Conditions: Hyperparathyroidism Hypercalcemia Parathyroid Neoplasm Multiple Endocrine Neoplasia MEN1
Keywords: Hypoglycemia Genetics Hyperparathyroidism
Allocation: NON_RANDOMIZED | Intervention model: PARALLEL
Enrollment: 1553
Healthy volunteers: no

Brief summary:
Observational Phase: Patients whose parathyroid activity is elevated above normal are referred to as having hyperparathyroidism. This study will help researchers better understand the causes of hyperparathyroidism and to evaluate and improve methods for diagnosis and treatment. Patients diagnosed with or suspected of having hyperparathyroidism will be selected to participate. In addition, patients with related conditions, such as parathyroid tumors, will also be selected.

Subjects will be asked to provide blood and urine for testing to confirm their condition. They will then be surgically treated by removal of the parathyroid gland(s) (parathyroidectomy). Subjects with parathyroid tumors will undergo several diagnostic tests to determine the exact location of the tumor as well as the tumor's activity. The tests may include; ultrasounds, nuclear scanning, CT scans, MRI, and specialized blood testing.

Sometimes parathyroidectomy leads to hypoparathyroidism. Options for treating the patients after the surgical procedure will also be addressed. Calcium and Vitamin D supplements are typically the mainstay of post parathyroidectomy therapy. Other potential treatments include transplanting the parathyroid gland(s) to other areas of the body.

Clinical Trial: An imaging substudy was added to this protocol in 2018. Patients with multiple endocrine neoplasia type 1 (MEN1) will have 68Gallium-Dotatate Positron Emission Tomography (PET) - Computed Tomography (CT), 18F-DOPA PET/CT, MRI, and CT scans and the number of lesions detected by each of these types of scans will be compared.

Detailed description:
Observational: Patients with confirmed or suspected primary hyperparathyroidism or complications therefrom (such as postoperative hypoparathyroidism) will be admitted for diagnosis and treatment. The principal diagnostic components are calcium in serum and urine, parathyroid hormone in serum, and mutation tests on germline or tumor DNA. Patients with moderate to severe primary hyperparathyroidism will be treated. Treatment will be mainly by parathyroidectomy. Other options are medications or no intervention. Patients with a hyperparathyroid syndrome may be managed for their extraparathyroid features. Preoperative testing to localize parathyroid neoplasm(s) will be used usually and with more extended methods in cases with prior neck surgery. Preoperative tumor localization tests will be selected according to clinical indications from the following: ultrasound, technetium-thallium scan, computerized tomography, magnetic resonance imaging, fine needle aspiration for parathyroid hormone assay, selective arteriogram, selective venous catheterization for parathyroid hormone assay. Options for management of postoperative hypocalcemia include calcium, vitamin D analogs, parathyroid autografts and synthetic parathyroid hormone. Research specimens may consist of blood or tumors.

Clinical Trial: An imaging substudy was added to this protocol in 2018. Patients with MEN1 will have 68Ga-Dotatate PET/CT, 18F-DOPA PET/CT, MRI, and CT scans and the number of lesions detected by each of these types of scans will be compared.

Arms:
arm 1: Patients with confirmed or suspected primary hyperparathyroidism or complications arm 2: Patients scanned using imaging agents 68GALLIUM-DOTATATE and 18F-DOPA

Interventions: intervention 1: 68Ga-Dotatate intervention 2: 18F-DOPA
Intervention descriptions: intervention 1: 68Ga-Dotatate PET/CT will be administered prior to a PET/CT scan to detect known and occult primary and metastatic bronchial, gastrointestinal and pancreatic neuroendocrine tumors. intervention 2: 18F-DOPA PET/CT will be administered prior to a whole-body scan to detect known and occult primary and metastatic bronchial, gastrointestinal and pancreatic neuroendocrine tumors.

Protocol document:
Prot_SAP_000.pdf: 
1
CLINICAL RESEARCH PROTOCOL
NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES
DATE: December 17, 2020
 PROTOCOL NUMBER: 91-DK-0085
[IND] [IDE] NO:  Appx. C substudy: 119098 and 35513
TITLE: STUDIES OF HYPERPARATHYROIDISM AND RELATED CONDITIONS
SHORT TITLE: HYPERPARATHYROIDISM
IDENTIFYING WORDS: PTH, MEN1, CASR, FHH, CDC73, HRPT2, IMAGING, CANCER, 
CALCIUM, BONE, NEPHROLITHIASIS, OSTEOPOROSIS
PRINCIPAL INVESTIGATOR:  Smita Jha, M.B.B.S.; MDB, NIDDK
          Metabolic Diseases Branch, NIDDK
          National Institutes of Health
          Clinical Research Center 
          Bldg. 10, RM 9C432A
          Tel: (301)- 827- 1930         
Email: smita.jha@nih.gov        
ESTIMATED DURATION OF STUDY: 40 Years
START DATE:
1991
END DATE:
2031


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NUMBER AND TYPE OF PATIENTS: 
Number
Sex
Age Range
Patients
Indef         M & F
 all
Volunteers
none
PROJECT USES IONIZING RADIATION:
__x__Medically indicated  
__x__Research radiation under imaging substudy (Appendix C) with separate consent form:  
The Radiation Safety Committee has reviewed and approved radiation use in this study 
(RAD Authorization # RA2682)
PROJECT USES "DURABLE POWER OF ATTORNEY":  
NO
OFF-SITE PROJECT: 
NO
MULTI-INSTITUTIONAL PROJECT:
NO
PROJECT (Appendix C substudy only) DOES INVOLVE AN IND/IDE:
IND/IDE Number: 68Ga-DOTATATE will be administered under IND # 119098.  
For Ga68 DOTATE the IND sponsor is: NIH Clinical Center; the Sponsor’s Authorized Representative 
is: Gini Guptill, PhD.
 
IND/IDE Number: [18F]-DOPA is administered under # 35513. 
For [18F]-DOPA the IND sponsor is: NIH Clinical Center; the Sponsor’s Authorized Representative is: 
Gini Guptill, PhD.
Précis: Patients with confirmed or suspected primary hyperparathyroidism or complications therefrom 
(such as postoperative hypoparathyroidism) will be admitted for diagnosis and treatment. The principal 
diagnostic components are calcium in serum and urine, parathyroid hormone in serum, and mutation 
tests on germline or tumor DNA. Patients with moderate to severe primary hyperparathyroidism will be 
treated. Treatment will be mainly by parathyroidectomy. Preoperative testing to localize parathyroid 
neoplasm(s) will be used usually and with more extended methods in cases with prior neck surgery.  
Other options are medications or no intervention. Patients with a hyperparathyroid syndrome may be 
managed for their extraparathyroid features (medical management or surgical treatment). Preoperative 
tumor localization tests will be selected according to clinical indications from the following: ultrasound, 
technetium-thallium scan, computerized tomography, magnetic resonance imaging, somatostatin 
receptor imaging, fine needle aspiration for parathyroid hormone assay, selective arteriogram, and 
selective venous catheterization for parathyroid hormone assay. Options for management of 
postoperative hypocalcemia include calcium, vitamin D analogs, parathyroid autografts and synthetic 
parathyroid hormone. Research specimens may consist of blood or tumors. In addition, a substudy for 
patients with multiple endocrine neoplasia type 1 (MEN1) will assess the utility of two PET/CT scans 
with radiotracers (68Gallium-DOTATATE and 18F-DOPA) as indicated in Appendix C. 


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Introduction: Primary hyperparathyroidism is a common disorder (1, 2, 3). Its complications include 
generalized weakness and fatigue, kidney stones, bone thinning and bone fracture. As a sporadic disease, 
it is commonest in postmenopausal women. It can also occur on a hereditary basis (4), the five 
commonest of these being familial isolated hyperparathyroidism (FIHP), multiple endocrine neoplasia 
type 1 (MENl) (5), familial hypocalciuric hypercalcemia (FHH), hyperparathyroidism-jaw tumor 
syndrome (HPT-JT) and multiple endocrine neoplasia type 2A (MEN2A). Primary hyperparathyroidism 
can often be cured by removal of one or more parathyroid tumors (these are almost always benign) (1). 
But many patients with mild disease might be followed for long periods of time without any intervention 
(2, 3).
Objectives: The purpose of this study is to understand the causes of primary hyperparathyroidism, to 
evaluate and improve methods for diagnosis and treatment, and to provide insight into the mechanisms 
of normal parathyroid function. Hereditary causes of primary hyperparathyroidism will be characterized. 
Methods of pre-operative parathyroid gland localization will be evaluated (6, 7, 8). Genes that contribute 
to development of parathyroid tumors will be analyzed (4, 9, 10).
Subjects: Patients (male or female any age) with known or suspected primary hyperparathyroidism or a 
related disorder (such as MENl) will be evaluated. There are no absolute exclusions. The vast majority 
of patients will be greater than age 18. In the rare occasion where special resources might be appropriate 
(uremic patient, young child), the availability of special resources would be confirmed prior to 
admission.
Study Design:
Initial outpatient workup not necessarily at NIH will include tests deemed necessary to diagnose primary 
hyperparathyroidism and to make preliminary assessment of its severity. The essential elements of this 
workup include measurement of calcium, phosphorus, and creatinine in serum and also measurement of 
parathyroid hormone by immunoassay in serum. Other features may include evaluation of family 
history, urinary calcium, bone density and evaluations relating to kidney stones. This workup will often 
have been partly done by the referring physician prior to admission to NIH.
Currently enrolled patients or patients in long-term follow up will receive a “Patient History Intake 
Form” via a secure electronic web application such as a REDCap, to be completed prior to inpatient 
admission or visit. This form will mainly be used to capture new medications that may interfere with 
testing, changes in family history, or new symptoms. This will allow the principal investigator and study 
team to better structure the visits and schedule the proper tests. 
Evaluation at NIH has six goals; (a) evaluate the diagnosis and severity of presumed primary 
hyperparathyroidism, (b) evaluate the indications for parathyroid surgery, (c) conduct the appropriate 
preoperative parathyroid gland localization tests, (d) treat primary hyperparathyroidism, (e) treat extra-
parathyroid associated conditions, and (f) collect data and specimens for research.
Informed Consent:
The following sections describing informed consent processes apply to any consent form on this study, 
including the standard study consent and the consent for the research imaging substudy described in 
Appendix C. The subset of patients who participate in the research imaging substudy will be consented 
to both the standard and research imaging substudy consent forms.


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One of the investigators on this protocol marked on page 1 with an asterisk will obtain informed consent 
from patients participating in this study. The consent discussion will review the scope of the study as 
well as the risks, benefits, and limitations of participating, and the patient will have the opportunity to 
ask questions about the protocol and/or consent. The investigator will also review with the participant 
the option to indicate on the standard consent form those family members with whom the research team 
may share genetic test results in the event that the subject becomes deceased or incapacitated, and the 
investigator will facilitate decision-making with regard to receiving or opting out of incidental findings 
in order to be sure that the participant fully understands the decision, the potential consequences, and the 
ability to alter this decision in the future by re-consenting. Informed consent will be obtained before any 
study-related procedures are performed, and this typically occurs upon admission of the patient to the 
clinical center.
The consent form will be completed and signed by the patient and the investigator obtaining the 
informed consent. A copy of the completed consent will be given to the patient to keep for his or her 
records. The original signed consent will be transmitted to the Medical Records Department for 
placement in the subject’s permanent Clinical Center medical record. The informed consent process, 
including its time and date, will be documented in a progress note, and a copy of the note and the signed 
informed consent will be filed in the subject’s electronic medical record.
Consent by Telephone:
A participant’s initial informed consent will rarely, if ever, be obtained by telephone because 
participants in this study typically come to the NIH as patients and the consent process occurs in-person 
in the clinical center. The telephone consent process would be used primarily for re-consenting 
participants to the study. 
The subject will receive a copy of the protocol consent in the mail prior to being consented. After he or 
she has had an opportunity to review the consent, the investigator will contact the subject by telephone. 
The investigator will review the investigational nature of the protocol with the subject and answer 
questions for the subject. If the subject chooses to participate, the subject will sign and date the consent 
form. The informed consent documents will be mailed to the principal or associate investigator who led 
the discussion, who will sign and date and mail back a copy for the subject’s records. The original 
signed consent will be transmitted to the Medical Records Department for placement in the subject’s 
permanent Clinical Center medical record. The informed consent process, including its time and date, 
will be documented in a progress note, and a copy of the note and the signed informed consent will be 
filed in the subject’s electronic medical record.
Consent for Spanish Speakers:
A Spanish version of the standard consent, assent, and research imaging substudy consent forms have 
been acquired from the NIH Library translation service. These will be used for obtaining informed 
consent from Spanish-speaking subjects, whether in-person or by phone, if they prefer using Spanish 
instead of English for that process. An interpreter or interpretation telephone service will be used to 
facilitate the consent discussion when needed. If there are significant changes to the consent form of this 
study in the future, then this might require an updated translation of these Spanish forms, which could 
result in a delay between the approval of that amendment to the standard English consent and the 


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approval of the updated Spanish version of the consent and/or assent; in that situation, the short form 
consent process described below would be used in the interim.


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Consent for Non-English Speakers:
We do not plan or anticipate the enrollment of non-English speaking subjects. However, they are not 
excluded from participation either. If there is unexpected enrollment of a research participant for which 
there is no translated extant IRB-approved consent document, the Principal Investigator and/or those 
authorized to obtain informed consent will use the short form consent process as described in MAS 
Policy M77-2, NIH SOP 12, and 45 CFR 46.117 (b) (2), and 21 CFR 50.27 (b) (a). The summary that 
will be used is the English version of the extant IRB-approved consent document. We request 
prospective IRB approval of the use of the short form consent process for up to a maximum of 5 
requests (either for individual participants or families of participants) in a given language, and will 
notify the IRB at the time of continuing review of the frequency of the use of the short form. Should we 
reach the threshold of 5 subjects and/or families speaking a single language, we will request an 
additional use of the short form from the IRB and will notify the Board that we plan to have any consent 
documents frequently used with that population translated into the language(s) they speak.
Participation of NIH employees:
NIH employees may participate in this study, although they will not be specifically targeted or solicited 
for participation. Neither participation nor refusal to participate as a subject in the research will have any 
effect, either beneficial or adverse, on the participant’s employment or position at NIH. Given the nature 
of this study, there is no foreseeable risk that research outcomes will be influenced by the inclusion of 
employees; however, in order to protect employee subjects’ privacy and confidentiality of medical 
information, additional precautions will be taken for these subjects. 
Employees who are considering enrolling in the study will be provided with the NIH Information Sheet 
on Employee Research Participation (NIH HRPP SOP 14F Appendix B) to help them understand the 
possible consequences. The consent session with an NIH employee will begin with a discussion of any 
potential issues that either party could see arising, the subject’s concerns or feelings related to any such 
issues, the subject’s right to refuse participation or raise a concern at any time without impact on 
employment, the safeguards in place to protect the patient’s privacy and confidentiality, and the 
limitations of those protections. Study staff will be trained that communication of any personal or 
medical information about a subject (especially an NIH employee), including the fact that they are 
participating in this study, should be restricted to those investigators who need to know this information, 
and such information will not be discussed with anyone outside of the study without permission from the 
subject. If the employee is within the same branch, section, or unit such that the individual obtaining 
consent is a supervisor or co-worker, then independent monitoring of the consent process will be 
included, as outlined in SOP 14F. 
Obtaining Consent for Minors:
The signature of a single parent or guardian will be required when obtaining consent for minors, 
consistent with category of research approvable under 45 CFR 46.405 since this research presents the 
prospect of direct benefit to the participant, such as the early detection of a neoplasm in the subject or 
identification of a predisposition to develop such neoplasms. The investigator and the parent/guardian 
will decide if the minor is capable of providing assent. If the minor is determined to be capable of doing 
so, then his or her refusal to participate will be respected. An Ethics Consult will be arranged to 
determine the appropriate course of action if it occurs that such a minor refuses to participate but the 
parent/guardian and the investigator agree that participation in the study is in the minor’s best interest 
because the research presents a prospect of direct benefit that is important to the health or well-being of 


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the child and is available only in the context of the research. If the minor is determined to be capable of 
understanding the standard consent form, then the standard consent will be used for the informed 
consent process; however, the minor will still read and sign the assent form and the standard consent 
form will be signed by the parent/guardian.
As with any participant in this study, research samples and data obtained from minors will continue to 
be stored and used for research as described in the protocol, even if the minor’s direct involvement with 
the study has ended, unless a parent/guardian or the participant himself/herself, having since reached the 
age of majority, specifically requests in writing that these samples and/or data be destroyed. If a 
participant who was consented as a minor reaches the age of majority, then he or she will be re-
consented if there is an ongoing or new interaction between the participant and the research team, which 
would make re-consent a practical exercise. Minors who reach the age of majority will not be 
specifically contacted for re-consent as adults unless there is another reason to attempt re-contact, such 
as the investigators’ interest in using the participant’s sample in a manner that is beyond the scope of the 
protocol version to which the participant consented, and in such a case, if the participant cannot be re-
contacted, then this may fall under the waiver of consent described in this protocol.
Waiver of Consent for NGS Analysis on Archived Specimens from Subjects We Cannot Re-Contact for 
Re-Consent:
A waiver of informed consent will be utilized for performing next-generation sequencing analysis, such 
as genome-wide testing as described in the “Testing DNA and RNA” section, on archived samples from 
subjects previously consented to the study who are not able to be contacted for re-consent if 1) such 
analysis of the sample is believed by the investigators to be critical to the research being done, 2) the 
extensive, documented efforts by the research team to re-contact the participant reveal that the 
participant is a) deceased or b) not able to be contacted using the information available to the research 
team, and 3) the request to use the waiver of consent for that individual, submitted to the IRB for 
expedited review, is approved. Such a circumstance meets the requirements for a waiver of informed 
consent because the research involves no more than minimal risk to the subjects as the gene testing is for 
research and will not affect patient care, it will not adversely affect the rights and welfare of the subjects 
since the results and data will be kept confidential, the research could not practicably be carried out 
without the waiver since the purpose of the waiver is to allow important research testing on samples 
deemed critical to the research, and, if it happened that a subject contacted the research team after the 
waiver was used, then, whenever appropriate, the subject would be provided with the pertinent 
information and given the option to re-consent.
It should be noted that, in almost any conceivable circumstance, it would be advantageous for our study 
to successfully re-contact subjects in order to re-consent them before proceeding with NGS analysis of 
archived specimens. This would be advantageous not only for informing the participant and following 
his or her wishes, but also for confirming, clarifying, or updating the phenotype and family history 
information before committing the significant time and resources involved with NGS analysis of a 
specimen. Therefore, the waiver of consent is only intended to be used in the case that the subject cannot 
be contacted despite the extensive efforts outlined below and the investigators are confident that analysis 
of the archived specimen is critical to the research question being studied.
In order to re-contact a subject, we will give our best effort and use all of the contact information 
available to us in the NIH medical record and in our office files.


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Re-Contact Procedure:

An investigator on the protocol will begin by calling the telephone number(s) listed for the 
subject in the electronic medical record and, if there is no answer, leaving a voicemail if possible 
to elicit a call back. In order to protect the subject’s privacy, the voicemail will not include the 
name or topic of the study. Although the investigator may try calling the same number a second 
or third time at a different time of day, or day of the week, a voicemail will not be left every 
time.

If there is an e-mail address listed for the subject, then an e-mail will be sent as well.

An internet search may be performed to look for a public listing or obituary fitting the subject. 
The information from such a search, such as a telephone number, address, or obituary indicating 
the patient is deceased, will only be used if it is specific enough to our subject such that the 
investigator is confident that it belongs to the subject.

At this point, additional contact information that is documented in our office records from 
previous interactions with the subject, such as a telephone number or email address different 
from those listed in CRIS, will also be used. 

If necessary, a letter will also be sent by surface mail to the subject’s street address listed in the 
medical record or in our office records. The letter will not contain the name or topic of the study.

If these attempts to re-contact the subject are not successful, then the investigator will use the 
telephone numbers listed in the medical record for the subject’s 
o
next of kin, 
o
emergency contact, and 
o
physician(s) to receive reports, 
so as to ask for updated contact information for the subject. Once again, a voicemail will be left, 
when possible, if there is no answer. Voicemails and correspondence with these individuals will 
involve the minimal amount of information adequate to convey the appropriateness and 
importance of the inquiry while still protecting the subject’s privacy by not disclosing the name 
or topic of the study (i.e., the caller is a researcher from the NIH trying to get in contact with the 
subject who has participated in our study in the past, and, while it is not an emergency, it is 
important that the study team get in contact with the subject as soon as possible). If one of these 
sources provides updated contact information for the subject, then that information will be used 
next.
The investigators will document each step in the effort to re-contact a subject, and this information will 
be retained in a corresponding office file. After all of the above resources are exhausted, the 
investigators will wait an additional month after the last voicemail, e-mail, or letter was sent, in order to 
allow further time for return of contact, before considering the subject as unable to be re-contacted and 
the waiver of consent to be appropriate. If at any point during this process the investigator gathers 
reliable information that the subject is deceased, then this will be documented and the effort to re-
contact will stop. We retain the right to perform NGS testing on samples previously collected from 
subjects who are now deceased, although we may work with the family, especially if it was through 
interaction with the family that we discovered the subject to be deceased, to respect their wishes 
regarding testing the subject’s sample, returning any primary findings to them, or even returning 
incidental findings that might happen to be discovered through this analysis. 


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For each use of the waiver of consent, the study team will submit for expedited review a request memo 
to the IRB explaining the circumstance and appropriateness of the waiver for that individual case, and 
the waiver of consent will be in effect for that participant only after that request is approved.
Although a subject may meet these criteria for a waiver of consent, NGS analysis might never be 
initiated or may not be initiated right away, so if the subject happens to contact the research team before 
testing is initiated, then the waiver of consent would no longer be appropriate; similarly, if a relative, 
friend, or physician contacts the team before testing is initiated, providing updated contact information 
for the subject, then the waiver of consent would no longer be appropriate and the re-contacting process 
would reopen with the new information. If this contact occurs after the testing has been initiated, then 
testing may still proceed, but the subject will be contacted if possible to explain that the test was or is 
being performed. The subject will be given three options at this point: 1) request that the data from this 
test is destroyed and not used for research, 2) allow us to keep and use the data from the test that was 
performed on their sample under the waiver of consent but decline to participate further by re-
consenting to the research protocol, or 3) re-consent to the protocol.
In the event of an unexpected occurrence that is not covered by the outlined plan, the research team will 
consult with the IRB and/or the NIH Department of Bioethics to determine the appropriate course of 
action.
This plan is consistent with the requirements for a waiver of consent because:
i. 
The research involves no more than minimal risk to the subjects.
This research does not physically affect the individual: reading the genes does not change the genes. 
Therefore, the possibilities for harm or discomfort come from either 1) the data resulting from the NGS 
analysis being used in some way to discriminate against the subject or to breach his or her privacy or 2) 
the potential for psychosocial distress resulting from disclosure of genetic information found by this 
NGS analysis; however, the first possibility has already been mitigated in this protocol through the use 
of a code to protect the subject’s identity, and the fact that these subjects cannot be contacted prevents 
the disclosure of any results, which eliminates the second potential risk.
The protocol already has safeguards in place to protect the subjects’ genetic information and 
confidentiality; specifically, a code is used to protect the subject’s identity when sending a specimen for 
testing and when storing the data resulting from testing. Results of the research will not affect clinical 
care of subjects since they are no longer in contact with the NIH, and the results of this research testing 
will not be entered into the patient’s medical record. Furthermore, these specimens will not be analyzed 
for incidental findings since there is no one to whom such a finding could be returned and therefore no 
purpose for analysis unrelated to the primary research question. Also, genome-scale data produced on a 
subject via waiver of consent will not be uploaded to a genomic data sharing (GDS) database because 
the specimens would have been collected before the effective date of the GDS policy and that use of the 
subject’s genetic information would be inconsistent with the previous informed consent, which stated 
that the subject’s DNA would only be used by our study to further our understanding of hereditary 
disorders of mineral metabolism.
ii. 
The waiver or alteration will not adversely affect the rights and welfare of the subjects.


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Results of the NGS analysis will not affect clinical care of the subject since he or she is no longer in 
contact with the NIH, and the results will not be entered into the medical record. In order to protect the 
subject’s confidentiality, a code will be used for sending a specimen for testing and for storing the data 
resulting from testing.
Furthermore, the use of this new gene testing technology is believed by the research team to be 
congruous with the spirit of the original consent. By previously consenting to participate in the study, 
subjects have given their permission for gene testing to be performed on their DNA in order to look for a 
genetic cause or predisposition for the development of hyperparathyroidism. This is the same and sole 
purpose for which NGS analysis will be used. The difference is the gene testing technology, which did 
not exist or was not in use previously and so could not be included in the previous consent. This new 
technology offers an improved likelihood of finding an answer to the research question, which is a 
research question that the subject has indicated his or her willingness to participate in trying to solve by 
allowing gene testing on his or her blood or tissue samples. Therefore, this use of the subject’s specimen 
is fitting with what was previously consented to, and it is expected that the subject would give consent 
for the use of this new gene testing technology for this purpose if he or she could be contacted.
iii. 
The research could not practicably be carried out without the waiver or alteration. 
The waiver of consent will only be used if it is necessary for the research. That is, the research would 
require that 1) NGS technology be used and 2) that it be used to study archived specimens from a 
subject who cannot be contacted for re-consent. 
One reason that the research would require the use of NGS technology is that the landscape of genetic 
testing has changed such that this technology is quickly becoming the primary option, or even the only 
commercially available option, for gene testing, especially for genes that are rarely tested or studied, 
which are important genes to analyze in order to research and discover the as-yet-unexplained etiology 
of some of these conditions. 
The reason this type of testing would need to be performed on archived specimens from a subject who 
cannot be re-contacted for re-consent is that, given the nature of this research, some of the specimens 
collected under this protocol represent potentially invaluable sources of information for studying 
hyperparathyroidism. While hyperparathyroidism as a whole is not necessarily a rare disease, we know 
that there are numerous different etiologies of hyperparathyroidism (even within its different subtypes), 
some of which remain to be explained, and elucidating those etiologies requires separating the disease 
into its subtypes and studying them individually. This separation drastically reduces the available sample 
size, which is a critical factor in drawing significant conclusions from such research; therefore, even a 
single archived specimen, and the genetic information gleaned from performing this type of testing on it, 
could be the key to making a meaningful discovery. The waiver is needed because the research of 
certain study questions cannot practicably be carried out without performing NGS analysis on archived 
samples, especially on particularly valuable samples of certain disease subtypes or variants that have 
taken years to collect due to their rarity, and without the waiver, if a subject cannot be contacted for re-
consent, then the inability to perform this testing on a critical research sample could undermine the 
feasibility of the research. Furthermore, over the years we have collected samples from multiple 
members of some unique families manifesting rare or interesting variants of the conditions that we 


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study. Such families are valuable and present a promising route for discovery as the inheritance of a 
familial predisposition suggests the presence of a shared genetic factor that could be found with this 
expanded gene testing, and this waiver of consent could be crucial for studying such families in the 
event that one or more members cannot be re-contacted for re-consent because it is imperative to have as 
many family members genotyped as possible when performing familial genetic studies.
iv.
Whenever appropriate, the subjects will be provided with additional pertinent information after 
participation.
If it occurs that a subject cannot be re-contacted during our extensive efforts but then contacts the 
research team later, after the team has used the waiver of consent to perform NGS analysis on the 
subject’s archived sample, then it would be explained to the subject that a newer type of genetic test, 
which has become available since he or she last participated in the study, was performed on the subject’s 
sample for the same reason as the gene testing to which he or she previously consented: to learn more 
about hyperparathyroidism and hopefully uncover answers about the condition for patients like him or 
her. The type of testing performed would be explained, as well as the potential risks, benefits, and 
limitations of that testing. The subject would have the option to be re-consented at that point, or at any 
point in the future, if he or she chooses; like any re-consent to this protocol, this would involve a 
discussion of the potential risks of participating, including the risk for psychosocial distress when 
receiving results of genetic testing, as well as the possibility of incidental findings and the option of 
whether or not to receive them. If the subject chooses to be re-consented, then any primary findings 
from the NGS analysis could be returned to the subject and entered into the medical record, and, if the 
subject chooses to receive incidental findings, then his or her stored NGS data could be re-analyzed to 
look for those. 
Waiver of Consent for Sharing with a Non-NIH Collaborator De-Identified Clinical and Research Data 
on Thirty Patients Who Have Had Parathyroid Cancer Treated Under this Protocol:
A waiver of informed consent will be utilized for sharing with our non-NIH collaborator Nancy Perrier, 
M.D., of MD Anderson Cancer Center, de-identified data collected on the thirty patients who have had 
parathyroid cancer treated at the NIH over the life of this protocol. The purpose of sharing this data is to 
help Dr. Perrier validate a new staging system for parathyroid cancer. In the opinion of our research 
team, this would be an important advancement in the medical care for this rare and deadly 
hyperparathyroidism condition and, therefore, it is a goal consistent with the purpose of this study and 
the spirit of the consent form. Previous versions of the consent form that were signed by these thirty 
patients did not mention whether de-identified data may be shared with other researchers, so we are 
asking the IRB to waive the informed consent requirement in this specific instance because we believe it 
meets the requirements for a waiver and is in the best interest of the research and the research 
participants. The consent form has been amended concurrently to add language specifying that de-
identified samples or data may be shared with outside investigators, so, in the future, any patient 
consented or re-consented to this study using the latest version of the consent form will be aware and 
have given permission for this type of data sharing.
Before any data is shared, a technology transfer agreement specific to this project will be arranged by 
the NIDDK Technology Advancement Office and signed by Dr. Perrier. In this agreement, she will 


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agree to use the de-identified data only for this research project and to not attempt to identify the 
individuals who may be the sources of the data. Only the data required for this validation will be pulled 
from the medical or research records, de-identified, and then shared. The data requested for this task at 
this time include clinical demographics, history and physical examination, preoperative and 
postoperative laboratory values and radiographic studies, genetic testing results, peri-operative 
information and details of surgery, pathology, outcome, treatments, and follow up.
This circumstance meets the requirements for a waiver of informed consent because:
1) The research involves no more than minimal risk to the subjects because the data has already 
been collected by our study and will be de-identified before it is shared with the collaborator.
2) It will not adversely affect the rights and welfare of the subjects since the shared data will not be 
linkable back to the subjects and the research to be done with the data is consistent with the 
research for which the subjects gave their consent. 
3) The research could not practicably be carried out without the waiver because, although some of 
these subjects may be contactable for re-consent, these subjects and data were accrued over 
multiple decades and it is likely that many of these patients who had parathyroid cancer are now 
deceased or are otherwise no longer contactable using the information that we have. Given the 
rarity of parathyroid cancer, the data from each of these patients is potentially quite valuable to 
the research, especially because the sample size will likely be a crucial factor in validating a new 
parathyroid cancer staging system. The waiver of consent is necessary to ensure that we can 
share data from enough of these important, rare cases to give our collaborator a sufficient sample 
size and the best chance of success with her research. 
4) If one of these thirty patients who had parathyroid cancer treated under this protocol, and whose 
de-identified data is being shared with this non-NIH collaborator, returns to the NIH to receive 
care under our protocol, then he or she will be re-consented using the latest version of the 
consent form and, through that re-consent process, explicitly informed that this type of de-
identified data sharing is a part of this study. If medically actionable information is discovered 
through the analysis of this patient data, then attempts will be made to re-contact the affected 
subjects and inform them of the finding(s); we would follow the re-contact procedure outlined in 
the “Waiver of Consent for NGS Analysis on Archived Specimens from Subjects We Cannot Re-
Contact for Re-Consent” section of the protocol.


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Tests and Procedures:
Tests and procedures (explanations included below) will be done according to standard clinical 
indications. All the data collected during clinically-indicated NIH evaluations will be used in analyses of 
methods of diagnosis, parathyroid gland localization, and treatment. Tests and procedures will be chosen 
principally from the following 17 categories:
GENERAL EVALUATION OF DIAGNOSIS AND SEVERITY AND INDICATIONS FOR 
PARATHYROIDECTOMY
l) Analyses from serum or plasma: calcium, ionized calcium, albumin, magnesium, phosphorus, 
creatinine, sugar, sodium, potassium, chloride, alkaline phosphatase, uric acid, cholesterol, SGOT, 
SGPT, 5'-nucleotidase, protein electrophoresis, thyroxine, tri-iodothyronine, thyroid stimulating 
hormone, parathyroid hormone, parathyroid hormone related protein, gastrin, prolactin, chromogranin 
A, 25hydroxyvitamin D, 1,25-dihydroxyvitamin D. These are necessary for diagnosis and for 
monitoring response to treatment.
2) Analyses from urine (usually 24 hour collections): calcium, magnesium, phosphorus, creatinine, 
oxalate, uric acid. Routine urine analysis and urine culture. These are necessary for evaluation of 
possible renal complications. Women of childbearing age will have urine sent for pregnancy test.  
Pregnancy is not an absolute contraindication to inclusion.  If a subject is pregnant or becomes 
pregnant, only her informed consent will be required for enrollment, or continuation, in the study.  A 
pregnant woman could be included in aspects of the research study that present no greater than 
minimal risk to patient or fetus, such as DNA testing of maternal blood.  Research testing of maternal 
blood DNA might hold out the prospect of direct benefit to both the mother and the fetus.  A pregnant 
woman might also be considered for more complex interventions that are not part of the research 
study, such as endocrine surgery, if careful clinical evaluation suggests the potential benefit outweighs 
the risks. Such decisions would be made in close consultation with the OB/GYN physicians of the 
reproductive endocrinology service.
3) Complete blood count, prothrombin time, partial thromboplastin time, platelet count.
4) Electrocardiogram.
5) Noninvasive imaging studies to evaluate conditions associated with hyperparathyroidism: 
-
Skeletal x-rays (evaluate bone thinning, fracture, focal lesions)
-
Pyelographic x-rays (if history of urolithiasis)
-
Bone mass (evaluate complications of hyperparathyroidism)
-
Renal Ultrasound
6) Isotope tests to evaluate extra-parathyroid manifestations or conditions associated with 
hyperparathyroidism (see also sestamibi parathyroid scan in #9) –
-
Bone scan (for evaluation of type, distribution, and activity of metabolic bone disease).  
-
68Gallium-DOTATATE PET/CT when clinically indicated and available, will be used instead of 
Octreoscan, for those patients not participating in the research imaging substudy (68Gallium-
DOTATATE vs. 18F-DOPA PET/CT) described in Appendix C


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-
(see Appendix C for description of substudy in which a subset of patients, who will also be 
consented to a separate consent form specific to this substudy, will receive 18F-DOPA PET/CT 
and 68Gallium-DOTATATE PET/CT as research imaging tests)
7) Ophthalmologic evaluation including slit lamp exam and perimetry (to evaluate effects of altered 
mineral metabolism on eye; perimetry is used to evaluate pituitary compression of optic nerves in 
FMENl).
8) Dental examination (to evaluate effects of altered mineral metabolism).
PREOPERATIVE LOCALIZATION OF PARATHYROID TUMOR
9) Noninvasive imaging tests (7, 8, 11): Computerized tomography, Sestamibi isotopic, parathyroid scan 
with isotopes, ultrasound, and magnetic resonance imaging of neck and mediastinum for parathyroid 
tumor(s). These noninvasive tests are optional in patients without prior neck surgery. All will be done in 
patients with prior neck surgery. Each of these tests shows some value in localizing parathyroid tumors. 
Their results are only partly redundant.
10) Fine needle aspiration of suspected parathyroid tumor with guidance by ultrasound or CT for assay 
of parathyroid hormone - gives hormone specific identification of possible mass previously identified 
with noninvasive test (12). Performed in some patients with prior neck surgery after noninvasive testing 
is judged suggestive but inconclusive.
11) Angiograms (11) -  
Selective parathyroid arteriogram, done in some patients with prior neck surgery and inadequate 
parathyroid tumor localization from parathyroid aspiration and/or noninvasive tests (ultrasound, 
computerized tomography, MRI, parathyroid scan) can show a tumor as a "shadow", can define venous 
anatomy to aid performance and interpretation of venous sampling (below), and may be combined with 
hypocalcemic challenge.
In hypocalcemic challenges, the arteriographic agent will lower ionized calcium in the perfused 
vessels.  This can cause PTH release from a perfused tumor.  Several peripheral venous blood samples 
are taken to measure for step up of acutely released PTH. 
Selective venous sampling for immunoassay of parathyroid hormone (PTH) - done in some 
patients who already met criteria for selective arteriogram (see above) but had inadequate tumor 
localization by that test. PTH gradient (more than 2-fold) defines vein(s) that drain a parathyroid tumor.
TREATMENT
12) Treatment of primary hyperparathyroidism -
       
When indicated, cure of primary hyperparathyroidism (benign or cancerous) will be attempted 
by surgical (6, 7, 14) or arteriographic ablation (15).   Two alternate treatments are available: follow-up 
without intervention, or medical therapy with calcimimetics, denosumab, bisphosphonates, phosphates, 
estrogen, or other drugs. 


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Medical therapy with a calcimimetic.  Calcimimetic drugs can directly bind to and inhibit the 
parathyroid cell (16).  One has been approved by the FDA for use in refractory cases of primary 
hyperparathyroidism.  It has also been approved in primary hyperparathyroidism caused by parathyroid 
cancer (16).  Trials for up to one year in typical primary hyperparathyroidism have shown rapid 
normalization of serum calcium but only partial suppression of PTH.  
Some patients with mild or severe disease and patients with contraindications to ablative 
treatments will be selected for these alternate treatments. If so, these treatments will be supervised by 
their local physicians with no requirement for follow-up visits to NIH. Alternately, patients residing near 
NIH may be followed for this purpose in our clinic.
13) Management of postoperative hypocalcemia - 
Patients will receive standard treatments for postoperative hypocalcemia (6). The main elements 
are combinations of calcium (orally or intravenously) and vitamin D analogs   In adults only, who have 
postoperative hypocalcemia, we may choose to use commercially available synthetic (1-84) human PTH 
as treatment of hypoparathyroidism, particularly in cases with difficulty in regulation of treatment with 
calcium and a vitamin D analog.  According to standard clinical indications certain patients (specifically, 
those with MEN l and no prior neck surgery) will undergo total parathyroidectomy with simultaneous 
autograft of fresh parathyroid tissue. Patients that develop long-term permanent hypoparathyroidism, 
diagnosed more than 3 months post-operation may be offered autografts of their own cryopreserved 
parathyroid tumor (6).
EVALUATION AND TREATMENT FOR ASSOCIATED TUMORS
14) Patients with familial forms of hyperparathyroidism sometimes have syndrome-specific associated 
tumors outside of the parathyroids as follows:
-MEN1 associated with: 
gastrinoma (30%), insulinoma (15%), other enteropancreatic neuroendocrine tumors including 
nonfunctioning (20%), foregut carcinoid (5%), prolactinoma (10%), other anterior pituitary (20%), 
nonfunctioning adrenocortical (20%), and other rare tumors (pheochromocytoma, ependymoma, muscle 
tumors; each less than 1%). MEN1 cases should have lifelong surveillance for emergence of new tumors 
(5, 18). Some will be offered periodic evaluations in the outpatient or inpatient service.
-Hyperparathyroidism-Jaw tumor syndrome associated with: 
parathyroid cancer (15%), cemento-ossifying fibromas of the jaw (15%), multiple renal cysts (15%), 
Wilms tumor (2%), renal hamartomas (5%)%), uterine tumors (unknown percentage of affected 
women).
Patients likely to have either syndrome will receive medically appropriate evaluations for the 
specific conditions likely to be associated with the syndrome in their family.
Standard treatment will be offered for associated conditions as recognized.
            MEN2A associated with medullary thyroid cancer or pheochromocytoma.
15) Cancer in the parathyroid or in a tumor related to a hyperparathyroid syndrome. Cancer of the 
parathyroid is very rare except for being found in 15% of cases with HPT-JT. Cancer is frequent 
(approximately 50% of cases beyond age 40) outside of the parathyroids in MEN1 (in duodenal 
submucosa, pancreatic islets, bronchial carcinoid, or thymic carcinoid). Approximately one third of 
MEN1 carriers will eventually die from an MEN1-related cancer. Standard evaluation and treatment 


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may be offered fully or in cooperation with outside resources for any of these cancers. These evaluations 
include imaging plus pathology examination of tissue specimens. The NIH investigators will decide, 
after discussion with the patient, what additional management that the NIH will offer. The principal 
evaluation for tumor emergence in MEN1 is imaging with several methods, which will be offered 
typically at 3-5 year intervals. If a patient elects not to come to Bethesda for these periodic evaluations, 
then any evaluations would be through their local resources.
RESEARCH TESTS
16) Certain specimens, offering no immediate benefit to the patient, will be obtained for research.
- Tumor tissue from PT and other tissues not required for pathology analysis or for 
cryopreservation will be used in research. Uses include analyses of oncogenes activated in the tumors 
and analyses of metabolic defects expressed in the tumors (for example loss of normal suppression of 
parathyroid hormone secretion and of gland growth by extracellular calcium).
17)  Testing DNA and RNA.  DNA and RNA testing will be done with tumor, with blood, saliva, or oral 
rinse, and/or with tissue from the inner cheek obtained by buccal swab. This includes patient tumor, 
blood, tissue, or DNA samples previously collected and stored under this protocol.  Previous versions of 
this consent included the possibility of DNA testing, including the statement that any information gained 
by the analysis of DNA is solely to further our understanding of hereditary disorders of mineral 
metabolism. Some versions did not specify the type of DNA testing technology that could be used, while 
others explained that only targeted testing would be performed on individual genes known to be 
associated with hyperparathyroidism. With this consent, we are expanding the options for testing on 
those previously collected samples to include next-generation sequencing technology such as genome-
scale testing and gene panels. While the technology has advanced, the purpose and primary focus of the 
DNA testing remains the same: to further our understanding of hereditary disorders of mineral 
metabolism. 
RNA testing may be performed to help the investigators understand the expression of genes related to 
hyperparathyroidism in the patient’s normal or abnormal tissue. It is hoped that this will help us 
understand which genes, DNA mutations or variants, and cellular processes are involved in 
hyperparathyroidism and related disorders. Because RNA production can vary with time and between 
tissues and is not directly transmitted between generations the way that DNA is, RNA testing does not 
carry the same implications or potential risks for the research subject as DNA testing; however, the 
subject may benefit from RNA testing performed on his or her sample if it improves our understanding 
of the disorder being studied and our ability to interpret the results of DNA testing.
The total amount of blood drawn will vary among subjects, depending on the number of clinical studies 
performed.  The total amount of blood drawn from a person over 18 years of age will never exceed. 10.5 
mL/kg or 550 ml, whichever is smaller, over an eight week period. For patients below age 18, no more 
than 5 mL/kg may be drawn for research purposes in a single day, and no more than 9.5 mL/kg over any 
eight week period.


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The NIH investigators will provide a patient identification code for the stored DNA.  The 
research subject’s identity will be known only by the NIH investigators.  Analyses of specimens (Blood, 
DNA, cells, serum, plasma) may be done at NIH or in collaborating laboratories.
The investigators will decide which genes, if any, to test for each patient. One or more among several 
different methods and selections of genes for testing may be performed. 
a) 
Targeted gene testing may be performed by selecting among the genes known to be associated 
with disorders of calcium metabolism, which include MEN1, CASR, GNA11, AP2S1, CDC73/HRPT2, 
GNAS, AIP, and four CDKIs (p15, p18, p21, p27).  Genes may be tested individually, or a single multi-
gene test called a gene panel may be used to test several target genes at the same time. Next generation 
sequencing may be used. Targeted testing may look for mutations using gene sequencing and/or 
deletion/duplication analysis. The results of targeted gene testing on targeted genes or on actionable 
genes will be verified in a CLIA certified laboratory and entered into the patient’s NIH medical record. 
b)
A genome-scale testing method such as exome sequencing, whole genome sequencing, or 
genome-wide copy number analysis (e.g., SNP array) may be used to analyze the genes known to be 
associated with hyperparathyroidism and/or to search for new gene changes that may be contributing to 
the disorder of calcium metabolism (19-21). The data generated from genome-scale testing may be 
stored for future analysis relating to this protocol, in which case the data will be stored on encrypted 
hard drives which will be stored securely in or near the MDB lab under the supervision of the PI or an 
associate investigator. Mutations found using genome-scale testing which are judged by the 
investigators to be informative to the medical condition being studied or to the patient’s immediate 
health (such as the incidental finding of known-pathogenic mutations in highly-penetrant medically-
actionable genes) will be verified in a CLIA certified laboratory and entered into the patient’s NIH 
medical record. 
There is the possibility of an incidental finding with genome-scale testing. Returned incidental findings 
will be limited to mutations that are found, which are known to be disease-causing, in medically 
actionable genes. The list of medically actionable genes will be based on the published 
recommendations by a professional genetics group, such as the American College of Medical Genetics, 
for return of incidental findings at the time that the data is analyzed. This list currently includes 56 genes 
but is expected to evolve over time (22, 23). Changes in these recommended genes will be amended at 
the time of annual renewal of the protocol. Estimated yield as of 2014 is that 1-4% of participants may 
have such a finding (24). If an incidental finding is found and meets the above criteria, then that 
mutation will be verified in a CLIA certified laboratory (if original testing was in a non-CLIA lab), 
entered into the patient’s NIH medical record, and returned to the patient by the research team, provided 
that the patient did not opt-out of receiving incidental findings (by signing the opt-out section of the 
consent document) and the team is able to get in contact with the patient. The consent document informs 
the patient that it is his/her responsibility to keep the research team informed of any changes to contact 
information, that an incidental finding could be life saving information, and that the patient may change 
his or her decision about receiving/opting-out of receiving incidental findings in the future by contacting 
the investigators and being re-consented to the study. This information, including the nature, probability, 
and potential importance of medically actionable incidental findings, will also be discussed during the 
consent session to be sure that participants fully understand the consequences of their decision as well as 
their right to change their minds about this decision at any time in the future.


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The participant may specify in the provided spaces on the consent form those relatives with whom we 
are authorized to share genetic test results in the event that the participant is deceased or permanently 
incapacitated.
Outcome parameters: The principal outcome to be monitored is cure of hyperparathyroidism. This is 
monitored by standard parameters (blood calcium and parathyroid hormone). Since this is a natural 
history protocol, description of other outcome parameters, such as definition of the regions of allelic loss 
in parathyroid tumors, is not appropriate.
Monitoring and follow-up:  Most patients without prior neck surgery will have all their testing 
completed prior to planning for parathyroid surgery.  Patients with prior neck surgery will generally 
require both diagnosis and tumor localization prior to surgical intervention.  Following treatment, 
patients may be followed if they develop recurrence of hyperparathyroidism or if they have end-organ 
sequelae that requires continued follow up care. Many patients will be referred back to local 
Endocrinologists if no further research is planned. For familial causes of hyperparathyroidism, including 
MEN1, patients will be followed as per standard of care. Some patients may be followed in the NIH 
outpatient clinic.
Benefits: Patients will benefit from diagnosis of their endocrine-metabolic disorder. Most patients will 
benefit from treatment of primary hyperparathyroidism.
Risks and complications and consent procedures: These are listed below with the same paragraph 
numbers as in the section on Study Design (see above). All tests and procedures that involve greater than 
minimal risk will be separately explained and documented by additional signed consent as indicated in 
parentheses below. A pregnancy test will be done on all potentially fertile women. No diagnostic or 
therapeutic procedure will be done on a pregnant woman unless clinically justified. In the rare situation 
where the patient is a small child or infant, appropriate precautions will be taken. For example, general 
anesthesia may be indicated in a young child for a clinically necessary procedure, such as arteriography.
RISKS FROM GENERAL EVALUATION OF DIAGNOSIS AND SEVERITY
l)  Serum or plasma. Standard inconvenience of diagnostic phlebotomy.
2) Urine specimens. Minor inconvenience of collecting timed urines.
3) Blood and clotting. Standard inconvenience of diagnostic phlebotomy.
4) EKG. Minimal inconvenience.
5) Radiographic noninvasive imaging Skeletal x rays. No risk.  Pyelographic x-rays. Risks and 
precautions for intravenous contrast agents as for computerized tomography. (Standard NIH 
consent for contrast) Bone mass - minimal risk.
6) Isotope tests. Inconvenience of venipuncture to administer isotope(s).  Minimal risk from 
isotope. Separate consent for 68-Gallium DOTATATE scan and 18F-DOPA (Appendix C)
7-8) Ophthalmologic and Dental evaluations. No risk.
RISKS FROM PARATHYROID TUMOR LOCALIZATION TESTS
9) Parathyroid noninvasive imaging Ultrasound - no risk.  Parathyroid isotope scan - 
inconvenience of venipuncture.  Computerized tomography (CT) - intravenous contrast agents 


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may cause renal damage or allergy. To avoid exacerbation of any renal disease, no patient will 
have radiologic studies requiring intravenous contrast (i.e. CT, pyelogram, arteriogram, 
venous sampling) on two successive days. Patients with history of dye-associated anaphylaxis 
will not receive dye. Patients with less severe allergy will be premedicated by standard 
methods. (Standard NIH permit for procedure with intravenous contrast).  Magnetic resonance 
imaging - inconvenience of being in small chamber with loud noise.  Magnetic field can 
disturb objects such as pacemakers. Patients with pacemakers or other metal objects at risk 
will not undergo this procedure. (Standard NIH permit for MRI).
10) Fine needle aspiration to locate parathyroid hormone (PTH) in a lesion. Discomfort of needle 
after local anesthesia. Needle might compromise nearby structure such as carotid artery. This 
non-research procedure is done according to clinical indications under guidance of ultrasound 
or computerized tomography depending on which imaged the mass better. (Standard NIH 
consent).
11) Selective parathyroid arteriogram - Risks of intravenous dye, arterial puncture, inadvertent 
injection or dissection of critical vessels (including those feeding the spinal cord and brain). 
(Standard NIH permit).  Selective venous sampling for PTH - Hazards of intravenous contrast, 
hazards of femoral vein catheter insertion (bleeding or thrombosis). (Standard NIH permit).  


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RISKS FROM TREATMENT
12) Treatment.  Parathyroid surgery - Risks of recurrent nerve damage, hypoparathyroidism, 
persistent hyperparathyroidism, anesthetic problems, recurrent hyperparathyroidism more 
than 6 months after surgery. (Standard NIH consent)  Angiographic ablation of tumor - Risks 
of intravenous contrast, compromise of another critical structure, parathyroid disruption with 
bleeding, persistent or recurrent hyperparathyroidism, hypoparathyroidism. Also lack of 
excised parathyroid tumor for pathology and for cryopreservation. (Standard NIH consent).  
Medical treatment including calcimimetics (risks of nausea, hypocalcemia), bisphposphonate 
(risks of atypical jaw or femur fracture). - estrogens given at high dose to women will 
exacerbate hypophosphatemia. Phosphates to control calcium increase the risk of soft tissue 
(including renal) calcification. Phosphates are contraindicated in patients with chronic 
hyperphosphatemia (i.e. uremia).
13) Management of hypocalcemia - hypocalcemia causes paresthesias, muscle cramps, and, if 
severe, seizure. Long-term treatment of hypoparathyroidism is usually with combinations of 
calcium and a vitamin D analog. These carry risks of calcium overload with hypercalcemia 
and renal damage (temporary or permanent). Long term treatment of hypoparathyroidism by 
self-injection with synthetic 1-84 PTH is now possible, for adult patients only, following 
approval by the Food and Drug Administration
15) Parathyroid autografts carry risk of graft failure, infection, and graft dependent recurrent 
hyperparathyroidism. (Standard NIH consent).
SPECIMENS FOR RESEARCH
16)  Additional blood and tissue. Minimal inconvenience of phlebotomy. Will not be taken from 
patient with severe anemia (Hematocrit below 30 %). Blood volume for research will be 
limited or omitted if total blood withdrawal approaches the NIH guideline of no more than 5 
mL/kg in a single day, and no more than 9.5 mL/kg over any eight week period for subjects 
less than 18 years old, or of 450 mL over 6 weeks in adults. DNA or RNA may be extracted 
from blood or tumor for frozen storage indefinitely (see Research Tests). Whole blood may 
also be frozen and stored indefinitely. Tumor tissue will also be cryopreserved indefinitely.
17) Risks from DNA and RNA testing.  There is a risk for the discovery of unexpected 
information such as misidentified paternity from an associated protocol (93-DK-0127) on family testing.  
Only information which directly affects an individual’s health, health-care choices, or reproductive 
choices will be imparted to him/her.  Specifically, families and individuals will not be confronted with 
issues of mis-specified paternity or adoption.  In the case where a pedigree must be published to support 
the research findings, all identifying information regarding the issue of mis-specified parenthood will be 
excluded, without changing the scientific information.  In all such cases a bioethics consultation will be 
sought to resolve specifically how the issue should be handled.
There is a possibility of an incidental or “unexpected” genetic finding when genome-scale testing 
is performed as well as the risk of emotional or psychological harm resulting from the discovery of a 
gene mutation that causes or contributes to a disorder. We will provide patients with information about 
incidental mutations in the selected important genes recommended for return by authorities (22, 23). 
 


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There is a risk to the insurability of the participating subject.
 Data Sharing Policy: The investigators will comply with the NIH Genomic Data Sharing (GDS) policy 
by submitting the required data and clinical information to dbGaP for any patient on whom genomic 
data is produced under this protocol, such as through exome sequencing, whole genome sequencing, or 
genome-wide copy number analysis (25). The deposited data can be used by other researchers for 
studies outside of the scope of this protocol; this is a controlled-access database and researchers must 
promise to keep the information confidential, and the information will not include the patient’s name or 
similar identifiers. 
We may share de-identified data or samples collected under this protocol with other researchers who 
would first be added as collaborators to the protocol. 
Current Non-NIH Collaborations:

Nancy Perrier, M.D., MD Anderson Cancer Center
o
We are sharing de-identified clinical and research data from 30 patients with parathyroid 
cancer to help validate a staging system for parathyroid cancer. This collaboration is 
described further in the waiver of consent earlier in this document. 
o
We are also sharing de-identified clinical data and research samples from 30 patients with 
multiple endocrine neoplasia type 1 (MEN1). This research project aims to further 
identify blood-based biomarkers for the detection of patients with metastatic 
gastrointestinal neuroendocrine tumors (dpNETs).  The aim of this collaboration is to (1) 
test the potential of plasma-derived metabolite biomarkers for early detection of patients 
with MEN1-related dpNETs with distant metastases (2) concomitantly, perform in-depth 
metabolomic, proteomic and immune complex profiling of plasma- and plasma-derived 
exosomes to facilitate identification of novel protein and autoantibody biomarker 
candidates for patients with MEN1.
Withdrawal from study: Most patients will be released from the study after discharge from the 
admission at which they received treatment for hyperparathyroidism or at the time it is decided that they 
are not currently appropriate for attempts (surgical or angiographic) to ablate parathyroid tumors. Some 
uncured patients and some cured patients will have return visits in the outpatient or inpatient service.
The subject may withdraw from the study at any time and refuse further study procedures or further 
contact initiated by investigators associated with this study. However, any information already obtained 
from the samples provided will be kept by the investigator. In addition, remaining samples will be 
retained by NIH for potential future studies unless the subject specifically indicates to us in writing that 
he or she wishes for us to destroy their samples. In this case we will destroy all samples (original 
specimen and derived materials) in our possession and will make every effort to have materials in the 
possession of outside collaborators destroyed as well. In the unlikely event that a subject’s sample, 
which he or she has requested to have destroyed, must be retained in order to protect the research (such 
as a sample that would be required so the investigators could confirm research results), then the sample 
would be anonymized so that no personal identifying information would be associated with it; the 
sample would then be destroyed as soon as its retention was no longer necessary. Data uploaded to a 


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genomic data-sharing database may not be able to be removed or destroyed, but such data will have 
already been de-identified.
Analysis of study: Not applicable as this is a natural history protocol.
Data and Safety Monitoring:  The Principal Investigator will function as the data and safety monitor and 
report any adverse events to the IRB.
Study procedures will be subject to audits and/or monitoring visits to ensure compliance with the 
protocol and applicable regulatory requirements consistent with the NIDDK quality assurance program 
plan.  Audit and/or monitoring visits results will be reported to the Principal Investigator for further 
reporting as appropriate.  Study documents and pertinent hospital or clinical records will be reviewed to 
verify that the conduct of the study is consistent with the protocol plan.
Reporting of Adverse Events:  
Adverse events, non-compliance both serious or continuing, protocol deviations both major and minor, 
as well as unanticipated problems are defined & described by the NIH Office of Human Subjects 
Research Protection policy #801 and will be reported in accordance with this policy. 
Research Use, Storage and Disposition of Human Subject’s Samples and Data
Only DNA samples and the data derived from testing of DNA samples will be stored. All samples will 
be coded per the current Core Laboratoy practices . Samples that go to another lab may have these 
codes, but identifying information such as patient name or date of birth will only be given if the lab 
requires the information and is a CLIA-approved genetics lab bound by HIPAA . The laboratory code is 
retained indefinitely because newly discovered hyperparathyroid genes may be analyzed in the future 
and the analysis should be related to the patient and family.
Samples are stored in a freezer in or near the MDB lab under direct supervision of Dr. Mary Walter of 
NIDDK. The freezer has an alarm to detect malfunction of the freezer.
Stored data generated from genome-scale testing will be held on encrypted hard drives which will be 
stored securely in or near the MDB lab under the supervision of the PI or an associate investigator.
Since the study has no set termination date, no finishing date for sample storage analysis has been set.
If any sample is lost, emptied, or destroyed, the PI will report the occurrence to the IRB.


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REFERENCES
1.
Aurbach GD, Marx SJ, Spiegel AM. Parathyroid hormone, calcitonin, and the calciferols. In 
Williams Textbook of Endocrinology: Eighth Edition. Eds Wilson JD and Foster DW WB Saunders Co. 
1992, pp 1397-1476.
2. 
Bilezekian JP, Khan AA, Potts JT jr on behalf of the Third International Workshop on 
Management of Asymptomatic Primary Hyperparathyroidism. Guidelines for the management of 
asymptomatic primary hyperparathyroidism: Summary statement from the Third International 
Workshop. J Clin Endocrinol Metab 94: 335-39, 2009.
3. 
Eastell E, Arnold A, Brandi ML, Brown E, D’Amour P, Hanley DA, Rao DS, Rubin M, 
Goltzman D, Silverberg S, Marx SJ, Peacock M, Moselikde L, Bouillon R, Lewiecki EM. Diagnosis of 
asymptomatic primary hyperparathyroidism: Proceedings of the third international workshop. J Clin 
Endocrinol Metab 94: 340-50, 2009.
4.
Arnold A, Marx SJ. Familial hyperparathyroidism (Including MEN, FHH, and HPT-JT). Primer 
on the Metabolic Bone Diseases and Mineral Metabolism 8th Edition. Ed Rosen C, et al. John Wiley & 
Sons, Inc. 553-561, 2013
5.
Marx SJ and Wells SA Jr.  Multiple Endocrine Neoplasia. Chapter 41. Williams Textbook of 
Endocrinology 12th Edition. Ed by Melmed S, Polonsky KS, Larsen PR, Kronenberg HM. Elsevier 
Saunders. Philadelphia. 1728-67, 2011
6. 
Norton J, Aurbach GD, Marx SJ, Doppman JL.  Surgical management of hyperparathyroidism.  
In DeGroot U  Ed. Endocrinology Vol 2. Saunders, Philadelphia.  1989, 1013-31.
7. 
Powell AC, Alexander HR, Chang R, Marx SJ, Skarulis MC, Pingpank JF, Simonds WF, Collins 
MF, Shawker T, Chen CC, Reynolds J, Cochran C, Steinberg SM, Libutti SK. Re-operation for 
parathyroid adenoma: A contemporary experience. Surgery 146: 144-55, 2009.
8.  
Nilubol N, Weinstein L., Simonds WF., Jensen RT., Phan GQ., Hughes MS., K. Libutti   SK., 
Marx S., Kebebew E. Preoperative localizing studies for initial Parathyroidectomy in MEN1 syndrome: 
Is there any benefit? World J Surg 36:1368-74, 2012. 
9.   
Agarwal S, Mateo CM, Marx SJ. Rare Germline Mutations in Cyclin-Dependent Kinase 
Inhibitor Genes in Multiple Endocrine Neoplasia Type 1 and Related States. J Clin Endocrinol Metab 
2009 94: 1826-1834 
10.  
Marx SJ  Hyperparathyroid genes: Sequences reveal answers and questions.  Endocrine Practice. 
Suppl 3, 18-27, 2011.  
11. 
Chang R, Marx SJ. Role of preoperative localization and intraoperative localization maneuvers 
including intraoperative PTH assay determination for patients with persistent or recurrent 
hyperparathyroidism. J Bone Min Res 17 (Suppl 2): N133-N140, 2002.


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12. 
MacFarlane MP, Fraker DL, Shawker TH, Norton JA, Doppman JL, Chang RA, Skarulis MC, 
Marx SJ, Spiegel AM, Alexander HR.  Use of preoperative fine-needle aspiration in patients undergoing 
reoperation for primary hyperparathyroidism.  Surgery  116:959-965, 1994
13.
Powell, AC; Alexander, HR; Pingpank, JF, et al. The utility of routine transcervical  thymectomy 
for multiple endocrine neoplasia 1-related hyperparathyroidism . Surgery 144: 878-83, 2008.
14.  
Yavuz S,  Simonds WF, Weinstein LS, Collins MT, Kebebew E, Nilubol N, Phan GQ, Libutti 
SK, Remaley AT, Van Deventer M, Marx SJ. Sleeping parathyroid tumor: rapid hyperfunction after 
removal of the dominant tumor.   J Clin Endocrinol Metab. 97: 1834-41, 2012
15. 
Miller DL, Doppman JL, Chang R, Simmons JT, O’Leary TJ, Norton, JA, Spiegel AM, Marx SJ, 
Aurbach GD.  Angiographic ablation of parathyroid adenomas:  lessons from a 10-year experience. 
Radiology 165: 601-7, 1987.
16. 
Ward DT and Riccardi D.  New concepts in calcium-sensing receptor pharmacology and 
signaling. Brit J Pharmacol 165: 35-48, 2012
18.  
Thakker RV, Newey PJ, Walls GV, Bilezikian J, Dralle H, Ebeling PR, Melmed S, Sakurai A, 
Tonelli F, Brandi ML  Clinical practice guidelines for multiple endocrine Neoplasia type 1 (MEN1).  J 
Clin Endocrinol Metab 97: 2990-3011, 2012
19.  
Cooper GM and Shendure J. Needles in stacks of needles: finding disease-causal variants in a 
wealth of genomic data. Nat Rev Genet. 12(9): 628-40, 2011.
20.  
Biesecker LG. Opportunities and challenges for the integration of massively parallel genomic 
sequencing into clinical practice: lessons from the ClinSeq project. Genet Med. 14(4): 393-8, 2012.
21. 
Deo RC, Musso G, Tasan M, Tang P, Poon A, Yuan C, et al. Prioritizing causal disease genes 
using unbiased genomic features. Genome Biol.15(12): 534, 2014.
22.  
Green RC, Berg JS, Grody WW, Kalia SS, Korf BR, Martin CL, et al. ACMG recommendations 
for reporting of incidental findings in clinical exome and genome sequencing.  Genet Med. 15(7): 565-
574, 2013.
23.  
ACMG Board of Directors. ACMG policy statement: updated recommendations regarding 
analysis and reporting of secondary findings in clinical genome-scale sequencing. Genet Med. 17(1): 68-
9, 2015.
24.  
Dorschner MO, Amendola LM, Turner EH, Robertson PD, Shirts BH, Gallego CJ, et al. 
Actionable, pathogenic incidental findings in 1,000 participants' exomes. Am J Hum Genet. 93(4): 631-
40, 2013.
25.  
National Institutes of Health Genomic Data Sharing Policy. August 27, 2014. See 
http://gds.nih.gov/PDF/NIH_GDS_Policy.pdf.


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Appendix A: Re-Contact Letter/Email Template (approved in 2015 Amendment U)
[DATE]
[PARTICIPANT’S NAME AND ADDRESS]
Dear [PARTICIPANT’S NAME],
I am a medical researcher working on a study that you have participated in at the National 
Institutes of Health (NIH) in Bethesda, Maryland. We are hoping to get back in touch with you to check 
in about your health, update your family medical history, and discuss the possibility of doing a new gene 
test on a stored specimen of yours as part of our research. This new test increases our chance to make 
discoveries, which could help us provide answers to patients like you, but it was not included in the 
original research consent form (that you previously signed) since it was not available at that time. We 
would do this test for exactly the same purpose as the previous gene testing that was in your consent (to 
learn about the condition being studied), but it is a new technology that merits its own discussion; 
therefore, before proceeding with the test, we would like to have a conversation with you to discuss your 
preferences and ask your permission. Please give me a call or e-mail back when you can, even just to 
schedule a convenient time to talk in the future. Thank you very much and have a great day.
Sincerely,
[INVESTIGATOR’S NAME]
[INVESTIGATOR’S CONTACT INFORMATION]


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Appendix B: Re-Contact Call/Voicemail Script (approved in 2015 Amendment U)
Call Script
Calling number for subject:
Hello, this is [CALLER’S NAME] calling from the National Institutes of Health in Bethesda, 
Maryland. May I please speak with [PARTICIPANT’S NAME]?
If explanation is needed:
I work on a medical research study that [PARTICIPANT’S NAME] is a participant in. I am hoping to 
get in contact with [HIM/HER]. Is [HE/SHE] available to speak? 
Participant not available:
I’m sorry I missed [HIM/HER/NAME].  What is the best time to reach [HIM/HER/NAME]?
Record: Time/Date
Thank you for your time, and may I ask who I’m speaking with?
[Record Initial Call Recipient]
Thanks again, [SPEAKER’S NAME].  I will try to reach [HIM/HER/NAME] again at [RECORDED 
TIME AND DATE]. 
Knows the participant but this is not the correct contact information:
Okay, well thank you for your time. Do you happen to have new contact information for 
[HIM/HER/NAME]?  While it’s by no means an emergency, it would be helpful for our research, 
and potentially helpful for [PARTICIPANT’S NAME] as well, if we could speak with [HIM/HER] as 
soon as possible.
Wrong number:
Thank you for your time and I’m sorry for the inconvenience.
Voicemail:
Hello, this is [CALLER’S NAME] calling from the National Institutes of Health in Bethesda, 
Maryland. I am hoping to get in contact with [PARTICIPANT’S NAME], who is a participant in our 
medical research study. We wanted to check in about [HIS/HER] health, ask about any updates to 
the family medical history, and discuss the possibility of doing a new test on a specimen that we 
have stored from [PARTICIPANT’S NAME] as part of our research. Please give me a call back 
whenever you can, even just to schedule a convenient time to talk in the future. My number is 
[CALLER’S NUMBER], and again my name is [CALLER’S NAME]. Thank you very much and have a 
great day.


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27
Calling number of next of kin, emergency contact, or physician to receive records:
Hello, this is [CALLER’S NAME] calling from the National Institutes of Health in Bethesda, 
Maryland. I work on a medical research study that [PARTICIPANT’S NAME] is a participant in. We 
are trying to get in contact with [HIM/HER/NAME], but unfortunately we’ve been unsuccessful so 
far using the contact information we have on file. I’m calling you because this number was listed as 
[HIS/HER] [NEXT OF KIN/EMERGENCY CONTACT/PHYSICIAN TO RECEIVE RECORDS]. Do you 
know how we might be able to get in touch with [PARTICIPANT’S NAME]?
Voicemail:
Hello, this is [CALLER’S NAME] calling from the National Institutes of Health in Bethesda, 
Maryland. I work on a medical research study that [PARTICIPANT’S NAME] is a participant in. 
We’re trying to get in contact with [HIM/HER/NAME], but unfortunately we’ve been unsuccessful 
so far using the contact information we have on file. I’m calling you because this number was 
listed as [HIS/HER] [NEXT OF KIN/EMERGENCY CONTACT/PHYSICIAN TO RECEIVE RECORDS], 
so I’m hoping you might have updated contact information for [HIM/HER/NAME]. While it’s by no 
means an emergency, it would be helpful for our research, and potentially helpful for 
[PARTICIPANT’S NAME] as well, if we could speak with [HIM/HER] as soon as possible. Please 
give us a call back when you get a chance, even if you don’t have new contact information because 
just knowing that could be helpful for us.  My number is [CALLER’S NUMBER], and again my name 
is [CALLER’S NAME]. Thank you very much and have a great day.


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Appendix C: Research Imaging Substudy – 68GALLIUM-DOTATATE versus 18F-DOPA 
(approved in 2018 Amendment AA) (Completed Enrollment on 7/29/2019)
The role of 68GALLIUM-DOTATATE PET/CT versus 18F-DOPA PET/CT 
in the imaging of neuroendocrine neoplasms in patients with 
Multiple Endocrine Neoplasia Type 1 (MEN1)
Précis
This amendment requests the addition of a study in the MEN1 subpopulation of the full protocol. This 
study is designed to compare the efficacy of 68Ga-Dotatate PET/CT scan versus 18F-DOPA PET/CT, MRI and CT 
scan in detecting known and occult primary and metastatic neuroendocrine tumors. Further research into 
identifying the best imaging modalities is important in this rare disease because (1) duodenal and pancreatic 
neuroendocrine tumors are the most important determinant of MEN1-related survival – and treatment (surgical or 
medical)  is based on the accurate localization and size of primary and metastatic lesions; (2) there is no clear 
evidence to suggest that MEN1 patients have a phenotype-genotype correlation, thus limiting the ability to predict 
tumor location and/or progression, (3) there are no adequate or sensitive serum tumor markers for the detection 
and surveillance of non-functional neuroendocrine tumors, thus requiring yearly functional and anatomical tumor 
screening for all MEN1 patients, and (4) the multiplicity and heterogeneity of neuroendocrine tumors in this 
disease can make detection using anatomical imaging challenging, thus requiring the addition of sensitive 
functional imaging. Using various standard-of-care imaging modalities (CT and MRI), the comparison of 68Ga-
Dotatate and 18F-DOPA offers the opportunity to further characterize NETs based on molecular transporters, 
delineate molecular tumor characteristics, and offer insights into promising therapeutic targets in the future.
Background
The Metabolic Disease Branch has studied patients with Multiple Endocrine Neoplasia type 1 (MEN1) for 
over four decades, with important discoveries and contributions to the field, most notably the discovery of the 
MEN1 gene to 11q13.1 This rare disease has an estimated prevalence of three to four per 100,000, and currently 
the MDB branch is actively following ~350 patients including multiple kindreds with MEN1. This disease 
manifests typically with parathyroid (90-95%), enteropancreatic neuroendocrine (30-70%) and anterior pituitary 
tumors (30-40%).2 Other recognized features include thymic and bronchial carcinoids (2-8%)3, adrenocortical 
tumors (40%), and cutaneous lesions (30-85%).2 
 The introduction of proton pump inhibitors has greatly reduced the mortality from gastrinoma-induced 
Zollinger Ellison syndrome.4 Currently, the cause of death in 50-70% of MEN1 patients is a malignant tumor 
process, or is directly related to manifestations of MEN1.5 Patients with neuroendocrine thymic tumors and 
secretory NETs (neuroendocrine tumors) have over four-times the risk of death, while non-functional pancreatic 
tumors have over three times the risk of death as compared to other tumor types in MEN1.6 Factors that determine 
the clinical course and outcome of NETs in MEN1 are complex and include the site of origin, hormone secretory 
properties, the size of the primary tumor, the extent of disease, and the grade (based on Ki-67 staining).7 
Characteristics of both sporadic and familial neuroendocrine tumors as described by the European 
Neuroendocrine Tumor Society and the WHO guidelines distinguish the differences between well- and poorly-
differentiated NET (Table 1). Well-differentiated neuroendocrine tumors typically have an indolent course, while 


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poorly differentiated tumors are often difficult to detect and rapidly progressive. In MEN1, most neuroendocrine 
tumors are slow growing, and have low oncologic properties such as low Ki67 index (%) and/or mitotic count. 
Identification of primary and metastatic disease represents the most important prognostic factor after 
tumor grading for NETs.8,9As such, clinical and pre-operative management decisions are dependent on the 
localization, assessment and accurate monitoring of functional and non-functional NETs and their metastases. 
Tumors arise from neuroendocrine cells, which are the largest group of hormone-producing cells in the body and 
metastasis may occur at any location. At least thirteen types of distinct gut neuroendocrine cells exist, all of which 
may oversecrete various bioactive peptides or amines or may be biochemically silent. Secreted peptides and 
biogenic amines include serotonin, somatostatin, histamine, bradykinin, gastrin, insulin, glucagon, pancreatic 
polypeptide, and vasoactive intestinal polypeptide. In MEN1 patients, the reported most common manifestations 
are gastrinoma (40%), insulinoma (10%), non-functional pNET and pancreatic polypeptidioma (20-55%), and 
glucagonoma and VIPoma (<1%). 2,10 
A tumor’s malignant potential is often related to the rate of growth and size of the tumor. Retrospective 
data demonstrates that patients with non-functional pancreaticoduodenal tumors with increased tumor size (>30 
mm vs. 10 mm – 30 mm vs <10 mm) have shorter survival times.11 Early surgical intervention for non-functional 
pancreatic neuroendocrine tumors with a size of ≥ 20 mm has become standard of care.2 Functional tumors, on the 
other hand, have potential to cause severe clinical sequelae and therefore surgical resection is recommended 
regardless of tumor size. In these situations, biochemical monitoring helps identify the type of tumor, which may 
be a microadenoma, and imaging is critical to localize the lesion.  


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Table 1. Characteristics of sporadic and familial neuroendocrine tumors (adapted from 12)
Characteristic
Well-differentiated neuroendocrine tumor or carcinoma
Poorly differentiated 
neuroendocrine 
carcinoma
Tumor grade#
1 (low)
2 (intermediate)
3 (high)
Ki67 index (%) and/or 
mitotic count (per 10 
HPF)
Ki67 <3% and <2 mitoses
Ki67 3–20% or 2–20 
mitoses
Ki67 >20% or >20 
mitoses
Clinical course and 
findings on CT or MRI
Indolent course
Intermediate
Rapid growth
Incidence FDG-PET-
positive lesions‡
Lower
Intermediate
Higher
Somatostatin receptor 
expression‡
Higher
Intermediate
Lower
Prognosis
Relatively good
Intermediate
Poor
First-line therapy
Curative surgery
Curative surgery
Curative surgery
Second-line therapy
Surgery (debulking of 
primary tumor and/or 
metastases)
SSA 
Sunitinib§
Everolimus§
Radiolabelled SSA (PRRT)
Chemotherapy for pNET
Interferon
HA(C)E, radioembolization 
or radiofrequency ablation
Surgery (debulking of 
primary tumor and/or 
metastases)
SSA
Sunitinib§
Everolimus§
Radiolabelled SSA (PRRT)
Chemotherapy for pNET
Interferon
HA(C)E, radioembolization 
or radiofrequency ablation
Chemotherapy
#According to the European Neuroendocrine Tumor Society and WHO guidelines
‡Findings on functional imaging.
§Registered for pNET.
Abbreviations: HA(C)E, hepatic artery (chemo)embolization; HPF, high power field; pNET, pancreatic 
neuroendocrine tumor; PRRT, peptide receptor radionuclide therapy; SSA, somatostatin analogue.


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Detection methods for NETs in MEN1
Many diagnostic recommendations, as well as data about surgery and chemotherapy, are derived from 
long-term experiences of specialists in the area, from clinical work of numerous specialist referral centers 
worldwide, and from trials performed on sporadic counterparts of MEN1-associated tumors. However, routine 
clinical practice incorporates a combination of anatomical imaging and functional or molecular imaging, most 
notably somatostatin receptor imaging, that has improved detection of NETs.13 In order to track and monitor these 
tumors, chest and abdominal imaging is recommended starting at diagnosis and every 1-2 years 
thereafter.2,14Anatomic imaging is important for localization of tumors (and their metastasis), and to evaluate 
vascularization, attenuation, invasion into local structures, and other characteristics like Hounsfield Units (MRI) 
or calcifications (CT).  Cross-sectional imaging with CT or MRI scan is recommended yearly for pancreatic NET, 
and every 1-2 years for thymic or bronchial NET.2 Non-functional pancreatic neuroendocrine tumors (pNETs), 
one of the main features of MEN1, have reported CT and MRI detection rates of 73% and 93% and specificity of 
96% and 88%, respectively.12 
Conventional imaging modalities can be limited by tumor size, the location and tissue contrast, resulting 
in some tumors escaping detection. For example, MRI is generally superior to CT for liver lesions, but CT may be 
able to detect pancreatic lesions with more accuracy.15 As a result, nuclear imaging augments anatomic imaging 
and is based on the fact that most well-differentiated neuroendocrine tumors express somatostatin receptors 
(SSTR), making radiolabeled somatostatin analogs an agent of choice.16 More than 70% of NETs in both the GI 
tract and pancreas express multiple subtypes, with a predominance of receptor subtypes 2 (SSTR2) and 5 
(SSTR5).17,18 Octreotide, an SSTR2 analog, is widely available as 111In-pentetreotide scintigraphy (also known 
as 111In-diethylene triamine penta-acetic acid-D-Phe1-octreotide or 111In-DTPA-octreotide) and has an overall 
sensitivity of detecting abdominal NETs of 78% (46% - 100%).19 However, this imaging modality fails to identify 
one-third of lesions identified at surgery, even in the case of sporadic gastrinomas.20 
68Ga-Dotatate in the detection of NETs in MEN1
A newer agent, 68Ga-Dotatate (DOTA-0-Tyr3-Octreotate) PET combined with CT imaging (PET/CT) was 
FDA approved in June 2016 for clinical imaging in patients with neuroendocrine tumors. The half maximal 
inhibitory concentration (IC50 ± SEM in nmol/l) for 68Ga-Dotatate at SSTR2 is 0.2 ± 0.04 compared to 22 ± 3.6 
for 111In-pentetreotide scintigraphy, demonstrating a ~100 fold higher affinity for SSTR2, and about an equal 
affinity for SSTR5.21 Superiority of localization compared to 111In-pentetreotide scintigraphy may be due to these 
higher binding affinity of the ligand for the SSTR2 and 5 receptors, higher spatial resolution allowing detection of 
microadenomas < 10mm, and better target-to-background ratios. 
68Ga Dotatate PET/CT for neuroendocrine tumors has been well documented in clinical trials for NETs22-
24. However, to date, only a small number of studies in patients with MEN1 are available: two with 68Ga-Dotatate 
and two with 68Ga Dotatoc (the affinity of 68Ga-Dotatate is approximately 10-fold higher than that of 68Ga-
Dotatoc in binding to SSTR2). The findings are summarized as follows:25-28
(1) Lastoria et al25 compared 68Ga Dotatate PET/CT with relevant conventional imaging (comprised of 
CT, MRI, duodeno-pancreatic endoscopic ultrasound, 111In-pentetreotide scintigraphy) in MEN1 
patients (n=18). 

68Ga Dotatate PET/CT identified 11/11 patients with pancreatic lesions, 9/12 patients with 
pituitary adenoma, 5/15 patients with parathyroid enlargements, and 5/7 patients with adrenal 
lesions. 


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
68Ga Dotatate PET/CT showed sensitivity and specificity of 100% and 100% in pancreas, 
75% and 83% in pituitary, 28% and 100% in parathyroids, and 62.5% and 100% in adrenals, 
respectively.

There was no mention of metastatic lesions, functional status of pancreatic lesions, and all 
patients were newly diagnosed.
(2) Sadowski et al26 compared 68Ga Dotatate PET/CT with 111In-pentetreotide scintigraphy and anatomic 
imaging with triphasic CT scan in MEN1 patients as part of a larger NET cohort and active 
surveillance program (n=26). 

68Ga Dotatate PET/CT detected 107 lesions, of which 33 were also detected by 111In-
pentetreotide scintigraphy and 43 were also detected by CT scan. In total, there were 18 
patients who had additional lesions detected by 68Ga Dotatate PET/CT.

 68Ga Dotatate PET/CT identified additional lesions in the pancreas, duodenum, gastric body, 
metastasis to the liver, lymph nodes, primary tumors in the appendix and lung. 

In an analysis based on available histology, 23 lesions were true positive and 5 lesions were 
false positive. It is not clear if any lesions were detected on MRI/CT that were not detected 
on 68Ga Dotatate. 
(3) Froeling et al28 (n=21 total, 19 MEN1) evaluated Ga-68 DOTATOC PET/CT compared to PET, CT 
contrast vs non-contrast and evaluated changes in treatment recommendations were recorded per a 
NET consensus 

Management alterations occurred in 10 of 21 (47.6 %) patients

68Ga-DOTATOC PET/CT conferred an overall sensitivity and specificity of 91.7 and 93.5 %, 
respectively, in detecting NET lesions

However, this study had a particularly low CT (contrast and non-contrast) 
sensitivity/specificity of 43.4%/61.3% and there was no mention of the location of the lesions 
that were not found on Dotatoc that were localized by other methods. 

Likewise, this study had a low detection rate of 89.2% in the contrast-enhanced Ga-68 
Dotatoc, lower than previously reported rate of 92% in NET29, and an unusually higher 
detection rate in non-contrast CT. 
(4) Albers et al27 (n=33 MEN1) evaluated 68Ga Dotatoc PET/CT as compared with conventional imaging 
(endoscopic ultrasound (EUS), MRI, CT and EGD) and found: 

68Ga Dotatoc failed to detect bronchial carcinoids (0/6; 6 detected by CT thorax), as well as a 
lower rate of detection of pancreatoduodenal NETs (44/117 detected by EUS). 

Conventional imaging (MRI, EUS, EGD and thoracic CT) detected 145 NETs in 27 (82%) of 
33 patients whereas 68DOTATOC PET/CT detected only 55 lesions in 23 (70%) of 33 
patients (p<0.001). 

The smallest NET visualized by 68DOTATOC PET/CT was 7 (range 7–50) mm in size, 
whereas conventional imaging, especially EUS, detected lesions as small as 2 (range 2–50) 
mm. 

The sensitivity of 68DOTATOC PET/CT for NETs <5, 5–10, 10–19 and >20 mm was 0, 29, 
81 and 100%, respectively, when using findings of all other imaging techniques as reference 
standard.


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In summary, the available data strongly support a role for the use of 68Ga-Dotatate PET/CT in 
neuroendocrine tumors in MEN1, even though the accumulation of evidence in this rare disease is limited. 
Nonetheless, there is discrepancy in the results in this cohort, suggesting that there may be (1) additional 
heterogeneity in tumor SSTR expression in MEN1 tumors, (2) unknown factors related to the location of the NET 
which may play a role in SSTR2 expression or that (3) differences or changes occur in SSTR expression in 
metastatic NET lesions compared to primary tumors. 
Tumor multiplicity, heterogeneity, location and metastasis: A call for further investigation
Koopmans et al19 have demonstrated that radionuclide tracer uptake may differ even within a single NET 
(Figure 1). In this example, a carcinoid tumor demonstrates uptake in one portion of the tumor based on 18F-
DOPA, while another area of the tumor has SSTR receptors that demonstrate uptake with octreotide scan. 
Metastatic NET lesions may require a multi-pronged approach as intra-individual heterogeneity may account for 
variations in detection, including de-differentiation. 
Figure 1. Intra-individual heterogeneity in the uptake of different tracers in a metastatic carcinoid patient (A: 18F-
DOPA PET, B: Octreotide scan, C: fusion image). From Koopmans et al19 
Albers et al.27 demonstrated that as many as 62% of neuroendocrine tumors detected by conventional 
imaging were missed by 68Ga Dotatoc PET/CT. These tumors were typically small (0-10mm) and frequently 
located in the lung. While the above studies report improved sensitivity in the detection of NETs in MEN1 as 


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compared to conventional 111In-Pentetreotide SPECT/CT, lesions that do not highly express SSTR may escape 
detection (estimated anywhere from 3-10% based on the available literature). 
In an NIH analysis30 of all-inclusive NET (n=131; sporadic and familial inclusive of Von Hippel-Lindau 
and MEN1), 16% (4/25 patients) with biochemical evidence of hormone excess symptoms failed to localize on all 
imaging modalities (68Ga-Dotatate PET/CT, 111In-Pentetreotide SPECT/CT, and CT/MRI). In addition, an 
analysis of the lesions detected by anatomic imaging demonstrated that 68Ga-Dotatate missed 25% of lung and 
mediastinum NETs that were detected by CT/MRI. The accumulation of this data suggests that additional imaging 
modalities would be helpful to detect small, sometimes functional, lesions, which occur in up to 5-10% in 
MEN131.  
Additionally, NETs may have different expression of SSTR subtypes and this expression many limit the 
ability to localize these tumors. Mizutani et al32 used RT-PCR and immunohistochemistry to analyze SSTR 
expression in 32 NETs (9 Grade 1 carcinoids: duodenum, colon, appendix, rectum and lung; 2 Grade 2: lung and 
stomach; 18 Grade 3: multiple locations including esophagus, lung, thymus, stomach, breast, etc). Interestingly, 
expression of SSTR2 was significantly high in the NETs located in the GI tract (Grade 1,2) but not in the lung 
(Figure 2). Likewise, expression of SSTR was lower in the hindgut carcinoids. While MEN1 most commonly 
manifests with foregut carcinoids,33 there are infrequently manifestations of hindgut carcinoids.26 Another analysis 
using in vitro receptor autoradiography demonstrated the variable presence of SSTR2 among various 
neuroendocrine tissues: 100% in gastrinomas (n=11), 70% incidence in insulinomas (n=27), and 60% in bronchial 
carcinoids (n=29).34 This data may suggest that treatment modalities with cold or ‘hot’ somatostatin analogs (e.g. 
peptide receptor radionuclide therapy [PRRT]) may have preferential benefit based on tissue of origin.
Figure 2. SSTR expression in a variety of NET, as published by Mizutani et al.32 
Detection of NETs in MEN1 are important for a variety of reasons, including: (1) detecting functional 
symptomatic NETs, or nonfunctional NETs at or exceeding the 20 mm size threshold, makes a surgical cure 
possible, (2) localizing metastatic disease prior to surgical resection is critical for staging, surgical plan, and 
follow-up and (3) documenting the presence of NETs by imaging techniques utilizing SSTR expression has 
implications for the therapy of NETs, particularly with respect to the possible use of PRRT with radiolabeled SST 
analogues.35 


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18F-DOPA for the detection of NET in MEN1
Another agent, 6-18F-fluoro-L-3,4-dihydroxyphenylalanine (18F-DOPA) has been investigated in NET. 
Particularly for MEN1, it shows promising results in both carcinoids as well as functional pancreatic NETs.19,36-43 
18F-DOPA is taken into the cells by L-Type Amino Acid Transporter 1 and 2 (LAT1 and LAT2), and has been 
useful in the diagnosis of pheochromocytoma/paraganglioma and suggested for use in medullary thyroid 
carcinoma.44-46 More recently, the use of 18F-DOPA has been evaluated in hyperinsulinemic hypoglycemia, with 
carbidopa.38-40 
In serotonin-secreting tumors (no mention if familial or sporadic), a head to head study by Haug et al37 of 
68Ga-Dotatate vs 18F-DOPA PET found that overall, 68Ga-Dotatate was superior to 18F-DOPA in 13 patients, but 
comparable in 12. However, for 13 patients with increased serotonin, 85% had localizing uptake with 18F-DOPA. 
While the overall sensitivity of localizing carcinoids was superior in 68Ga-Dotatate, 18F-DOPA PET demonstrated 
evidence of more metastatic lesions in two patients as compared to 68Ga Dotatate, particularly in the liver. 
In unpublished data made available from by Dr. Stephen Wank from protocol 08-DK-0098, which 
includes the evaluation of the detection of familial carcinoids with 68Ga Dotatate as compared to 18F-DOPA with 
premedication carbidopa (an efficient inhibitor of the peripheral aromatic amino acid decarboxylase, significantly 
reducing the physiological pancreatic FDOPA uptake, and has been shown to be beneficial in other NETs38,39,44-47) 
there are case detections as demonstrated below that highlight the utility of this added detection method (Figure 3-
6) in the detection of serotonin-secreting tumors. 
Figure 3. Patient example 1


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36
Figure 4. Patient example 2
Figure 5. Patient example 3


37
37
Figure 6. Patient example 4
While the carcinoids that are present in MEN1 are typically foregut carcinoids, which is a different 
population that those studied above, the detection of these lesions especially in the liver and lung may be of utility 
as the sensitivity of detection for those locations in the available MEN1 data have a lower detection rate in 68Ga-
Dotatate. Reports of mid- and hindgut MEN1 related carcinoids have been reported26,48-50 and could be detected 
by 18F-DOPA if they escape detection by 68Ga-Dotatate. In summary, MEN1 offers a unique patient population 
because of tumor multiplicity in distinct anatomical sites51,52, the simultaneous presence of (often small) 
functional tumors that may oversecrete various bioactive peptides or amines (including insulin, serotonin, 
somatostatin, histamine, and gastrin, among others), and the heterogeneity of tumor presentation and malignant 
potential.  Interestingly, it should be noted that the MEN1 mutation is not only found in hereditary syndromes. 
Somatic inactivating mutations in the MEN1 gene have been reported in sporadic tumors like those that are 
present in MEN1 syndrome. Unlike the ‘first hit – second hit’ hypothesis for inactivating mutations (germline -> 
somatic) in inherited familial conditions, in sporadic tumors, the 2-hits occur in the MEN1 gene for biallelic 
inactivations.  Using targeted sequencing of MEN1 exons or whole-exome sequencing approaches, the frequency 
of somatic MEN1 mutations reported in sporadic tumors is as follows: glucagonoma (60%), VIPoma (57%), non-
functioning PNETs (44%), gastrinoma (38%), bronchial carcinoid (35%), parathyroid adenoma (35%), lipoma 
(28%), insulinoma (2–19%), angiofibroma (10%), anterior pituitary tumor (3.5%) and adrenocortical tumor (2%). 
53  Similar to the distribution of mutations occurring in MEN1 hereditary germ line mutations, the somatic 
mutations are also spread over the entire coding region of MEN1 with no hot spots. This finding may have 
relevance in the future as we continue to explore the role of MEN1 mutations in tumorigenesis. 
Without a clear phenotype-genotype correlation nor adequate serum tumor markers for the detection and 
surveillance of non-functional NETs, tumor screening and detection is necessary for all patients.54 Using various 
standard-of-care imaging modalities (CT and MRI), the comparison of 68Ga-Dotatate and 18F-DOPA offers the 
opportunity to further characterize NETs based on molecular transporters, further delineate molecular tumor 
characteristics, and offer insights into promising therapeutic targets in the future.


38
38
Study Design 
Study Objectives

Primary Objective: To compare the efficacy of 68Ga-Dotatate PET/CT scan versus 18F-DOPA PET/CT, 
MRI and CT scan in detecting known and occult primary and metastatic bronchial, gastrointestinal and 
pancreatic neuroendocrine tumors.

Secondary Objectives: (1) To evaluate 68Gallium-Dotatate versus 18F-DOPA PET/CT uptake in NETs and 
its association with tumor differentiation. (2) To determine whether 68Gallium-Dotatate and/or 18F-DOPA 
PET/CT uptake value is predictive of tumor growth and/or disease progression and of its differentiation 
state.
Inclusion Criteria

Patients who have genetically confirmed MEN1 or have clinical criteria of MEN1 as per guidelines2 

Age ≥ 18 years of age

For females: Negative urine pregnancy test OR post-menopausal for at least 2 years OR patient has had a 
hysterectomy.
Exclusion Criteria

Serious underlying medical conditions that restrict diagnostic testing or therapy such as renal failure or 
congestive cardiac failure 

Patients unable or unwilling to give informed consent  

Pregnant or lactating women: Pregnant women are excluded from this study because the effects of 68Ga-
DOTATATE in pregnancy are not known. Because there is an unknown but potential risk for adverse 
events in nursing infants secondary to administration of 68Ga-DOTATATE in the mother, women who are 
breastfeeding are also excluded from this study

Patients that have recognized concurrent active infection

Patients with known hypersensitivity to carbidopa, or who are concurrently taking a nonselective 
monoamine oxidase (MAO) inhibitor. 
Patient Registration and Consent 
See page 3 of the protocol for consent procedures. Patients with MEN1 will be identified from the standard 
protocol by the investigators and consented to this additional substudy if they choose to participate. The potential 
candidates for the study will be screened for the eligibility criteria by the Principal Investigator and/or Associate 
Investigators, and research team. The patients who are eligible and sign the Research Imaging Substudy informed 
consent form in addition to the standard consent form.


39
39
Study Implementation and Methods
A 68Ga-DOTATATE PET/CT scan will be done per the standard FDA approved protocol.55 The 68Ga-
DOTATATE PET/CT will be compared to the 18F-DOPA and CT and MRI as outlined in the full amendment 
description. From the original protocol, 111In-Pentetreotide SPECT/CT will no longer be performed. All other 
testing (blood sampling, parathyroid testing, and other localization studies as required per patient’s biochemical 
evaluation) will continue as per the original protocol, on a yearly basis.  
For both scans, the subject reports to the PET scanning facility. All patients should fast for at least 4 hours prior to 
the PET examination, oral water is permitted. An intravenous line is inserted into an arm vein for administration 
of radiopharmaceutical. The subject then is placed in the PET/CT scanner, with the head, neck, chest, abdomen, 
pelvis, or extremities in the field of view. CT scanning is done to correct for attenuation of emitted radiation and 
localize the potential abnormalities. The tracer is prepared and tested for purity just prior to use. 
Scans are performed with the Siemens mCT (PET/CT) tomograph-scanner. Scans will be acquired in 3D mode, 
producing a reconstructed resolution of ~7 mm in all directions. Although at this point the CT portion of the PET 
scan is not considered diagnostic (because it is performed at a lower energy and without i.v. or oral contrast) in 
the future we may have the capability to perform a diagnostic quality CT in which case it could be substituted for 
conventional diagnostic CT that the patients currently undergo.
The two scans will typically be performed at least one day apart, but in extenuating circumstances, the scans may 
be performed on the same day, at least 7 hours apart. In these situations, the 68Ga-DOTATATE scan must be done 
first, in the morning, followed by 18F-DOPA in the late afternoon, due to the half-lives of the agents (68min for 
68Ga-DOTATATE, and there must be 6 half-lives between scans.)
Standardized 68Ga-Dotatate Protocol
Using the established IV line and, with the patient supine, around 5mCi of 68Ga-DOTATATE will be 
administered intravenously, followed by incubation for approximately 60 minutes. Then the patient will be 
positioned in a PET/CT scanner and images from the upper thighs to the base of the skull will be obtained. To 
date, there are no known allergic reactions to 68Ga-DOTATATE.
Standardized 18-Fluorodopa ([18F]-DOPA) PET Scan Protocol 
Carbidopa (200 mg) is given p.o. one hour before the injection of [18F]-DOPA. A dose of 12 mCi of [18F]-DOPA 
is injected i.v. over 1-3 minutes. The whole-body scan is started approximately 60 minutes after [18F]-DOPA is 
administered. [18F] DOPA is produced by using a standard procedure as indicated in the IND. Altogether, the 
[18F]-DOPA PET scanning will proceed for up to 2 hours on the Siemens mCT. Typically scans will extend from 
the top of the skull to the upper thighs.
Clinical Evaluation
As per the natural history protocol, patients will be evaluated based on the manifestations of their disease. The 
current lab testing as outlined in the protocol will continue, and the addition of 18F-DOPA and 68Ga-Dotatate will 
be added to the protocol based on availability during the week of testing. However, Octreotide scanning will no 
longer be utilized. 


40
40
Example of Calendar
Day 0 
(Sunday)
Day 1 
(Monday)
Day 2 
(Tuesday)
Day 3 (Weds)
Day 4 (Thrs)
Day 5 
(Friday)
Day 6
(Sat)
Admission
History/Physical 
exam
Blood work
Pregnancy test 
if appropriate
CT 
C/Ab/Pelvis
Consults as 
needed
MRI 
C/Ab/Pelvis
And MRI 
Pituitary
18F-DOPA 
68Ga 
DOTATATE
D/C
HUMAN SUBJECTS PROTECTIONS 
Rationale For Subject Selection
Patients with MEN1, with unknown primary tumor or metastatic neuroendocrine disease found on anatomic 
imaging (CT/MRI) or patients with biochemically active disease will be selected for this study. Both functional 
and non-functional solid tumors will be included in this study. Furthermore, asymptomatic and symptomatic, and 
both sporadic and familial cases of NETs in the setting MEN1 will be included. Patient selection for this protocol 
will not be based on gender, race or ethnic background.
Participation of Children
Children below the age of 18 will not be included on this protocol. Only patients age 18 and older will be eligible 
for this substudy because the research PET/CT scans are being investigated to their potential to characterize and 
identify neuroendocrine tumors and metastasis which are uncommon manifestations in children under the age of 
18. Thus, the risk:benefit ratio of this additional research radiation may not be justified at this time in this 
population. Children will still be able to receive clinically indicated 68Ga-Dotatate scans in the standard natural 
history protocol. 
Evaluation of Benefits and Risks/Discomforts
There is the potential for direct benefit for patients participating in this study if the study results show 18F-DOPA 
PET/CT imaging to be more accurate than the current standard 68Gallium-DOTATATE at detecting primary 
lesions or metastasis. The future application of 18F-DOPA imaging modality in other patients could lead to early 
detection of solid gastrointestinal or pancreatic lesions and metastatic lesions, which would improve early 
management of these lesions and potentially have an impact on the overall course of the disease. 
Most complications are expected to be minor and require no treatment. There may be some discomfort 
associated with lying on the hard imaging table for the duration of the study. Risks and discomforts 
include the discomfort of an IV placement and the theoretical effects of the amount of additional radiation 


41
41
exposure. However, exposure to ionizing radiation is considered by the radiation safety committee 
(RSC) and quantified in the accompanying NIH Form 88-23. The RSC has determined that this 
substudy involves greater than minimal risk to the subject due to the research-related radiation of the 
68Ga-DOTATATE, 18F-DOPA and PET/CT imaging.  
[18F]-DOPA and 68Ga-DOTATATE has been used at the NIH in several clinical protocols.  They are 
investigational agents approved by the FDA for use under IND #35513 and 119098, respectively (IND Sponsor is 
NIH Clinical Center). Carbidopa is a peripheral decarboxylase inhibitor with little or no pharmacological activity 
when given alone as a single dose of 200 mg as indicated for this procedure.
The effective radiation dose for adults per PET/CT scan with 5.0 mCi of 68Ga-DOTATATE administered is 0.91 
rem per year. The effective radiation dose for adults per PET/CT scan with 12.0 mCi of 18F-DOPA is 
administered is 1.4 rem per year. The cumulative research dose is below the maximum of 5.0 rem per year 
recommended by the radiology safety guidelines for adult research subjects. In this study, the subject will be 
required to lie still on his back for around 30 minutes during image acquisition in the PET/CT scanner, and this 
might produce some discomfort.
Data Sharing, Use, and Storage: 
The same policies and procedures for data sharing, use, and storage described in the main protocol pages 20-22 
will apply to this substudy. 
Reporting of Adverse Events 
IRB reporting will follow the same guidelines as the original protocol. In addition, if either the 68Ga-DOTATATE 
or 18F-DOPA radiotracer does not pass quality control by the manufacturer (external or NIH facility) and the scan 
needs to be cancelled, this information will be relayed to the IRB at the time of the continuing review.  
IND SPONSOR REPORTING CRITERIA
Unanticipated problems, adverse events and protocol deviations will also be reported to the IRB and the Clinical 
Director as outlined in the main protocol on page 21, consistent with SOP 16. 
Expedited Adverse Event Reporting Criteria to the IND Sponsor
An investigator must immediately report to the sponsor using the mandatory MedWatch form 3500a, any serious 
adverse event whether or not considered drug related, including those listed in the protocol or investigator 
brochure and must include an assessment of whether there is a reasonable possibility that the drug caused the 
event. 
Study endpoints that are serious adverse events (e.g. all-cause mortality) will be reported in accordance with the 
protocol unless there is evidence suggesting a causal relationship between the drug and the event (e.g. death from 
anaphylaxis).  In that case, the investigator must immediately report the death to the sponsor.
Expedited Adverse Event Reporting Criteria to the IND Manufacturer. 
Investigators will submit reports of all SAEs, regardless of attribution to RPS within 24 hours of learning of the 
events. For initial SAE reports, Investigators should record all case details that can be gathered within 24 hours on 
a SAE Report Form and submit the report via fax to:


42
42
Research Pharmaceutical Services (RPS) Drug Safety
Fax Number: (800) 516-5542 or (+ 1) 484 533-2817
Relevant follow-up information should be submitted to RPS’s Drug Safety Department as soon as it becomes 
available and/or upon request.
IND Safety Reports to the FDA (Refer to 21 CFR 312.32)
The Sponsor will notify the FDA of any unexpected fatal or life-threatening suspected adverse reactions as soon 
as possible but no later than 7 calendar days of initial receipt of the information using the MedWatch Form 3500a. 
The Sponsor is responsible for reporting any: 

suspected adverse reaction that is both serious and unexpected 

any findings from clinical, epidemiological, or pooled analysis of multiple studies or any findings from 
animal or in vitro testing that suggest a significant risk in humans exposed to the drug

clinically important increase in the rate of a serious suspected adverse reaction over that listed in the 
protocol or investigator brochure
to the FDA and to all investigators no later than 15 calendar days after determining that the information qualifies 
for reporting using the MedWatch Form 3500a. If FDA requests any additional data or information, the sponsor 
must submit it to the FDA as soon as possible, but no later than 15 calendar days after receiving the request.
FDA Annual Reports (Refer to 21 CFR 312.33)
The study Sponsor will submit a brief report annually of the progress of the trial within 60 days of the anniversary 
date that the IND went into effect as indicated in 21CFR 312.33, and any associated FDA correspondences 
regarding the IND annual report. 
STATISTICAL CONSIDERATIONS
Sample size
The primary goal of this study is to identify patients whose primary, unknown or metastatic lesions are 
characterized by SSTR2 expression documented by 68Ga-DOTATATE uptake compared to 18F-DOPA PET/CT. 
The anticipated recruitment time for the study will be 5 years. The total number of patients per year is expected to 
be 250. 


43
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