Musculoskeletal Diseases

Nutritional and Metabolic Diseases

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Gland and Hormone Related Diseases

Neoplasms

Rare Diseases

Osteoporosis

Hyperparathyroidism

Hyperparathyroidism, Primary

Parathyroid Neoplasms

Bone Diseases

Bone Diseases, Metabolic

Metabolic Diseases

Parathyroid Diseases

Endocrine System Diseases

Endocrine Gland Neoplasms

Head and Neck Neoplasms

Primary Hyperparathyroidism

All Drugs and Chemicals

Parathyroid Hormone

Patients with primary hyperparathyroidism at diagnosis (HPT) treated with parathyroidectomy (HPT-PTX)

Biomarker assays

Sabrina Corbetta, PhD, MD

Sara Zacchetti

The PARABONE study aims to investigate the interaction between bone and parathyroid glands in patients with primary hyperparathyroidism (HPT). The study consists of a clinical part aimed at evaluating a series of circulating molecules of bone derivation (osteocalcin, molecules of the WNT pathway, RANKL, osteoprotegerin, Scelrostin, FGF23) in patients with HPT. In particular, the study has as its primary objective to identify the correlation between circulating levels of PTH and levels of GlaOC and GluOC in patients with HPT.

The parathyroid glands are responsible for controlling mineral homeostasis in order to keep circulating calcium levels constant by acting on the target organs, where they induce mobilization of calcium from the bone matrix, and they promote the reabsorption of calcium from the ultra-filtrate at renal level. In turn, kidney and bone can affect the functioning of the parathyroid glands, for example through the action of FGF23 secreted by osteocytes. Primary hyperparathyroidism (HPT) is an endocrine disorder that causes bone demineralization, osteoporosis and fragility fractures, representing a frequent cause of secondary osteoporosis. It is prevalent in postmenopausal women, where it is the third most frequent endocrine pathology after diabetes and thyroid disease. In postmenopausal women, the pattern of demineralization induced by estrogen deficiency may overlap with that secondary to HPT. HPT is sustained by tumors of the parathyroid glands, mainly of a benign nature, associated with inappropriate secretion of parathyroid hormone (PTH), which causes hypercalcemia and bone, kidney and cardiovascular complications. It is known that persistent secondary hyperparathyroidism, such as that induced by idiopathic hypercalciuria or malabsorption related to vitamin D deficiency, can stimulate the proliferation of parathyroid cells and the autonomous hypersecretion of PTH. Therefore, it is conceivable that also alterations in bone metabolism, such as a persistently increased release of osteocalcin (OC), can promote the proliferation of parathyroid cells and/or hypersecretion of PTH. Interestingly, the circulating levels of carboxylated and decarboxylated osteocalcin (GlaOC and GluOC) were found to be increased in patients with HPT. Furthermore, elevated circulating OC levels appear to be predictive of multiglandular disease in HPT patients. Osteoblasts are one of the main targets of PTH action and release biologically active molecules with paracrine and endocrine action, including osteocalcin (GlaOC and GluOC), the molecules of the intracellular signaling pathway WNT and the RANK ligand (Receptor Activator for Nuclear Factor-κB, RANKL). Therefore, it is conceivable that these biologically active molecules released by osteoblasts can induce biological effects of modulating the functioning of parathyroid cells, in a sort of bone-parathyroid regulatory loop, and thus modulate the presentation phenotype and clinical severity of HPT. RANKL and sclerostin are the specific targets of monoclonal anti-osteoporotic treatments currently available; therefore understanding their potential effect on parathyroid function in HPT can provide the rationale for new therapeutic approaches for patients with HPT. The expected results will allow to improve the diagnosis of HPT, in particular to better define the extent of bone compromise related to it, evaluating circulating bone markers so far not explored. The investigators therefore intend to clarify the effect of hormones released by osteoblasts on parathyroid function, taking into account that these hormones are the target of currently available anti-osteoporotic therapies. The translational study will therefore allow to identify new pathogenetic mechanisms in parathyroid tumorigenesis promoted by endocrine factors released by osteoblasts, which will be able to provide potential targets for targeted medical treatments.

Parathyroid tumor samples derived from patients undergoing excisional surgery and peripheral blood samples at diagnosis will be collected

The Bone-parathyroid Crosstalk in Primary Hyperparathyroidism

Interactions Between Bone and Parathyroid Tumors in Patiens With Primary Hyperparathyroidism (The PARABONE Study)

The study aims to investigate the effect of the circulating carboxylated osteocalcin isoform (GlaOC) on the biochemical phenotype in patients with HPT

Correlation between the clinical and biochemical characteristics of HPT patients with circulating levels of the two isoforms of osteocalcin and other hormones produced by bone (molecules of the WNT pathway, RANKL, Osteoprotegerin, Sclerostin, FGF23, IL-17). Analysis of the expression of circulating lncRNAs and microRNAs in patients with HPT in relation to the osteo-metabolic state. Analysis of the expression pattern of genes involved in parathyroid tumorigenesis and in bone-parathyroid crosstalk, lncRNAs and microRNAs in parathyroid cancer cells in order to further define the heterogeneity of the adenoma histotype in relation to the osteo-metabolic state.Define the biological effect of the hormones released from bone on parathyroid cancer cells. Define the biological effect and the interaction with the parathyroid function of the hormones released from bone in HEK293A models transfected with the CASR and / or transfected with the receptors of the molecules released by bone.

I.R.C.C.S Ospedale Galeazzi-Sant'Ambrogio

Adenoma

Neoplasms, Glandular and Epithelial

Neoplasms by Histologic Type

Patients will undergo a single fluorocholine PET imaging study prior to surgery.

One-time injection of 4-7 millicurie (mCi)

18F-Fluorocholine

Imaging technique that uses radioactive substances known as radiotracers to visualize and measure changes in metabolic processes, and in other physiological activities

Positron emission tomography (PET)

Daniel Thompson

UCSF Fluorocholine Team

Thomas Hope, MD

This is a prospective single arm single center Phase III study evaluating the ability of 18F-fluorocholine to detect the location of parathyroid adenomas.

PRIMARY OBJECTIVE:

I. To investigate the performance (accuracy) of 18F-fluorocholine PET in the detection of hyperfunctioning parathyroid glands in surgical patients with biochemically proven primary hyperparathyroidism.

OUTLINE:

Participants will receive a single dose of 18F-Fluorocholine at the time the participant undergoes a single imaging study using 18F-fluorocholine. Study related procedures will end after the study visit. Participants who undergo subsequent parathyroidectomy, will have the results reviewed and compared to the results from the imaging study

18F-Fluorocholine Positron Emission Tomography (PET) for the Detection of Parathyroid Adenomas

Sensitivity of 18F-fluorocholine PET for the detection of abnormal parathyroid adenomas confirmed by pathology as compared to sestamibi imaging. Location of parathyroid adenoma at imaging as read by three blinded readers, will be correlated to the location at surgery. True positive will be defined as an adenoma on imaging in the same location as seen at surgery. Sensitivity will be reported by individual reader.

Sensitivity of 18F-fluorocholine PET for the detection of abnormal parathyroid adenomas confirmed by pathology compared to a predefined threshold. Location of parathyroid adenoma at imaging as read by three blinded readers, will be correlated to the location at surgery. True positive will be defined as an adenoma on imaging in the same location as seen at surgery. Sensitivity will be reported by individual reader.

The detection rate of 18F-fluorocholine PET in participants who have not undergone surgical resection will be reported

Thomas Hope

Associate Professor

Hypercalcemia

Calcium Metabolism Disorders

Water-Electrolyte Imbalance

Bone Density Conservation Agents

Hormones

Calcium

Calcium, Dietary

For patients assigned to the study arm, the surgeon will use the PTeye as an intraoperative tool to identify if a suspect tissue is a parathyroid or not, during the parathyroid surgery.

The surgeon will proceed with the parathyroid surgery as usual, while relying solely on her/his surgical experience in identifying the parathyroid glands during the operations.

Parathyroid Eye (PTeye)

Brandon Yap

Quan-Yang Duh, MD, FACS

The goal of this study is to assess whether using PTeye (AiBiomed, Santa Barbara, CA) - a NIRAF detection modality - can improve patient outcomes and reduce healthcare associated costs after parathyroid surgeries. By being able to quickly and definitively locate parathyroid glands while in the operating room, the duration of surgical procedure could be further reduced. In addition, the number of frozen section biopsy and associated costs can be minimized. Furthermore, repeat surgeries as a result of missing a diseased parathyroid gland at the time of the initial parathyroidectomy for hyperparathyroidism could potentially be avoided.

This is a prospective, single-blinded, randomized study comparing the use of PTeye during parathyroidectomy to usual standard practice.

PRIMARY OBJECTIVES:

I. Assess the impact of PTeye on intra-operative identification of parathyroid tissues.

II. Assess the impact of PTeye on improving efficiency of parathyroid surgeries.

III. Assess the impact of PTeye on minimizing risk of post-surgical complications.

Participants will be randomized to either the experimental or control arm.

The surgeon will first take 5 baseline NIRAF measurements on the thyroid gland (or neck muscles, if thyroid is absent) using the disposable sterile fiber probe that is connected to the PTeye console, as per device functionality requirements. The subsequent step would involve touching the target tissue in the neck with the fiber optic probe, following which the PTeye will indicate to the surgeon if the tissue is likely parathyroid or not.

For patients assigned to the control arm, the surgeon will not use the PTeye and will proceed with the parathyroid surgery as usual, while relying solely on her/his surgical experience in identifying the parathyroid glands during the operations.

Participants will be follow-ed up for up to 6 months after surgery.

Only participants will be masked to the intervention

Near Infrared Autofluorescence (NIRAF) Detection for Identifying Parathyroid Glands During Parathyroidectomy

Evaluating Impact of Near Infrared Autofluorescence (NIRAF) Detection for Identifying Parathyroid Glands During Parathyroidectomy

Number of frozen sections (or PTH aspirate) sent for analysis during the Parathyroidectomy (PTx) procedure to confirm potential parathyroid tissue

Failure of intra-operative parathyroid hormone (PTH) to normalize (defined as failure of PTH to drop \> 50% of its baseline value at final intra-operative PTH assay and/or failure of PTH to drop \< 65 pg/ml or 6.9 pmol/L). Participants will be categorized as having persistent hyperparathyroidism (Immediate) Yes or No.

Elevated blood calcium levels (total blood calcium level \> 10.5 mg/dL or 2.6 mmol/L) with/without elevated parathyroid hormone (PTH) (serum intact PTH \> 65 pg/ml or 6.9 pmol/L) at first postoperative visit. Participants will be categorized as having persistent hyperparathyroidism or hypercalcemia (transient) Yes or No.

If blood calcium with/without parathyroid hormone (PTH) has not normalized at 1st post-operative visit, calcium and/or PTH is subsequently measured as necessary. Patient is defined to have a failed parathyroidectomy if hypercalcemia/hyperparathyroidism (defined as total blood calcium level \> 10.5 mg/dL or 2.6 mmol/L, with/without elevated serum intact PTH \> 65 pg/ml or 6.9 pmol/L) persists at or after the 6th postoperative month. Participants will be categorized has having persistent hyperparathyroidism or hypercalcemia (failed parathyroidectomy), Yes or No.

Overall number of parathyroid glands identified (Experimental Group: Glands identified with naked eye + NIRAF;Control Group: Glands identified with naked eye)

Median number of parathyroid glands identified with NIRAF, which was not seen with surgeon's naked eye

Median number of diseased parathyroid glands identified intra-operatively versus glands localized preoperatively using sestamibi, Computerized tomography (CT) or ultrasound

Median number of intra-operative parathyroid hormone assays per person sent during the procedure to the lab

Median duration in minutes taken to identify 1st parathyroid gland in PTx procedure - timed from skin incision to finding PG

Median duration taken to identify last parathyroid gland in PTx procedure - timed from skin incision to finding the last PG

Median duration of PTx procedure - timed from skin incision until the surgeon notifies the anesthesia team to awaken the patient in minutes

Median time in minutes taken for PTH to attain cure criteria or normalize - timed from skin incision until the PTH levels drops \> 50% of its baseline value and/or PTH drops \< 65 pg/ml or 6.9 pmol/L

Number of nights spent for postoperative recovery in the hospital after the surgical procedure

Median number of tissues per person that were excised by surgeon assumed to be parathyroid tissue, but is later validated as nonparathyroid tissue (false positive) by histology

Number of doctor visits/emergency department visits or hospital admissions due to persistent hypercalcemia and/or associated symptoms after parathyroidectomy procedure will be categorized as binary (yes or no)

Number of patients with repeat PTx procedure performed after the current procedure will be categorized as binary (yes or no)

Vanderbilt University Medical Center

National Cancer Institute (NCI)

University of California, San Francisco

Imaging technique that uses radioactive agents known as radiotracers to visualize and measure changes in metabolic processes, and in other physiological activities

Positron Emission Tomography (PET)

The investigators are studying the ability of F18 labeled fluorocholine PET to localize parathyroid adenomas in patients with hyperparathyroidism prior to surgery.

18F-Fluorocholine for the Detection of Parathyroid Adenomas

The true positive (sensitivity) rate is defined as the proportion of participants with location of the suspected adenoma on 18F-Fluorocholine PET correlating with location of an abnormal parathyroid at time of participant surgery. For a patient with multiple hyperplastic glands, only one gland needs to correlate for the patient to count as a true positive. For analysis, adenomas described as arising in the mid thyroid bed will considered correct if located in either the inferior or superior bed. Patients will be followed-up to determine if they undergo a parathyroidectomy for up to 1 year.

The true positive (sensitivity) rate is defined as the proportion of participants with location of the suspected adenoma on 18F-Fluorocholine PET correlating with location of an abnormal parathyroid at time of participant surgery. For a patient with multiple hyperplastic glands, only one gland needs to correlate for the patient to count as a true positive. In patients who had a sestamibi study performed prior to the fluorocholine imaging study, the original dictated report from the sestamibi will be used for comparison. For analysis, adenomas described as arising in the mid thyroid bed will considered correct if located in either the inferior or superior bed. Patients will be followed-up to determine if they undergo a parathyroidectomy for up to 1 year.

The detection rate is defined as the proportion of participants with a 18F-fluorocholine PET positive read who do not subsequently undergo parathyroidectomy, using the dictated reports to determine the detection sensitivity for parathyroid adenomas. Patients will be followed-up to determine if they undergo a parathyroidectomy for up to 1 year.

Associate Professor, Radiology

Patients will undergo a single fluorocholine PET imaging study prior to surgery.

18F-Fluorocholine: Given intravenously

Positron Emission Tomography (PET): Imaging technique that uses radioactive agents known as radiotracers to visualize and measure changes in metabolic processes, and in other physiological activities

18F-Fluorocholine PET

Age, Continuous

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

United States

Region of Enrollment

Prior History of Parathyroidectomy at Baseline

Dr. Thomas A. Hope, MD

Proportion of True Positives for the Overall Detection of the Abnormal Parathyroid Adenoma

Only 66 of the 77 participants who underwent surgery had an available sestamibi study

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
The Bone-parathyroid Crosstalk in Primary Hyperparathyroidism	NCT05556499	Hyperparathyroi... Osteoporosis Parathyroid Neo...	Biomarker assay...	18 Years -	I.R.C.C.S Ospedale Galeazzi-Sant'Ambrogio
18F-Fluorocholine Positron Emission Tomography (PET) for the Detection of Parathyroid Adenomas	NCT04895631	Hyperparathyroi...	18F-Fluorocholi... Positron emissi...	13 Years -	University of California, San Francisco
Near Infrared Autofluorescence (NIRAF) Detection for Identifying Parathyroid Glands During Parathyroidectomy	NCT05152927	Parathyroid Dis... Parathyroid Dys... Parathyroid Neo... Parathyroid Ade... Hypercalcemia Neoplasms, Glan... Endocrine Gland... Adenoma Hyperparathyroi... Hyperparathyroi...	Parathyroid Eye...	18 Years -	University of California, San Francisco
The Bone-parathyroid Crosstalk in Primary Hyperparathyroidism	NCT05556499	Hyperparathyroi... Osteoporosis Parathyroid Neo...	Biomarker assay...	18 Years -	I.R.C.C.S Ospedale Galeazzi-Sant'Ambrogio
18F-Fluorocholine for the Detection of Parathyroid Adenomas	NCT03764007	Hyperparathyroi...	18F-Fluorocholi... Positron Emissi...	13 Years -	University of California, San Francisco

Spots Global Cancer Trial Database for hyperparathyroidism, primary