The Role of the Vagus Nerve in Cancer Prognosis: A Systematic and a Comprehensive Review

Marijke De Couck, Ralf Caers, David Spiegel, Yori Gidron, Marijke De Couck, Ralf Caers, David Spiegel, Yori Gidron

Abstract

This article reviews the role of the vagus nerve in tumor modulation and cancer prognosis. We present a systematic review of 12 epidemiological studies examining the relationship between heart rate variability, the main vagus nerve index, and prognosis in cancer patients (survival and tumor markers). These studies show that initially high vagal nerve activity predicts better cancer prognosis, and, in some studies, independent of confounders such as cancer stage and treatments. Since the design of the epidemiological studies is correlational, any causal relationship between heart rate variability and cancer prognosis cannot be inferred. However, various semi-experimental cohort studies in humans and experimental studies in animals have examined this causal relationship. The second part of this paper presents a comprehensive review including human and animal cohort and experimental studies showing that vagotomy accelerates tumor growth, while vagal nerve activation improves cancer prognosis. Based on all reviewed studies, it is concluded that the evidence supports a protective role of the vagus nerve in cancer and specifically in the metastatic stage.

References

    1. Global Burden of Disease Cancer Collaboration. Global, regional, and national cancer incidence, mortality, years of life lost, years lived with disability, and disability-adjusted life years for 32 cancer groups, 1990 to 2015: a systematic analysis for the Global Burden of Disease Study 2015. JAMA Oncol. 2017;3(4):524–548.
    1. Hanahan D., Weinberg R. A. Hallmarks of cancer: the next generation. Cell. 2011;144(5):646–674. doi: 10.1016/j.cell.2011.02.013.
    1. Voronov E., Shouval D. S., Krelin Y., et al. IL-1 is required for tumor invasiveness and angiogenesis. Proceedings of the National Acadamy of Sciences of the United States of America. 2003;100(5):2645–2650. doi: 10.1073/pnas.0437939100.
    1. Valko M., Izakovic M., Mazur M., Rhodes C. J., Telser J. Role of oxygen radicals in DNA damage and cancer incidence. Molecular and Cellular Biochemistry. 2004;266(1-2):37–56. doi: 10.1023/B:MCBI.0000049134.69131.89.
    1. Mantovani A., Allavena P., Sica A., Balkwill F. Cancer-related inflammation. Nature. 2008;454(7203):436–444. doi: 10.1038/nature07205.
    1. Entschladen F., Drell VI T. L., Lang K., Joseph J., Zaenker K. S. Tumour-cell migration, invasion, and metastasis: Navigation by neurotransmitters. The Lancet Oncology. 2004;5(4):254–258. doi: 10.1016/S1470-2045(04)01431-7.
    1. Thaker P. H., Han L. Y., Kamat A. A., et al. Chronic stress promotes tumor growth and angiogenesis in a mouse model of ovarian carcinoma. Nature Medicine. 2006;12(8):939–944. doi: 10.1038/nm1447.
    1. Thaker P. H., Sood A. K., Ramondetta L. M. Importance of adrenergic pathways in women's cancers. Cancer Biomarkers. 2013;13(3):145–154. doi: 10.3233/CBM-130324.
    1. Tsutsumi T., Ide T., Yamato M., et al. Modulation of the myocardial redox state by vagal nerve stimulation after experimental myocardial infarction. Cardiovascular Research. 2008;77(4):713–721. doi: 10.1093/cvr/cvm092.
    1. Ek M., Kurosawa M., Lundeberg T., Ericsson A. Activation of vagal afferents after intravenous injection of interleukin-1β: Role of endogenous prostaglandins. The Journal of Neuroscience. 1998;18(22):9471–9479. doi: 10.1523/JNEUROSCI.18-22-09471.1998.
    1. Tracey K. J. Reflex control of immunity. Nature Reviews Immunology. 2009;9(6):418–428. doi: 10.1038/nri2566.
    1. Maki A., Kono H., Gupta M., et al. Predictive power of biomarkers of oxidative stress and inflammation in patients with hepatitis C virus-associated hepatocellular carcinoma. Annals of Surgical Oncology. 2007;14(3):1182–1190. doi: 10.1245/s10434-006-9049-1.
    1. Dubeykovskaya Z., Si Y., Chen X., et al. Neural innervation stimulates splenic TFF2 to arrest myeloid cell expansion and cancer. Nature Communications. 2016;7 doi: 10.1038/ncomms10517.10517
    1. Gidron Y., Perry H., Glennie M. Does the vagus nerve inform the brain about preclinical tumours and modulate them? The Lancet Oncology. 2005;6(4):245–248. doi: 10.1016/S1470-2045(05)70096-6.
    1. De Couck M., Mravec B., Gidron Y. You may need the vagus nerve to understand pathophysiology and to treat diseases. Clinical Science. 2012;122(7):323–328. doi: 10.1042/CS20110299.
    1. Tracey K. J. The inflammatory reflex. Nature. 2002;420(6917):853–859. doi: 10.1038/nature01321.
    1. Guarini S., Cainazzo M. M., Giuliani D., et al. Adrenocorticotropin reverses hemorrhagic shock in anesthetized rats through the rapid activation of a vagal anti-inflammatory pathway. Cardiovascular Research. 2004;63(2):357–365. doi: 10.1016/j.cardiores.2004.03.029.
    1. Guarini S., Altavilla D., Cainazzo M.-M., et al. Efferent vagal fibre stimulation blunts nuclear factor-κB activation and protects against hypovolemic hemorrhagic shock. Circulation. 2003;107(8):1189–1194. doi: 10.1161/01.cir.0000050627.90734.ed.
    1. Ottani A., Giuliani D., Galantucci M., et al. Melanocortins counteract inflammatory and apoptotic responses to prolonged myocardial ischemia/reperfusion through a vagus nerve-mediated mechanism. European Journal of Pharmacology. 2010;637(1-3):124–130. doi: 10.1016/j.ejphar.2010.03.052.
    1. Vonck K., Raedt R., Naulaerts J., et al. Vagus nerve stimulation. . .25 years later! What do we know about the effects on cognition? Neuroscience & Biobehavioral Reviews. 2014;45:63–71. doi: 10.1016/j.neubiorev.2014.05.005.
    1. Li J., Xie H., Wen T., Liu H., Zhu W., Chen X. Expression of high mobility group box chromosomal protein 1 and its modulating effects on downstream cytokines in systemic lupus erythematosus. The Journal of Rheumatology. 2010;37(4):766–775. doi: 10.3899/jrheum.090663.
    1. Feldmann M., Brennan F. M., Maini R. N. Role of cytokines in rheumatoid arthritis. Annual Review of Immunology. 1996;14:397–440. doi: 10.1146/annurev.immunol.14.1.397.
    1. Bonaz B., Bazin T., Pellissier S. The Vagus Nerve at the Interface of the Microbiota-Gut-Brain Axis. Frontiers in Neuroscience. 2018;12 doi: 10.3389/fnins.2018.00049.
    1. Pal G. K., Adithan C., Ananthanarayanan P. H., et al. Sympathovagal Imbalance contributes to prehypertension status and cardiovascular risks attributed by insulin resistance, inflammation, dyslipidemia and oxidative stress in first degree relatives of type 2 diabetics. PLoS ONE. 2013;8(11) doi: 10.1371/journal.pone.0078072.e78072
    1. Huston J. M., Gallowitsch-Puerta M., Ochani M., et al. Transcutaneous vagus nerve stimulation reduces serum high mobility group box 1 levels and improves survival in murine sepsis. Critical Care Medicine. 2007;35(12):2762–2768. doi: 10.1097/.
    1. van Westerloo D. J., Giebelen I. A., Florquin S., et al. The Vagus Nerve and Nicotinic Receptors Modulate Experimental Pancreatitis Severity in Mice. Gastroenterology. 2006;130(6):1822–1830. doi: 10.1053/j.gastro.2006.02.022.
    1. Müller H. H., Moeller S., Lücke C., Lam A. P., Braun N., Philipsen A. Vagus Nerve Stimulation (VNS) and Other Augmentation Strategies for Therapy-Resistant Depression (TRD): Review of the Evidence and Clinical Advice for Use. Frontiers in Neuroscience. 2018;12 doi: 10.3389/fnins.2018.00239.
    1. Chakravarthy K., Chaudhry H., Williams K., Christo P. J. Review of the Uses of Vagal Nerve Stimulation in Chronic Pain Management. Current Pain and Headache Reports. 2015;19(12, article no. 54) doi: 10.1007/s11916-015-0528-6.
    1. Morris G. L., III, Mueller W. M. Long-term treatment with vagus nerve stimulation in patients with refractory epilepsy. Neurology. 1999;53(8):1731–1735. doi: 10.1212/WNL.53.8.1731.
    1. Weber C. S., Thayer J. F., Rudat M., et al. Low vagal tone is associated with impaired post stress recovery of cardiovascular, endocrine, and immune markers. European Journal of Applied Physiology. 2010;109(2):201–211. doi: 10.1007/s00421-009-1341-x.
    1. Ohira H., Matsunaga M., Osumi T., et al. Vagal nerve activity as a moderator of brain-immune relationships. Journal of Neuroimmunology. 2013;260(1-2):28–36. doi: 10.1016/j.jneuroim.2013.04.011.
    1. Zhou X., Ma Z., Zhang L., et al. Heart rate variability in the prediction of survival in patients with cancer: A systematic review and meta-analysis. Journal of Psychosomatic Research. 2016;89:20–25. doi: 10.1016/j.jpsychores.2016.08.004.
    1. Couck M. D., Maréchal R., Moorthamers S., Laethem J.-L. V., Gidron Y. Vagal nerve activity predicts overall survival in metastatic pancreatic cancer, mediated by inflammation. Cancer Epidemiology. 2016;40:47–51. doi: 10.1016/j.canep.2015.11.007.
    1. Kim K., Chae J., Lee S. The role of heart rate variability in advanced non-small-cell lung cancer patients. Journal of Palliative Care. 2015;31(2):103–108. doi: 10.1177/082585971503100206.
    1. Giese-Davis J., Wilhelm F. H., Tamagawa R., et al. Higher vagal activity as related to survival in patients with advanced breast cancer: An analysis of autonomic dysregulation. Psychosomatic Medicine. 2015;77(4):346–355. doi: 10.1097/PSY.0000000000000167.
    1. Wang Y.-M., Wu H.-T., Huang E.-Y., Kou Y. R., Hseu S.-S. Heart rate variability is associated with survival in patients with brain metastasis: A preliminary report. BioMed Research International. 2013;2013 doi: 10.1155/2013/503421.503421
    1. Couck M. D., Brummelen D. V., Schallier D., Grève J. D., Gidron Y. The relationship between vagal nerve activity and clinical outcomes in prostate and non-small cell lung cancer patients. Oncology Reports. 2013;30(5):2435–2441. doi: 10.3892/or.2013.2725.
    1. Chiang J.-K., Kuo T. B. J., Fu C.-H., Koo M. Predicting 7-Day Survival Using Heart Rate Variability in Hospice Patients with Non-Lung Cancers. PLoS ONE. 2013;8(7) doi: 10.1371/journal.pone.0069482.e69482
    1. Kim D. H., Kim J. A., Choi Y. S., Kim S. H., Lee J. Y., Kim Y. E. Heart rate variability and length of survival in hospice cancer patients. Journal of Korean Medical Science. 2010;25(8):1140–1145. doi: 10.3346/jkms.2010.25.8.1140.
    1. Fadul N., Strasser F., Palmer J. L., et al. The association between autonomic dysfunction and survival in male patients with advanced cancer: a preliminary report. Journal of Pain and Symptom Management. 2010;39(2):283–290. doi: 10.1016/j.jpainsymman.2009.06.014.
    1. Mouton C., Ronson A., Razavi D., et al. The relationship between heart rate variability and time-course of carcinoembryonic antigen in colorectal cancer. Autonomic Neuroscience: Basic and Clinical. 2012;166(1-2):96–99. doi: 10.1016/j.autneu.2011.10.002.
    1. Hoffmann J., Grimm W., Menz V., et al. Prognostic value of heart rate variability analysis in patients with carcinoid syndrome. Digestion. 2001;63(1):35–42. doi: 10.1159/000051870.
    1. Guo Y., Koshy S., Hui D., et al. Prognostic Value of Heart Rate Variability in Patients with Cancer. Journal of Clinical Neurophysiology. 2015;32(6):516–520. doi: 10.1097/WNP.0000000000000210.
    1. Chiang J.-K., Koo M., Kuo T. B. J., Fu C.-H. Association Between Cardiovascular Autonomic Functions and Time to Death in Patients With Terminal Hepatocellular Carcinoma. Journal of Pain and Symptom Management. 2010;39(4):673–679. doi: 10.1016/j.jpainsymman.2009.09.014.
    1. Gidron Y., De Couck M., De Greve J. If you have an active vagus nerve, cancer stage may no longer be important. Journal of Biological Regulators and Homeostatic Agents. 2014;28(2):195–201.
    1. de Couck M., Gidron Y. Norms of vagus nerve activity, indexed by heart rate variability, in cancer patients. Cancer Epidemiology. 2013;37(5):737–741. doi: 10.1016/j.canep.2013.04.016.
    1. Sharma S. Tumor markers in clinical practice: General principles and guidelines. Indian Journal of Medical and Paediatric Oncology. 2009;30(1):p. 1. doi: 10.4103/0971-5851.56328.
    1. Ulloa L. The vagus nerve and the nicotinic anti-inflammatory pathway. Nature Reviews Drug Discovery. 2005;4(8):673–684. doi: 10.1038/nrd1797.
    1. Buck S. H., Burks T. F. The neuropharmacology of capsaicin: review of some recent observations. Pharmacol Rev. 1986;38(3):179–226.
    1. Offerhaus G. J. A., Tersmette A. C., Huibregtse K., et al. Mortality caused by stomach cancer after remote partial gastrectomy for benign conditions: 40 years of follow up of an Amsterdam cohort of 2633 postgastrectomy patients. Gut. 1988;29(11):1588–1590. doi: 10.1136/gut.29.11.1588.
    1. Toftgaard C. Gastric cancer after peptic ulcer surgery: An historic prospective cohort investigation. Annals of Surgery. 1989;210(2):159–164. doi: 10.1097/00000658-198908000-00004.
    1. Åhsberg K., Olsson H., Staël Von Holstein C. Increased mortality in prostate carcinoma and smoking-related disease after parietal cell vagotomy: A long-term follow-up study. Scandinavian Journal of Gastroenterology. 2009;44(8):947–951. doi: 10.1080/00365520903039945.
    1. Stockbrugger R. W., Cotton P. B., Eugenides N., Bartholomew B. A., Hill M. J., Walters C. L. Intragastric nitrites, nitrosamines, and bacterial overgrowth during cimetidine treatment. Gut. 1982;23(12):1048–1054. doi: 10.1136/gut.23.12.1048.
    1. Sharma B. K., Santana I. A., Wood E. C., et al. Intragastric bacterial activity and nitrosation before, during, and after treatment with omeprazole. BMJ. 1984;289(6447):717–719. doi: 10.1136/bmj.289.6447.717.
    1. Ekbom A. Risk of Cancer in Ulcerative Colitis. Journal of Gastrointestinal Surgery. 1998;2(4):312–313. doi: 10.1016/S1091-255X(98)80067-X.
    1. Morgenstern L. Vagotomy, Gastroenterostomy and Experimental Gastric Cancer. JAMA Surgery. 1968;96(6):920–923. doi: 10.1001/archsurg.1968.01330240066014.
    1. Kowalewski K. Relationship between vagotomy, peptic ulcer and gastric adenocarcinoma in rats fed 2,7-diacetylaminofluorene. Can JSurg. 1973;16:210–217.
    1. Junghanns K., Seufert R., von Gerstenbergk L., Ivankovic S. Does vagotomy and pyloroplasty change the location of gastrointestinal tumors? World Journal of Surgery. 1979;3(4):497–499. doi: 10.1007/BF01556116.
    1. Fujita M., Takami M., Usugane M., NamDei S., Taguchi T. Enhancement of gastric carcinogenesis in dogs given n-methyl-N'-nitro-n-nitrosoguanidine following vagotomy. Cancer Research. 1979;39(3):811–816.
    1. Mori H., Domellof L., Weisburger J. H., Williams G. M. Enhancing effect of vagotomy and pyloroplasty on gastro-intestinal carcinogenesis induced by nitrosamide in hamsters. GANN Japanese Journal of Cancer Research. 1981;72(3):440–445.
    1. Tatsuta M., Yamamura H., lishi H., et al. Promotion by Vagotomy of Gastric Carcinogenesis Induced by N-Methyl-N'-nitro-N-nitrosoguanidine in Wistar Rats. Cancer Research. 1985;45(1):194–197.
    1. Tatsuta M., Iishi H., Yamamura H., Baba M., Taniguchi H. Effects of bilateral and unilateral vagotomy on gastric carcinogenesis induced by N‐methyl‐N′‐nitro‐N‐nitrosoguanidine in wistar rats. International Journal of Cancer. 1988;42(3):414–418. doi: 10.1002/ijc.2910420318.
    1. Nelson R. L., Briley S., Vaz O. P., Abcarian H. The effect of vagotomy and pyloroplasty on colorectal tumor induction in the rat. Journal of Surgical Oncology. 1992;51(4):281–286. doi: 10.1002/jso.2930510416.
    1. Lundegardh G., Ekbom A., McLaughlin J. K., Nyren O. Gastric cancer risk after vagotomy. Gut. 1994;35(7):946–949. doi: 10.1136/gut.35.7.946.
    1. Bayón Lara A. M., Landa García I., Alcalde Escribano J., Rodríguez Dapena S., Ortega Medina L., Balibrea Cantero J. L. Colonic carcinogenesis in vagotomyzed rats. Revista Española de Enfermedades Digestivas. 2001;93(9):582–586.
    1. Schlag P., Weber E., Meister H., Meyer H. Animal experiments to assess the risk of cancer in the stomach after vagotomy. Langenbecks Archiv für Chirurgie. 1982;357(2):105–116. doi: 10.1007/BF01237456.
    1. Rumpf P., Schacht U., Palomba P., Kremer K., Borchard E. Chemically induced stomach carcinomas in rats following vagotomy and Bilroth II gastrectomy. Chirurgisches Forum fur experimentelle und klinische Forschung. 1977:58–62.
    1. Erin N., Boyer P. J., Bonneau R. H., Clawson G. A., Welch D. R. Capsaicin-mediated Denervation of Sensory Neurons Promotes Mammary Tumor Metastasis to Lung and Heart. Anticancer Reseach. 2004;24(2 B):1003–1009.
    1. Erin N., Akdas Barkan G., Harms J. F., Clawson G. A. Vagotomy enhances experimental metastases of 4THMpc breast cancer cells and alters Substance P level. Regulatory Peptides. 2008;151(1-3):35–42. doi: 10.1016/j.regpep.2008.03.012.
    1. Novotny A., Ryberg K., Heiman Ullmark J., et al. Is acetylcholine a signaling molecule for human colon cancer progression? Scandinavian Journal of Gastroenterology. 2011;46(4):446–455. doi: 10.3109/00365521.2010.539252.
    1. Trombino S., Bisio A., Catassi A., Cesario A., Falugi C., Russo P. Role of the non-neuronal human cholinergic system in lung cancer and mesothelioma: possibility of new therapeutic strategies. Current Medicinal Chemistry—Anti-Cancer Agents. 2004;4(6):535–542. doi: 10.2174/1568011043352687.
    1. Pettersson A., Nilsson L., Nylund G., Khorram-Manesh A., Nordgren S., Delbro D. S. Is acetylcholine an autocrine/paracrine growth factor via the nicotinic α7-receptor subtype in the human colon cancer cell line HT-29? European Journal of Pharmacology. 2009;609(1-3):27–33. doi: 10.1016/j.ejphar.2009.03.002.
    1. Schachter S. C. Vagus nerve stimulation therapy summary: Five years after FDA approval. Neurology. 2002;59(6):S15–S20. doi: 10.1212/WNL.59.6_suppl_4.S15.
    1. Corcoran C., Connor T. J., O'Keane V., Garland M. R. The effects of vagus nerve stimulation on pro- and anti-inflammatory cytokines in humans: A preliminary report. Neuroimmunomodulation. 2005;12(5):307–309. doi: 10.1159/000087109.
    1. Wustmann K., Kucera J. P., Scheffers I., et al. Effects of chronic baroreceptor stimulation on the autonomic cardiovascular regulation in patients with drug-resistant arterial hypertension. Hypertension. 2009;54(3):530–536. doi: 10.1161/HYPERTENSIONAHA.109.134023.
    1. Bernik T. R., Friedman S. G., Ochani M., et al. Pharmacological stimulation of the cholinergic antiinflammatory pathway. The Journal of Experimental Medicine. 2002;195(6):781–788. doi: 10.1084/jem.20011714.
    1. Borovikova L. V., Ivanova S., Zhang M., et al. Vagus nerve stimulation attenuates the systemic inflammatory response to endotoxin. Nature. 2000;405(6785):458–462. doi: 10.1038/35013070.
    1. Wang H., Yu M., Ochani M., et al. Nicotinic acetylcholine receptor α7 subunit is an essential regulator of inflammation. Nature. 2003;421(6921):384–388. doi: 10.1038/nature01339.
    1. Czura C. J., Tracey K. J. Autonomic neural regulation of immunity. Journal of Internal Medicine. 2005;257(2):156–166. doi: 10.1111/j.1365-2796.2004.01442.x.
    1. Lerman I., Hauger R., Sorkin L., et al. Noninvasive Transcutaneous Vagus Nerve Stimulation Decreases Whole Blood Culture-Derived Cytokines and Chemokines: A Randomized, Blinded, Healthy Control Pilot Trial. Neuromodulation: Technology at the Neural Interface. 2016;19(3):283–291. doi: 10.1111/ner.12398.
    1. Hein E., Nowak M., Kiess O., et al. Auricular transcutaneous electrical nerve stimulation in depressed patients: a randomized controlled pilot study. Journal of Neural Transmission. 2013;120(5):821–827. doi: 10.1007/s00702-012-0908-6.
    1. Kubota Y., Sato W., Toichi M., et al. Frontal midline theta rhythm is correlated with cardiac autonomic activities during the performance of an attention demanding meditation procedure. Cognitive Brain Research. 2001;11(2):281–287. doi: 10.1016/S0926-6410(00)00086-0.
    1. Paul-Labrador M., Polk D., Dwyer J. H., et al. Effects of a randomized controlled trial of transcendental meditation on components of the metabolic syndrome in subjects with coronary heart disease. JAMA Internal Medicine. 2006;166(11):1218–1224. doi: 10.1001/archinte.166.11.1218.
    1. Peng C.-K., Henry I. C., Mietus J. E., et al. Heart rate dynamics during three forms of meditation. International Journal of Cardiology. 2004;95(1):19–27. doi: 10.1016/j.ijcard.2003.02.006.
    1. Cowan M. J., Kogan H., Burr R., Hendershot S., Buchanan L. Power spectral analysis of heart rate variability after biofeedback training. Journal of Electrocardiology. 1990;23:85–94. doi: 10.1016/0022-0736(90)90081-C.
    1. Nolan R. P., Kamath M. V., Floras J. S., et al. Heart rate variability biofeedback as a behavioral neurocardiac intervention to enhance vagal heart rate control. American Heart Journal. 2005;149(6):1137–e7. doi: 10.1016/j.ahj.2005.03.015.
    1. Sakakibara M., Hayano J., Oikawa L. O., Katsamanis M., Lehrer P. Heart rate variability biofeedback improves cardiorespiratory resting function during sleep. Applied Psychophysiology and Biofeedback. 2013;38(4):265–271. doi: 10.1007/s10484-013-9232-7.
    1. Terathongkum S., Pickler R. H. Relationships among heart rate variability, hypertension, and relaxation techniques. Journal of Vascular Nursing. 2004;22(3):78–82. doi: 10.1016/j.jvn.2004.06.003.
    1. Van Dixhoorn J., White A. Relaxation therapy for rehabilitation and prevention in ischaemic heart disease: A systematic review and meta-analysis. European Journal of Preventive Cardiology. 2005;12(3):193–202. doi: 10.1097/.
    1. Pavlov V. A., Ochani M., Gallowitsch-Puerta M., et al. Central muscarinic cholinergic regulation of the systemic inflammatory response during endotoxemia. Proceedings of the National Acadamy of Sciences of the United States of America. 2006;103(13):5219–5223. doi: 10.1073/pnas.0600506103.
    1. Kemeny M. M., Botchkina G. I., Ochani M., Bianchi M., Urmacher C., Tracey K. J. The tetravalent guanylhydrazone CNI-1493 blocks the toxic effects of interleukin-2 without diminishing antitumor efficacy. Proceedings of the National Acadamy of Sciences of the United States of America. 1998;95(8):4561–4566. doi: 10.1073/pnas.95.8.4561.
    1. Atkins M. B., Redman B., Mier J., et al. A Phase I Study of CNI-1493, an Inhibitor of Cytokine Release, in Combination with High-Dose Interleukin-2 in Patients with Renal Cancer and Melanoma. Clin Cancer Res. 2001;7:486–492.
    1. Erin N., Duymuş Ö., Öztürk S., Demir N. Activation of vagus nerve by semapimod alters substance P levels and decreases breast cancer metastasis. Regulatory Peptides. 2012;179(1-3):101–108. doi: 10.1016/j.regpep.2012.08.001.
    1. Armaiz-Pena G. N., Allen J. K., Cruz A., et al. Src activation by adrenoreceptors is a key switch for tumour metastasis. Nature Communications. 2013;4, article no. 1403 doi: 10.1038/ncomms2413.
    1. Magnon C., Hall S. J., Lin J., et al. Autonomic nerve development contributes to prostate cancer progression. Science. 2013;341(6142) doi: 10.1126/science.1236361.1236361
    1. Agelaki S., Tsatsanis C., Gravanis A., Margioris A. N. Corticotropin-releasing hormone augments proinflammatory cytokine production from macrophages in vitro and in lipopolysaccharide-induced endotoxin shock in mice. Infection and Immunity. 2002;70(11):6068–6074. doi: 10.1128/IAI.70.11.6068-6074.2002.
    1. Kerzerho J., Wunsch D., Szely N., et al. Effects of systemic versus local administration of corticosteroids on mucosal tolerance. The Journal of Immunology. 2012;188(1):472–476. doi: 10.4049/jimmunol.1101405.
    1. Thayer J. F., Åhs F., Fredrikson M., Sollers J. J., Wager T. D. A meta-analysis of heart rate variability and neuroimaging studies: implications for heart rate variability as a marker of stress and health. Neuroscience & Biobehavioral Reviews. 2012;36(2):747–756. doi: 10.1016/j.neubiorev.2011.11.009.
    1. Matthews S. C., Paulus M. P., Simmons A. N., Nelesen R. A., Dimsdale J. E. Functional subdivisions within anterior cingulate cortex and their relationship to autonomic nervous system function. NeuroImage. 2004;22(3):1151–1156. doi: 10.1016/j.neuroimage.2004.03.005.
    1. Tashiro M., Itoh M., Kubota K., et al. Relationship between trait anxiety, brain activity and natural killer cell activity in cancer patients: A preliminary pet study. Psycho-Oncology. 2001;10(6):541–546. doi: 10.1002/pon.548.
    1. Rosas-Ballina M., Olofsson P. S., Ochani M., et al. Acetylcholine-synthesizing T cells relay neural signals in a vagus nerve circuit. Science. 2011;334(6052):98–101. doi: 10.1126/science.1209985.

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