Amyloid Proteins From Medullary Thyroid Cancer and Laryngeal Amyloidosis

NCT04760171 | Not Yet Recruiting

• 1 other identifier: EN21/138414
• Study Type: observational
• Target: 10
• Locations: 0 countries
• Sites: N/A

Brief Summary

Using excess tumour samples that contain amyoid, from patients with Medullary Thyroid Cancer, we aim to determine the structures of ex vivo amyloid fibrils from human tumour tissue samples and compare them with that of existing stock of in vitro formed amyloid fibrils. This will permit the analysis of the effects of gene mutation and post-translational modification on the development of amyloid from a disease state. Amyloid is known to accumulate in the brain tissue of patients with neuro-degenerative conditions such as Alzheimer's disease and Dementia. Therefore solving the structure of amyloid fibrils may aid the development of future treatments for these conditions.

Conditions

Amyloid; Medullary Thyroid Cancer; Alzheimer Disease; Dementia

Outcome Measures

Primary Outcomes (5)

• Amyloid extraction by tissue homogenization and centrifugation

  A standard laboratory technique for subsequent analysis

  12-24 months

• Transmission electron microscopy

  To characterize the gross features of the extracted amyloid fibrils at low resolution (\>20Å). This relatively simple procedure allows for quick characterization of the samples in order to optimize them for Atomic Force Microscopy (AFM) and Cryo-Electron Microscopy (Cryo-EM).

  12-24 months

• Atomic force microscopy

  To characterize helical parameters of the amyloid fibrils needed to calculate the structure from Cryo-EM data.

  12-24 months

• Cryo-electron microscopy (Cryo-EM)

  To elucidate the structure of the amyloids extracted from tissue affected in each disease

  12-24 months

• Mass spectrometry

  Analysis to identify and characterize the most prominent proteins present in the amyloid deposits and their possible post-translational modifications.

  12-24 months

Study Arms (1)

Group 1

Patients diagnosed with medullary thyroid cancer (MTC) who are undergoing standard surgical treatment for their disease. This will be either hemithyroidectomy or total thyroidectomy. Patients with laryngeal amyloidosis (LA) who are undergoing standard surgical treatment of this disease. This will be microlaryngoscopy \& biopsy/debulking

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Age Groups: Adult (18-64), Older Adult (65+)
• Sampling Method: Non-Probability Sample

Study Population

Patients with MTC, who have been recommended via the Thyroid Multi-Disciplinary team meeting, to undergo hemi or total thyroidectomy surgery. Patients with LA, who agree with their surgeon, to undergo surgical treatment of that condition

You may qualify if:

• Diagnosed with known or suspected MTC or LA
• Age \>= 18 years, no upper age limit
• For MTC patients, treatment recommendation from the Thyroid MDT is for either hemithyroidectomy or total thyroidectomy
• for LA patients, agreement with their attending clinician to undergo surgical debulking of disease under general anaesthetic. The procedure is called 'microlaryngoscopy and biopsy/debulking'

You may not qualify if:

• No known or suspected diagnosis of MTC or LA
• Age \<18 years
• Unable to provide informed consent
• Treatment recommendation from Thyroid MDT is for any treatment excluding primary surgery (ie palliation, best supportive care, chemotherapy, radiotherapy etc)
• For LA patients, no agreement between patient and attending clinician to proceed with surgery as primary treatment.

Sponsors & Collaborators

• The Leeds Teaching Hospitals NHS Trust: lead
• University of Leeds: collaborator

Related Publications (4)

• GBD 2016 Neurology Collaborators. Global, regional, and national burden of neurological disorders, 1990-2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet Neurol. 2019 May;18(5):459-480. doi: 10.1016/S1474-4422(18)30499-X. Epub 2019 Mar 14.

  PMID: 30879893 BACKGROUND

• Knowles TP, Vendruscolo M, Dobson CM. The amyloid state and its association with protein misfolding diseases. Nat Rev Mol Cell Biol. 2014 Jun;15(6):384-96. doi: 10.1038/nrm3810.

  PMID: 24854788 BACKGROUND

• Gallardo R, Iadanza MG, Xu Y, Heath GR, Foster R, Radford SE, Ranson NA. Fibril structures of diabetes-related amylin variants reveal a basis for surface-templated assembly. Nat Struct Mol Biol. 2020 Nov;27(11):1048-1056. doi: 10.1038/s41594-020-0496-3. Epub 2020 Sep 14.

  PMID: 32929282 BACKGROUND

• Gallardo R, Ranson NA, Radford SE. Amyloid structures: much more than just a cross-beta fold. Curr Opin Struct Biol. 2020 Feb;60:7-16. doi: 10.1016/j.sbi.2019.09.001. Epub 2019 Nov 1.

  PMID: 31683043 BACKGROUND

Biospecimen

Retention: SAMPLES WITH DNA

Excess tumour tissue resected from patients with known medullary thyroid cancer, or, laryngeal amyloidosis.

MeSH Terms

Conditions

Alzheimer Disease; Carcinoma, Medullary; Dementia

Condition Hierarchy (Ancestors)

Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Tauopathies; Neurodegenerative Diseases; Neurocognitive Disorders; Mental Disorders; Carcinoma, Neuroendocrine; Neuroendocrine Tumors; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Adenocarcinoma; Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms, Ductal, Lobular, and Medullary; Neoplasms, Nerve Tissue

Study Officials

• James Moor, FRCS

  Leeds Teaching Hospitals NHS Trust

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Anne Gowing

CONTACT

+441132060469; anne.gowing@nhs.net

Study Design

• Study Type: observational
• Observational Model: COHORT
• Time Perspective: PROSPECTIVE
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: February 10, 2021
• First Posted: February 18, 2021
• Study Start: February 1, 2021
• Primary Completion: February 1, 2023
• Study Completion: February 1, 2026
• Last Updated: February 18, 2021

Record last verified: 2021-02

Data Sharing

• IPD Sharing: Will not share