Clinical trial NCT06440122: The Incidence and Outcomes of Metabolically Active Brown Adipose Tissue (aBAT) in Patients With Pheochromocytoma or Paraganglioma (PPGLs)
Official title: The Incidence and Outcomes of Metabolically Active Brown Adipose Tissue (aBAT) in Patients With Pheochromocytoma or Paraganglioma (PPGLs)
Study type: OBSERVATIONAL
Overall status: RECRUITING
Conditions: Pheochromocytoma
Paraganglioma
Keywords: Brown Adipose Tissue
FDG-PET
Activation
Pheochromocytoma
Paraganglioma
Lead sponsor: King's College Hospital NHS Trust
Sponsor class: OTHER
First posted: 2024-06-03
Enrollment: 100
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Observational model: COHORT
Time perspective: RETROSPECTIVE
Sampling method: PROBABILITY_SAMPLE
Study population: Any patients with confirmed pheochromocytoma or paraganglioma treated at King's College Hospital NHS Foundation Trust Endocrinology department who underwent an FDG-PET scan.

Brief summary: White adipose tissue (WAT) and brown adipose tissue (BAT) form the main adipose tissue subtypes in humans and several animals. BAT, owing to its unique metabolic function, has been of increased focus and interest in metabolic research (1). BAT forms the major organ of non-shivering thermogenesis in the body, and is dependent on the large concentration of mitochondria and increased uncoupling protein-1 (UCP-1) activity present in this type of tissue (2). There are numerous triggers for the metabolic activation of BAT including cold temperature, low body mass index (BMI), adrenergic agonists, and elevated concentration of thyroid hormones (3).

BAT is found more abundantly in fetuses and infants, with significant regression into adulthood. The main areas where BAT can be found are the neck, mediastinum, axilla, retroperitoneum, and abdominal wall (4). Clinical research suggests that activation and thermogenesis in BAT are mediated by noradrenaline release from the sympathetic nervous system (5). With the increasing use of fluorodeoxyglucose positron emission tomography (18FDG-PET) imaging, there has been an increased detection rate of activated brown adipose tissue (aBAT); this may affect diagnoses and lead to false-positive reporting (6).

Phaeochromocytomas/paragangliomas (PPGLs) are chromaffin-cell-derived endocrine tumors that emerge from the adrenal medulla or extra-adrenal ganglia. High FDG accumulation has been commonly noted in aBAT in patients with catecholamine-producing tumours, with subsequent resolution of these findings after resection of the tumour (7). This finding is likely related to the increased glucose transport related to noradrenaline excess (4). BAT has traditionally been considered to mainly express β3-adrenoreceptors; however, in vitro studies have indicated that activated β2-adrenoreceptors may be the main driving force behind thermogenesis (8).

Studies reviewing PPGLs have shown an aBAT detection rate of 7.8% to 42.8% on FDG-PET imaging, correlating with elevated catecholamine levels but without clear correlation to germline mutations (9-12). In one study, this imaging finding was associated with a statistically significant reduction in overall survival (12). Standardisation for the 'standardised uptake value' (SUV) cut-offs for aBAT on FDG-PET are lacking, but these are often reported between 1.0 and 2.0 (13); in previous studies of PPGL, a cut-off value of \>1.5 has been employed (10, 12).

Research on the clinical implications of aBAT in patients with PPGL remains scarce. The main objectives of this study were to gain further insights into BAT activation rates in patients with PPGLs and how this may relate to patient demographics, biochemistry, radiological features, mutational status, and outcomes. The main hypotheses were that aBAT rates would be significantly linked to the severity of catecholamine excess and could be considered a poor prognostic feature.

Detailed description: References:

1. Santhanam P, Solnes L, Hannukainen JC, Taïeb D. Adiposity-related cancer and functional imaging of brown adipose tissue. Endocr Pract. 2015;21(11):1282-90.
2. Fenzl A, Kiefer FW. Brown adipose tissue and thermogenesis. Horm Mol Biol Clin Investig. 2014;19(1):25-37.
3. Marlatt KL, Ravussin E. Brown adipose tissue: An update on recent findings. Curr Obes Rep. 2017;6(4):389-96.
4. Iyer RB, Guo CC, Perrier N. Adrenal pheochromocytoma with surrounding brown fat stimulation. AJR Am J Roentgenol. 2009;192(1):300-1.
5. Bartness TJ, Vaughan CH, Song CK. Sympathetic and sensory innervation of brown adipose tissue. Int J Obes (Lond). 2010;34 Suppl 1(S1):S36-42.
6. Nedergaard J, Bengtsson T, Cannon B. Unexpected evidence for active brown adipose tissue in adult humans. Am J Physiol Endocrinol Metab. 2007;293(2):E444-52.
7. Terada E, Ashida K, Ohe K, Sakamoto S, Hasuzawa N, Nomura M. Brown adipose activation and reversible beige coloration in adipose tissue with multiple accumulations of 18F-fluorodeoxyglucose in sporadic paraganglioma: A case report. Clin Case Rep. 2019;7(7):1399-403.
8. Blondin DP, Nielsen S, Kuipers EN, Severinsen MC, Jensen VH, Miard S, et al. Human brown adipocyte thermogenesis is driven by β2-AR stimulation. Cell Metab. 2020;32(2):287-300.e7.
9. Wang Q, Zhang M, Ning G, Gu W, Su T, Xu M, et al. Brown adipose tissue in humans is activated by elevated plasma catecholamines levels and is inversely related to central obesity. PLoS One. 2011;6(6):e21006.
10. Puar T, van Berkel A, Gotthardt M, Havekes B, Hermus ARMM, Lenders JWM, et al. Genotype-dependent brown adipose tissue activation in patients with pheochromocytoma and paraganglioma. J Clin Endocrinol Metab. 2016;101(1):224-32.
11. Hadi M, Chen CC, Whatley M, Pacak K, Carrasquillo JA. Brown fat imaging with (18)F-6-fluorodopamine PET/CT, (18)F-FDG PET/CT, and (123)I-MIBG SPECT: a study of patients being evaluated for pheochromocytoma. J Nucl Med. 2007;48(7):1077-83.
12. Abdul Sater Z, Jha A, Hamimi A, Mandl A, Hartley IR, Gubbi S, et al. Pheochromocytoma and paraganglioma patients with poor survival often show brown adipose tissue activation. J Clin Endocrinol Metab. 2020;105(4):1176-85.
13. Sampath SC, Sampath SC, Bredella MA, Cypess AM, Torriani M. Imaging of brown adipose tissue: State of the art. Radiology. 2016;280(1):4-19.

Eligibility criteria: Inclusion Criteria:

* Patients with confirmed pheochromocytoma or paraganglioma who have undergone a FDG-PET as part of staging process.

Exclusion Criteria:

* Patients with any other neoplasm other than pheochromocytoma or paraganglioma

Primary outcomes:
measure: Number of patients with pheochromocytoma and metabolically active brown adipose tissue on FGD-PET scan
timeFrame: through study completion, an average of 1 year
measure: Number of patients with paraganglioma and metabolically active brown adipose tissue on FGD-PET scan
timeFrame: through study completion, an average of 1 year
Secondary outcomes:
measure: Metabolically active brown adipose tissue and presence of germ-line mutations (NHL) in patients with pheochromocytoma and paraganglioma
timeFrame: through study completion, an average of 1 year
measure: Metabolically active brown adipose tissue and presence of germ-line mutations (NF-1) in patients with pheochromocytoma and paraganglioma
timeFrame: through study completion, an average of 1 year
measure: Metabolically active brown adipose tissue and presence of germ-line mutations (MEN) in patients with pheochromocytoma and paraganglioma
timeFrame: through study completion, an average of 1 year
Other outcomes:
Locations:
city: London
country: United Kingdom
facility: King's College Hospital NHS Foundation Trust
state: United Kingdom Of Great Britain And Northern Ireland
Study officials:
affiliation: King's College Hospital NHS Trust
name: Georgios Dimitriadis
role: PRINCIPAL_INVESTIGATOR
References:
citation: Santhanam P, Solnes L, Hannukainen JC, Taieb D. ADIPOSITY-RELATED CANCER AND FUNCTIONAL IMAGING OF BROWN ADIPOSE TISSUE. Endocr Pract. 2015 Nov;21(11):1282-90. doi: 10.4158/EP15870.RA. Epub 2015 Aug 17.
citation: Fenzl A, Kiefer FW. Brown adipose tissue and thermogenesis. Horm Mol Biol Clin Investig. 2014 Jul;19(1):25-37. doi: 10.1515/hmbci-2014-0022.
citation: Marlatt KL, Ravussin E. Brown Adipose Tissue: an Update on Recent Findings. Curr Obes Rep. 2017 Dec;6(4):389-396. doi: 10.1007/s13679-017-0283-6.
citation: Iyer RB, Guo CC, Perrier N. Adrenal pheochromocytoma with surrounding brown fat stimulation. AJR Am J Roentgenol. 2009 Jan;192(1):300-1. doi: 10.2214/AJR.08.1166. No abstract available.
citation: Bartness TJ, Vaughan CH, Song CK. Sympathetic and sensory innervation of brown adipose tissue. Int J Obes (Lond). 2010 Oct;34 Suppl 1(0 1):S36-42. doi: 10.1038/ijo.2010.182.
citation: Nedergaard J, Bengtsson T, Cannon B. Unexpected evidence for active brown adipose tissue in adult humans. Am J Physiol Endocrinol Metab. 2007 Aug;293(2):E444-52. doi: 10.1152/ajpendo.00691.2006. Epub 2007 May 1.
citation: Terada E, Ashida K, Ohe K, Sakamoto S, Hasuzawa N, Nomura M. Brown adipose activation and reversible beige coloration in adipose tissue with multiple accumulations of 18F-fluorodeoxyglucose in sporadic paraganglioma: A case report. Clin Case Rep. 2019 Jun 11;7(7):1399-1403. doi: 10.1002/ccr3.2259. eCollection 2019 Jul.
citation: Blondin DP, Nielsen S, Kuipers EN, Severinsen MC, Jensen VH, Miard S, Jespersen NZ, Kooijman S, Boon MR, Fortin M, Phoenix S, Frisch F, Guerin B, Turcotte EE, Haman F, Richard D, Picard F, Rensen PCN, Scheele C, Carpentier AC. Human Brown Adipocyte Thermogenesis Is Driven by beta2-AR Stimulation. Cell Metab. 2020 Aug 4;32(2):287-300.e7. doi: 10.1016/j.cmet.2020.07.005.
citation: Wang Q, Zhang M, Ning G, Gu W, Su T, Xu M, Li B, Wang W. Brown adipose tissue in humans is activated by elevated plasma catecholamines levels and is inversely related to central obesity. PLoS One. 2011;6(6):e21006. doi: 10.1371/journal.pone.0021006. Epub 2011 Jun 20.
citation: Puar T, van Berkel A, Gotthardt M, Havekes B, Hermus AR, Lenders JW, van Marken Lichtenbelt WD, Xu Y, Brans B, Timmers HJ. Genotype-Dependent Brown Adipose Tissue Activation in Patients With Pheochromocytoma and Paraganglioma. J Clin Endocrinol Metab. 2016 Jan;101(1):224-32. doi: 10.1210/jc.2015-3205. Epub 2015 Nov 17.
citation: Hadi M, Chen CC, Whatley M, Pacak K, Carrasquillo JA. Brown fat imaging with (18)F-6-fluorodopamine PET/CT, (18)F-FDG PET/CT, and (123)I-MIBG SPECT: a study of patients being evaluated for pheochromocytoma. J Nucl Med. 2007 Jul;48(7):1077-83. doi: 10.2967/jnumed.106.035915. Epub 2007 Jun 15.
citation: Abdul Sater Z, Jha A, Hamimi A, Mandl A, Hartley IR, Gubbi S, Patel M, Gonzales M, Taieb D, Civelek AC, Gharib AM, Auh S, O'Mara AE, Pacak K, Cypess AM. Pheochromocytoma and Paraganglioma Patients With Poor Survival Often Show Brown Adipose Tissue Activation. J Clin Endocrinol Metab. 2020 Apr 1;105(4):1176-85. doi: 10.1210/clinem/dgz314.
citation: Sampath SC, Sampath SC, Bredella MA, Cypess AM, Torriani M. Imaging of Brown Adipose Tissue: State of the Art. Radiology. 2016 Jul;280(1):4-19. doi: 10.1148/radiol.2016150390.