Fong Y, Melstrom L |title=Surgical Intervention in Gastric Carcinoid is Associated With Improved Survival in Local and Regional Disease |journal=Am. J. Clin. Oncol. |volume=41 |issue=9 |pages=882–887 |date=September 2018 |pmid=28763328 |doi=10.1097/COC.0000000000000392 |url=}}</ref> | |||
*Type II [[tumors]] can usually be managed with [[Endoscopic|endoscopic resection]] ([[tumors]] <1 cm) followed by close [[endoscopic]] surveillance.<ref name="pmid29257854">{{cite journal |vauthors=Dias AR, Azevedo BC, Alban LBV, Yagi OK, Ramos MFKP, Jacob CE, Barchi LC, Cecconello I, Ribeiro U, Zilberstein B |title=GASTRIC NEUROENDOCRINE TUMOR: REVIEW AND UPDATE |journal=Arq Bras Cir Dig |volume=30 |issue=2 |pages=150–154 |date=2017 |pmid=29257854 |pmc=5543797 |doi=10.1590/0102-6720201700020016 |url=}}</ref> | |||
*For larger or multifocal [[Tumour|tumours]] liberal surgical excision or gastric resection with regional [[lymphadenectomy]] is performed.<ref name="pmid16360380">{{cite journal |vauthors=Mullen JT, Wang H, Yao JC, Lee JH, Perrier ND, Pisters PW, Lee JE, Evans DB |title=Carcinoid tumors of the duodenum |journal=Surgery |volume=138 |issue=6 |pages=971–7; discussion 977–8 |date=December 2005 |pmid=16360380 |doi=10.1016/j.surg.2005.09.016 |url=}}</ref> | |||
* Type II [[Carcinoid tumor|carcinoids tumor]] can usually be managed with [[endoscopic]] resection (tumors <1 cm) followed by close endoscopic surveillance. | |||
* For larger or multifocal tumors liberal surgical excision or [[Gastric|gastric resection]] with regional [[lymphadenectomy]] is performed. | |||
* For type III [[Carcinoid tumor|gastric carcinoids]] larger than 2 cm or those with atypical histology or [[Gastric|gastric wall]] invasion are most appropriately dealt with by [[gastrectomy]] or radical [[gastrectomy]]. | |||
=== Duodenal carcinoids === | |||
* Primary [[Carcinoid tumor|duodenal carcinoids]] smaller than 1 cm are treated by [[endoscopic]] excision. | |||
* Duodenal [[Carcinoid tumor|carcinoids]] smaller than 2 cm may be excised locally. [[Tumors]] between 1 cm and 2 cm, complete resection is ensured by operative full-thickness [[excision]]. Follow-up [[endoscopy]] is indicated. | |||
*[[Tumors]] larger than 1 cm may be difficult to remove completely [[Endoscopic|endoscopically]] and should be evaluated with [[endoscopic]] [[ultrasonography]] before [[endoscopic]] resection is attempted because of their potential to [[Invasion|invade]] beyond the [[submucosa]].<ref name="pmid12086896">{{cite journal |vauthors=Zyromski NJ, Kendrick ML, Nagorney DM, Grant CS, Donohue JH, Farnell MB, Thompson GB, Farley DR, Sarr MG |title=Duodenal carcinoid tumors: how aggressive should we be? |journal=J. Gastrointest. Surg. |volume=5 |issue=6 |pages=588–93 |date=2001 |pmid=12086896 |doi= |url=}}</ref> | |||
*[[Tumors]] larger than 2 cm can be treated with operative full-thickness [[excision]] and [[lymphadenectomy|regional lymphadenectomy]].<ref name="pmid12086896">{{cite journal |vauthors=Zyromski NJ, Kendrick ML, Nagorney DM, Grant CS, Donohue JH, Farnell MB, Thompson GB, Farley DR, Sarr MG |title=Duodenal carcinoid tumors: how aggressive should we be? |journal=J. Gastrointest. Surg. |volume=5 |issue=6 |pages=588–93 |date=2001 |pmid=12086896 |doi= |url=}}</ref> | |||
*A regional [[lymphadenectomy]] includes the [[lymph nodes]] in the following locations: | |||
:*[[Posterior]] to the [[duodenum]] and [[Pancreas|pancreatic head]] and anterior to the [[inferior vena cava]] | |||
:*Posterolateral to the [[bile duct]] and [[portal vein]] | |||
:*[[Anterior]] to the [[common hepatic artery]] | |||
===Jejunal and Ileal Carcinoids=== | |||
*[[Carcinoid tumors|Carcinoids]] of the [[small intestine]] have metastatized in the regional [[lymph nodes]] or the [[liver]] in 50%-60% of cases<ref name="surgery">Treatment Option Overview for gastrointestinal Carcinoid Tumors | |||
. NATIONAL CANCER INSTITUTE . http://www.cancer.gov/types/gi-carcinoid-tumors/hp/gi-carcinoid-treatment-pdq#link/_97_toc Accessed on September 22, 2015</ref> | |||
*Early [[Surgery|surgical treatment]] should include removal of the [[mesentery]] by wedge [[resection]] and resection of [[Lymph nodes|lymph node]] [[metastases]] surrounding the [[mesenteric artery]] and [[Veins|vein]] to preserve [[Intestine|intestinal]] [[Blood|vascular supply]] and to limit the [[intestinal]] resection.<ref name="pmid20664473">{{cite journal |vauthors=Boudreaux JP, Klimstra DS, Hassan MM, Woltering EA, Jensen RT, Goldsmith SJ, Nutting C, Bushnell DL, Caplin ME, Yao JC |title=The NANETS consensus guideline for the diagnosis and management of neuroendocrine tumors: well-differentiated neuroendocrine tumors of the Jejunum, Ileum, Appendix, and Cecum |journal=Pancreas |volume=39 |issue=6 |pages=753–66 |date=August 2010 |pmid=20664473 |doi=10.1097/MPA.0b013e3181ebb2a5 |url=}}</ref> | |||
*Surgical treatment for advanced carcinoids involves prophylactic removal of [[mesenteric]] [[metastases]] early on because later the [[disease]] may become impossible to manage surgically. | |||
*Due to [[fibrosis]] between regions of the [[intestine]],surgery may result in [[fistulae]], [[intestinal]] devascularization, or creation of a short [[bowel]]. | |||
===Appendiceal Carcinoids=== | |||
*[[Appendix|Appendiceal]] [[Carcinoid tumor|carcinoids]] smaller than 1 are cured by [[appendectomy]].<ref name="pmid20664473">{{cite journal |vauthors=Boudreaux JP, Klimstra DS, Hassan MM, Woltering EA, Jensen RT, Goldsmith SJ, Nutting C, Bushnell DL, Caplin ME, Yao JC |title=The NANETS consensus guideline for the diagnosis and management of neuroendocrine tumors: well-differentiated neuroendocrine tumors of the Jejunum, Ileum, Appendix, and Cecum |journal=Pancreas |volume=39 |issue=6 |pages=753–66 |date=August 2010 |pmid=20664473 |doi=10.1097/MPA.0b013e3181ebb2a5 |url=}}</ref> | |||
*[[Appendix|Appendiceal]] [[Carcinoid tumor|carcinoids]] larger than 2 cm require right-sided [[hemicolectomy]] and [[ileocecal]] [[lymphadenectomy]] because of the significant risk of [[Metastasis|metastasis.]]<ref name="surgery">Treatment Option Overview for gastrointestinal Carcinoid Tumors | |||
. NATIONAL CANCER INSTITUTE . http://www.cancer.gov/types/gi-carcinoid-tumors/hp/gi-carcinoid-treatment-pdq#link/_97_toc Accessed on September 22, 2015</ref> | |||
*For [[tumors]] between 1 to 2 cm, treatment is controversial, but [[hemicolectomy]] may be appropriate if there is [[invasion]] in the [[mesoappendix]], if there is residual [[tumor]] in the resection margins, or in the presence of [[lymph node]] [[metastases]]. | |||
===Colonic Carcinoids=== | |||
*[[Colon|Colonic]] [[carcinoid tumors]] of the [[colon]] are treated similarly to [[adenocarcinoma]] of the [[colon]]. | |||
*Radical resection by [[hemicolectomy]] or subtotal [[colectomy]] with [[lymphadenectomy]] should be done for [[Colon|colonic]] [[Carcinoid tumors|carcinoids tumors]]. | |||
===Rectal Carcinoids=== | |||
*[[Tumors]] smaller than 1 cm can be removed by [[endoscopic]] excision but excised specimens should be examined [[histologically]] to exclude [[Muscularis mucosa|muscularis]] [[invasion]].<ref name="pmid8044398">{{cite journal |vauthors=Mani S, Modlin IM, Ballantyne G, Ahlman H, West B |title=Carcinoids of the rectum |journal=J. Am. Coll. Surg. |volume=179 |issue=2 |pages=231–48 |date=August 1994 |pmid=8044398 |doi= |url=}}</ref> | |||
*Patients with [[tumors]] that are greater than 2 cm or that have [[invasion]] of the [[muscularis]] as seen by [[endoscopic ultrasound]] or [[MRI]], surgical resection with [[abdominoperineal resection]] (APR) or low anterior resection (LAR) is recommended because of the high rate of [[Lymph nodes|nodal]] [[metastases]] and risk of distant [[metastatic]] [[disease]]. | |||
*There is considerable debate about whether local excision or [[rectal]] resection (i.e., APR or LAR) is needed for [[tumors]] that are 1 cm to 2 cm. | |||
*Although it may be possible to recognize [[tumors]] with particular atypia and high [[mitotic index]] before embarking on the more radical [[surgery]], the presence of [[muscularis]] [[invasion]] or regional [[metastases]] generally supports [[rectal]] resection. | |||
===Metastatic Gastrointestinal Carcinoid Tumors=== | |||
Definitive role of [[surgery]] in [[metastatic]] disease has not been established, conservative [[resections]] of the [[intestine]] [[mesenteric]] [[tumors]], and [[Fibrosis|fibrotic]] areas may improve [[symptoms]] and quality of life substantially in patients with [[metastatic]] [[hepatic]], [[mesenteric]], and [[peritoneal]] carcinoids.<ref name="surgery">Treatment Option Overview for gastrointestinal Carcinoid Tumors | |||
. NATIONAL CANCER INSTITUTE . http://www.cancer.gov/types/gi-carcinoid-tumors/hp/gi-carcinoid-treatment-pdq#link/_97_toc Accessed on September 22, 2015</ref><ref name="ModlinLye2003">{{cite journal|last1=Modlin|first1=Irvin M.|last2=Lye|first2=Kevin D.|last3=Kidd|first3=Mark|title=A 5-decade analysis of 13,715 carcinoid tumors|journal=Cancer|volume=97|issue=4|year=2003|pages=934–959|issn=0008-543X|doi=10.1002/cncr.11105}}</ref> | |||
*The primary tumor should be resected to prevent an emergency presentation with [[obstruction]], [[perforation]], or [[bleeding]] if the condition of the patient is such that surgery is not a greater risk than the disease | |||
*Management of [[hepatic]] [[metastases]] may include: | |||
#[[Surgical]] resection | |||
#[[Hepatic artery]] [[embolization]] | |||
#[[Cryoablation]] | |||
#[[Radiofrequency ablation]] | |||
#Orthotopic [[liver transplantation]]. | |||
*In the case of [[Liver (2)|liver]] [[metastases]], localization and resection of the [[primary tumor]] may be considered, even among patients in whom the [[Neoplasm|primary neoplasm]] is [[Asymptomatic condition|asymptomatic]]. | |||
*[[Palliative therapy|Palliative]] [[radiation therapy]] has some [[efficacy]] for [[bone]] and [[brain]] [[metastases]] and in the management of [[spinal cord]] [[Metastases|metastase]]<nowiki/>s. | |||
===Recurrent gastrointestinal Carcinoid Tumors=== | |||
Treatment of recurrent [[gastrointestinal]] [[carcinoid tumor]] depends on many factors:<ref name="surgery">Treatment Option Overview for gastrointestinal Carcinoid Tumors | |||
. NATIONAL CANCER INSTITUTE . http://www.cancer.gov/types/gi-carcinoid-tumors/hp/gi-carcinoid-treatment-pdq#link/_97_toc Accessed on September 22, 2015</ref> | |||
*Previous treatment | |||
*Site of recurrence | |||
*Individual [[patient]] considerations | |||
==Carcinoid heart disease== | |||
*[[Valve replacement]] is the most effective treatment option for advanced [[Carcinoid disease|carcinoid heart disease]].{{cite web |url=https://doi.org/10.1007/s11936-013-0265-2 |title=Carcinoid Valve Disease | SpringerLink |format= |work= |accessdate=}}<ref name="pmid26564596">{{cite journal |vauthors=Connolly HM, Schaff HV, Abel MD, Rubin J, Askew JW, Li Z, Inda JJ, Luis SA, Nishimura RA, Pellikka PA |title=Early and Late Outcomes of Surgical Treatment in Carcinoid Heart Disease |journal=J. Am. Coll. Cardiol. |volume=66 |issue=20 |pages=2189–2196 |date=November 2015 |pmid=26564596 |doi=10.1016/j.jacc.2015.09.014 |url=}}</ref> | |||
==References== | ==References== | ||
{{reflist|2}} | {{reflist|2}} | ||
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Latest revision as of 23:03, 6 May 2019
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Parminder Dhingra, M.D. [2]
Overview
Surgery is the mainstay of treatment for carcinoid tumor. The feasibility of surgery depends on the stage of carcinoid tumor at diagnosis.
Surgery
Surgery, if feasible, is the only curative therapy. If the tumor has metastasized (most commonly, to the liver), the tumor may be ineligible for surgery (unresectable), though there are many promising treatment modalities, such as radiolabeled octreotide, that are very effective in arresting the growth of the tumors and prolonging survival in patients with liver metastases.
Gastric Carcinoids
- Type I gastric carcinoids: smaller than 1 cm can be removed with endoscopic mucosal resection. Local surgical excision may be performed for larger tumors.[1][2]
- Type II tumors can usually be managed with endoscopic resection (tumors <1 cm) followed by close endoscopic surveillance.[3]
- For larger or multifocal tumours liberal surgical excision or gastric resection with regional lymphadenectomy is performed.[4]
- Type II carcinoids tumor can usually be managed with endoscopic resection (tumors <1 cm) followed by close endoscopic surveillance.
- For larger or multifocal tumors liberal surgical excision or gastric resection with regional lymphadenectomy is performed.
- For type III gastric carcinoids larger than 2 cm or those with atypical histology or gastric wall invasion are most appropriately dealt with by gastrectomy or radical gastrectomy.
Duodenal carcinoids
- Primary duodenal carcinoids smaller than 1 cm are treated by endoscopic excision.
- Duodenal carcinoids smaller than 2 cm may be excised locally. Tumors between 1 cm and 2 cm, complete resection is ensured by operative full-thickness excision. Follow-up endoscopy is indicated.
- Tumors larger than 1 cm may be difficult to remove completely endoscopically and should be evaluated with endoscopic ultrasonography before endoscopic resection is attempted because of their potential to invade beyond the submucosa.[5]
- Tumors larger than 2 cm can be treated with operative full-thickness excision and regional lymphadenectomy.[5]
- A regional lymphadenectomy includes the lymph nodes in the following locations:
- Posterior to the duodenum and pancreatic head and anterior to the inferior vena cava
- Posterolateral to the bile duct and portal vein
- Anterior to the common hepatic artery
Jejunal and Ileal Carcinoids
- Carcinoids of the small intestine have metastatized in the regional lymph nodes or the liver in 50%-60% of cases[1]
- Early surgical treatment should include removal of the mesentery by wedge resection and resection of lymph node metastases surrounding the mesenteric artery and vein to preserve intestinal vascular supply and to limit the intestinal resection.[6]
- Surgical treatment for advanced carcinoids involves prophylactic removal of mesenteric metastases early on because later the disease may become impossible to manage surgically.
- Due to fibrosis between regions of the intestine,surgery may result in fistulae, intestinal devascularization, or creation of a short bowel.
Appendiceal Carcinoids
- Appendiceal carcinoids smaller than 1 are cured by appendectomy.[6]
- Appendiceal carcinoids larger than 2 cm require right-sided hemicolectomy and ileocecal lymphadenectomy because of the significant risk of metastasis.[1]
- For tumors between 1 to 2 cm, treatment is controversial, but hemicolectomy may be appropriate if there is invasion in the mesoappendix, if there is residual tumor in the resection margins, or in the presence of lymph node metastases.
Colonic Carcinoids
- Colonic carcinoid tumors of the colon are treated similarly to adenocarcinoma of the colon.
- Radical resection by hemicolectomy or subtotal colectomy with lymphadenectomy should be done for colonic carcinoids tumors.
Rectal Carcinoids
- Tumors smaller than 1 cm can be removed by endoscopic excision but excised specimens should be examined histologically to exclude muscularis invasion.[7]
- Patients with tumors that are greater than 2 cm or that have invasion of the muscularis as seen by endoscopic ultrasound or MRI, surgical resection with abdominoperineal resection (APR) or low anterior resection (LAR) is recommended because of the high rate of nodal metastases and risk of distant metastatic disease.
- There is considerable debate about whether local excision or rectal resection (i.e., APR or LAR) is needed for tumors that are 1 cm to 2 cm.
- Although it may be possible to recognize tumors with particular atypia and high mitotic index before embarking on the more radical surgery, the presence of muscularis invasion or regional metastases generally supports rectal resection.
Metastatic Gastrointestinal Carcinoid Tumors
Definitive role of surgery in metastatic disease has not been established, conservative resections of the intestine mesenteric tumors, and fibrotic areas may improve symptoms and quality of life substantially in patients with metastatic hepatic, mesenteric, and peritoneal carcinoids.[1][8]
- The primary tumor should be resected to prevent an emergency presentation with obstruction, perforation, or bleeding if the condition of the patient is such that surgery is not a greater risk than the disease
- Management of hepatic metastases may include:
- Surgical resection
- Hepatic artery embolization
- Cryoablation
- Radiofrequency ablation
- Orthotopic liver transplantation.
- In the case of liver metastases, localization and resection of the primary tumor may be considered, even among patients in whom the primary neoplasm is asymptomatic.
- Palliative radiation therapy has some efficacy for bone and brain metastases and in the management of spinal cord metastases.
Recurrent gastrointestinal Carcinoid Tumors
Treatment of recurrent gastrointestinal carcinoid tumor depends on many factors:[1]
- Previous treatment
- Site of recurrence
- Individual patient considerations
Carcinoid heart disease
- Valve replacement is the most effective treatment option for advanced carcinoid heart disease."Carcinoid Valve Disease | SpringerLink".[9]
References
- ↑ 1.0 1.1 1.2 1.3 1.4 Treatment Option Overview for gastrointestinal Carcinoid Tumors.<ref name="pmid12972355">Kulke MH (October 2003). "Neuroendocrine tumours: clinical presentation and management of localized disease". Cancer Treat. Rev. 29 (5): 363–70. PMID 12972355.
- Type II carcinoids,the surgery is focused on removing the source of hypergastrinemia, typically by excision of duodenal gastrinomas via duodenotomy with resection of lymph node metastases.<ref name="pmid9298884">Bordi C, Falchetti A, Azzoni C, D'Adda T, Canavese G, Guariglia A, Santini D, Tomassetti P, Brandi ML (September 1997). "Aggressive forms of gastric neuroendocrine tumors in multiple endocrine neoplasia type I". Am. J. Surg. Pathol. 21 (9): 1075–82. PMID 9298884.
- ↑ Callahan AF, White M, Ituarte P, Gagandeep S, Woo Y, Fong Y, Melstrom L (September 2018). "Surgical Intervention in Gastric Carcinoid is Associated With Improved Survival in Local and Regional Disease". Am. J. Clin. Oncol. 41 (9): 882–887. doi:10.1097/COC.0000000000000392. PMID 28763328.
- ↑ Dias AR, Azevedo BC, Alban L, Yagi OK, Ramos M, Jacob CE, Barchi LC, Cecconello I, Ribeiro U, Zilberstein B (2017). "GASTRIC NEUROENDOCRINE TUMOR: REVIEW AND UPDATE". Arq Bras Cir Dig. 30 (2): 150–154. doi:10.1590/0102-6720201700020016. PMC 5543797. PMID 29257854. Vancouver style error: initials (help)
- ↑ Mullen JT, Wang H, Yao JC, Lee JH, Perrier ND, Pisters PW, Lee JE, Evans DB (December 2005). "Carcinoid tumors of the duodenum". Surgery. 138 (6): 971–7, discussion 977–8. doi:10.1016/j.surg.2005.09.016. PMID 16360380.
- ↑ 5.0 5.1 Zyromski NJ, Kendrick ML, Nagorney DM, Grant CS, Donohue JH, Farnell MB, Thompson GB, Farley DR, Sarr MG (2001). "Duodenal carcinoid tumors: how aggressive should we be?". J. Gastrointest. Surg. 5 (6): 588–93. PMID 12086896.
- ↑ 6.0 6.1 Boudreaux JP, Klimstra DS, Hassan MM, Woltering EA, Jensen RT, Goldsmith SJ, Nutting C, Bushnell DL, Caplin ME, Yao JC (August 2010). "The NANETS consensus guideline for the diagnosis and management of neuroendocrine tumors: well-differentiated neuroendocrine tumors of the Jejunum, Ileum, Appendix, and Cecum". Pancreas. 39 (6): 753–66. doi:10.1097/MPA.0b013e3181ebb2a5. PMID 20664473.
- ↑ Mani S, Modlin IM, Ballantyne G, Ahlman H, West B (August 1994). "Carcinoids of the rectum". J. Am. Coll. Surg. 179 (2): 231–48. PMID 8044398.
- ↑ Modlin, Irvin M.; Lye, Kevin D.; Kidd, Mark (2003). "A 5-decade analysis of 13,715 carcinoid tumors". Cancer. 97 (4): 934–959. doi:10.1002/cncr.11105. ISSN 0008-543X.
- ↑ Connolly HM, Schaff HV, Abel MD, Rubin J, Askew JW, Li Z, Inda JJ, Luis SA, Nishimura RA, Pellikka PA (November 2015). "Early and Late Outcomes of Surgical Treatment in Carcinoid Heart Disease". J. Am. Coll. Cardiol. 66 (20): 2189–2196. doi:10.1016/j.jacc.2015.09.014. PMID 26564596.