The use of an iodine 125 marker for perioperative localization in primary hyperparathyroidism, a pilot study.

The parathyroid glands provide the calcium metabolism in the human body through
the regulation of parathormone. Most people have four parathyroid glands, two
cranial and two caudal to the thyroid. However, 4-22% of those people have more
than four parathyroid glands. Primary hyperparathyroidism (PHPT) occurs if too
much parathyroid hormone is produced resulting in an increased calcium. The
diagnosis is made on biochemical abnormalities with an elevated serum calcium
and increased PTH. Causes of PHPT are mostly a solitary adenoma (~ 80-90%),
sometimes multiple adenomas (~ 5%), multiple hyperplasia (~ 5 - 10%), rarely
thyroid carcinoma (1%) and familiar in the context of a MEN 1 or MEN 2A
syndrome (~ 4.5%). Preoperative diagnostic tools are ultrasound and
thyroidscintigraphy. However, a CT scan or an MRI are also possible. The
treatment options for primary hyperparathyroidism are mainly surgical. If there
is a preoperative suspicion of a solitary adenoma in one of the parathyroid
glands, it is preferred to perform a minimally invasive parathyroidectomy
(MIP). With a MIP the surgeon makes a small incision in the neck above the
preoperatively localized parathyroid to find the adenoma and resects it. This
is in contrast with the conventional neck exploration in which the entire neck
is explored to search for one or more affected parathyroid glands. Parathyroid
glands can be localized on their entire embryological route in the neck and
mediastinum, so it can be difficult to localize parathyroid glands during
surgery. It is therefore important to perform a pre-operative localization
before a parathyroidectomy. Especially in a patient who has been operated in
the neck, localizing the affected parathyroid can cause problems with an
increased risk of damage to surrounding structures such as the recurrent
laryngeal nerve. There are several methods described to localize to the
parathyroid glands. A common method is preoperative marking using ultrasound
pre- or intraoperatively. This is a cheap, non-invasive and highly sensitive
technique in experienced hands. A different localization method has been the
use of 99m Tc-sestamibiscan. This technique requires a gamma probe
intraoperatively and logistic adjustment, because the injection of 99mTc has to
be performed on the same day as the operation should take place. There is also
an increased exposure to radioactive material. Taking into account the
logistical problems, this is in our view, certainly of importance in the
treatment of the patient. The most common method, the ultrasound marker, is
placed briefly prior to the surgery and is performed by the radiologist. This
requires proper planning in according to localization and surgery. In our
hospital localization is often not done for a minimally invasive procedure, in
cases where the preoperative diagnostics are good and clear. This comes
together with a potential risk of reoperation or even a conventional neck
exploration is required, with more risks and an increased morbidity.

To facilitate the localization of a parathyroid adenome during surgery (MIP)
with a radioactive iodine 125 (I-125) marker. This marker is placed
preoperatively ultrasound guided in the affected parathyroid gland, and can be
detected with a gamma probe. It is a cylindrical seed with a length of 4 mm and
a diameter of 0.8 mm, consisting of a titanium capsule containing material with
radioactive iodine-125. There are no studies or centers known which uses this
technique for preoperative localization of parathyroid.

The question we want to answer in this pilot study is twofold:
1. Is it possible to (safely) place iodine markers in the affected parathyroid
gland(s)? Without the migration of the iodine marker?
2. Is it possible to locate the iodine marker during a parathyroidectomy
procedure and perform a resection of the affected parathyroid gland? Does it
facilitate a minimally invasive parathyroidectomy, with a high success rate (>
95%) and with a low(er) risk of collateral damage?

Patients in whom primary hyperparathyroidism was diagnozed due to an adenoma /
hyperplasia / carcinoma, where a parathyroidectomy is indicated (symptomatic or
progressive asymptomatic), are eligible for localization with I-125. Because we
want to carry out a pilot study, a randomization between conventional
ultrasound-guided marking and an I-125 marker has not been performed. If this
study shows a safe use of an I-125 marker (ie, a similar risk of bleeding and
surgical yield as ultrasound-guided marking), the following study will consist
of a randomized study. The use of an I-125 marker will be compared with the
standard procedure (ultrasound-guided marking).

The indication for a MIP (with I-125 marking) is set by endocrinologists, head
and neck surgeons, radiologists and nuclear medicine physicians after a
multidisciplinary meeting that takes place once in every two weeks. If a
patient is eligible for a MIP with I-125 marker, this will be first discussed
by the endocrinologist and then by the head-neck surgeon with the patient. Then
the patient receives an information leaflet with an informed consent form.
Afterwards a conversation with one of the researchers is offered to the
patient. If the patient agrees, he will be included and a day will be scheduled
when both the I-125 marking and the surgery (MIP) will take place. At any time
the patient has all the rights to withdraw from the study. In that case, the
standard procedure is performed (ultrasound-guided marking and MIP). Enrolled
patients are insured by Medirisk. We choose in this study not to deviate from
the logistical situation as it exists in our hospital. This means that the
I-125 marker and the operation will take place on the same day. It is possible
that this may change in the future.

The placement of the I-125 marker is done by the radiologist and the
endocrinologist under ultrasound-guidens, preferably if possible in beachchair
position. If problems arise during the placement of the I-125 marker, depending
on the symptoms (direct) treatment is performed. The most common complication
is bleeding, however, asymptomatic and therefore require mostly no (direct)
treatment.

During the MIP procedure we will use a gamma probe (PI Medical Diagnostic
Equipment BV), to detect the I-125 marker. If the marker is localized (and thus
also the parathyroid gland) a resection will be performed. Then, a specimen
X-ray of the removed parathyroid tissue is made. This to capture and verify the
I-125 marker was actually removed from the patient. In addition, with the gamma
probe will be checked whether there is still radioactivity present in the
patient.The removed piece of parathyroid tissue is isolated and brought to the
anatomic pathology laboratory. They will safely remove the I-125 marker and
store it like described in the specific protocols.

After surgery, the patient received standard of care after parathyroid surgery
in the surgical ward. The postoperative treatment is determined by the
endocrinologist and head-neck surgeon. The final results of the pathology will
be discussed with the patient by the head-neck surgeon.

The use of these radioactive I-125 markers, is because of its activity (about
10 MBq), placed under the Nuclear Energy Authorization from the Amphia
Hospital. One of its requirements is that there is a good accounting of these
I-125 markers. The loss of an I-125 marker can lead to several problems. The
radiation protection / logistical support and management of the I-125 markers
is managed under the supervisory radiation specialist of Nuclear Medicine.
Since 2009 we are using the I-125 marker in breast surgery and since 2011 in
lung surgery. The placement of iodine markers has therefore been everyday
practice for the radiologists. In the operating room, the use of the gamma
probe and the removal of tissue (with an iodine marker) from the operating room
to the pathology laboratory is a well known practice nowadays.

The placement of an I-125 marker for the localization of a parathyroid gland
ultrasound guided.

Burden for the patient: additional information regarding explaintion of the
study

Risks of I-125 marker placement: possible minor bleeding, which is usually
asymptomatic and usually does not need (direct) treatment. The risk of
remaining the iodine marker is minimal, due to direct intraoperative control of
the specimen by means of X-rays. If the marker is not present in the specimen,
the surgeon immediately continues to search for the marker in the patient.