Hurthle Cell Cancer Surgery
Hurthle cell cancer surgery is introduced here. The correct operation depends upon the hurthle cell cancer, patient evaluation, and surgeon’s expertise. What is most important, is that all of the hurthle cell cancer is removed from the neck in the initial surgery! That surgery can frequently be a minimally invasive surgery with a small incision about an inch in length in the lower front of the neck. But that is not really the point. The issue is all of the hurthle cell cancer must be effectively removed at the initial surgery. The problem is that both the patient and the surgeon may not know that the thyroid mass is a hurthle cell cancer until after the surgery is completed. Still, an expert thyroid cancer surgeon is necessary to accomplish the right surgery from the beginning independent of the timing of the diagnosis (which will be after you have recovered from the surgery)!
For hurthle cell cancer, surgery, by far, is the most common first treatment. In fact, hurthle cell cancer surgery is not only the first treatment but is commonly the only treatment that may be indicated. It is critical that a highly experienced surgeon and the correct surgery is obtained the first time. Hurthle cell cancer surgery should only be done by expert surgeons. By choosing the right surgeon and surgery, you are cured. The wrong choice may lead to repeated surgeries, complications, and even an inability to ultimately control the hurthle cell cancer! Be well aware, that you may not know that you have a hurthle cell cancer. Most people that have developed hurthle cell cancers have been told that you have a “hurthle cell lesion” or similarly, a “hurthle cell neoplasm” (means “new growth”). But the surgery you will require for these non-specific diagnoses from FNA, still needs to be a surgery that addresses the complete removal of your hurthle cell cancer. Be aware, the wrong first surgery with a hurthle cell cancer can be a dire misstep! Don’t be lulled into a sense that it is likely a benign thyroid lump so anyone can take it out.
Thyroid surgery was one of the first ever described surgeries in medicine, but early on it wasn’t very pretty or safe. Over the past 100 years, thyroid surgery has evolved into its current state of the art by some of the most recognized names in surgical history. Today, in skilled hands, thyroid hurthle cell cancer surgery may be considered an art form in its own right.
Hurthle cell cancer surgery must be considered in several different lights when you think about the neck. Surgery of the thyroid gland itself and surgery for the surrounding soft tissues and lymph nodes around the thyroid gland. Since the lymph nodes are commonly involved with hurthle cell cancers, I strongly advocate for routine removal of lymph nodes for hurthle cell lesions and neoplasms or known hurthle cell cancers. The basic concept is however very simple, remove all of the cancer.
- One is removal of about half of the thyroid gland called thyroid lobectomy.
- The other is removal of all of the thyroid gland and is called total thyroidectomy.
- The third type of thyroidectomy is called a subtotal thyroidectomy where almost all of the thyroid gland is removed
In this surgery, the entire thyroid gland is removed. A small incision in the lower neck is required which is about an inch in length unless the thyroid mass requires a longer length to allow it to be “delivered”. The length of a total thyroidectomy incision is no longer than an incision for a thyroid lobectomy. Realize that most hurthle cell cancers are 4 cm or greater and therefore the respective incision must be long enough to accommodate the largest dimension of the hurthle cell cancer or thyroid itself. All of the critical structures on both sides of the thyroid are maintained including all four parathyroid glands and all four nerves that provide movement (recurrent laryngeal nerves) and sensation to the voice box (superior laryngeal nerves). The lymph nodes along the side and beneath the hurthle cell cancer/neoplasm are also removed during this surgery to make sure that they are not cancerous as well.
- The hurthle cell cancer is more than 2.5 centimeters or 1 inches
- The hurthle cell cancer appears to have extended outside of the surface of the thyroid gland (called its capsule)
- The hurthle cell cancer has spread to the lymph nodes underneath the thyroid gland (called central compartment lymph nodes [also called Level VI or VII lymph nodes] of the neck) or the lateral neck. This is commonly found!!!!!!
- The hurthle cell cancer has spread to distant sites outside of the neck (most commonly the lungs, bones, or liver)
- The hurthle cell cancer patient with a small thyroid cancer, does not accept the potential of another surgery to remove the remainder of the thyroid gland if a new thyroid cancer should develop within the remaining thyroid tissue.
- The hurthle cell cancer patient desires the ability to monitor blood levels of thyroglobulin for their cancer surveillance
Extended or Complicated Thyroidectomy
Hurthle cell cancer can sometimes be more aggressive locally when it presents. Imaging prior to surgery such as ultrasound or CT may detect these aggressive hurthle cell cancers. In some instances, imaging may not adequately predict this invasive component of the hurthle cell cancer. Let me tell you that these hurthle cell cancers are not “the good cancers” and the first surgery must be the right surgery and the only surgery!!. In these cases, an expert surgeon that recognizes those “more aggressive” intraoperative findings such as growth or extension of the cancer outside of the thyroid gland or invasion of the cancer into adjacent structures such as the nerve to the voice box (recurrent laryngeal nerve), breathing tube (trachea), voice box, or esophagus-must adapt the surgery to adequately address the complete removal of the cancer. Unfortunately, occasional thyroid surgeons are commonly unprepared to perform the appropriate surgery and a subsequent surgery for persistent disease will be required.
Hurthle Cell Cancer Surgery for Central Compartment Lymph Nodes (the lymph nodes beneath and surrounding the thyroid gland, breathing tube (trachea) and swallowing tube (esophagus)
The removal of the lymph nodes of the central neck should be performed initially when the thyroid gland is removed in the treatment of hurthle cell cancer on the side of the cancer or hurthle cell neoplasm. It may be necessary following the initial surgery if the hurthle cell cancer recurs or persists. The central compartment lymph node surgery spares all critical structures including the nerves to the voice box and all parathyroid glands not directly involved by cancer. Central compartment dissection extends from the carotid arteries on both sides of the neck, below to the blood vessels of the upper chest, and above to where the blood vessel of the upper portion of the thyroid gland begins off of the carotid artery (called the superior thyroid artery).
In hurthle cell cancer when it is recurrent or persistent, these surgeries are complex, difficult, and complicated with the risk of further recurrence. These surgeries should only be undertaken by the most skilled of thyroid cancer surgeons. Recurrent or persistent hurthle cell cancer is commonly not confined within lymph nodes and be found sometimes in just deposits in the area of prior surgery (not even within lymph nodes). The central compartment neck dissection is more commonly seen as a method of three dimensionally “getting around the cancer” more often than just removing the lymph nodes themselves.
- In hurthle cell cancer, the central compartment lymph nodes are at risk of containing cancer in at least 20% of patients. That risk increases with the size of the hurthle cell cancer. Even prior to surgery, most central compartment lymph nodes can be well examined with high quality ultrasound to determine if they are cancerous. Enlarged or abnormal lymph nodes seen on ultrasound next to the thyroid gland before surgery should be examined. These abnormal lymph nodes undergo fine needle aspiration (FNA) examination to determine whether cancer is present. In this way, an expert ultrasound can tell the difference between a hurthle cell neoplasm and a hurthle cell cancer even before you go to surgery.
- Some lymph nodes which lay immediately underneath the thyroid gland cannot be seen until the time of surgery and required a skilled surgeon to identify them and can then be confirmed during the surgery by a process called frozen section pathology. Some lymph nodes are below the collar bone and also not seen by ultrasound but can be seen by CT scan before surgery. They should be identified by the expert thyroid cancer surgeon prior to surgery (in the planning process) and sent to the pathologist to be examined while you are asleep during the surgery!!
- If hurthle cell cancer is determined to be present in central compartment lymph nodes at any time in a patient’s lifetime, an expert surgeon who does this surgery routinely is needed to remove the lymph nodes in the central compartment, on both sides) and spare the nerves to the voice box and the critical glands that control calcium (parathyroid glands).
- In larger hurthle cell cancers (and hurthle cell neoplasms!!!!) which are greater than one inch or have grown outside of the capsule of the thyroid, removal of the lymph nodes of the central compartment on the side of the cancer should be done routinely since:
- The nerve to the voice box (recurrent laryngeal nerve) has already, by necessity from the thyroid surgery itself, been significantly identified along most of its course and another surgery on the same side would be more difficult because of scarring and this subsequent surgery would put the nerve to the voice box at high risk for injury.
- The risk of microscopic lymph node metastasis is over 20%. The removal of these local lymph nodes with hurthle cell cancer also allows surgery to “get around” the cancer.
Hurthle Cell Cancer Surgery For Spread of Cancer to Lymph Nodes Along The Side Of The Neck (anterolateral neck)
- Just the presence of enlarged lymph nodes does not mean hurthle cell cancer has spread and does not require additional surgery
- A procedure called an anterolateral neck dissection (or modified neck dissection), in untreated patients, should only be performed in instances of ultrasound with fine needle aspiration confirmed hurthle cell cancer spread to lymph nodes in the side of the neck
- The hurthle cell cancer anterolateral neck dissection is not the same neck dissection as for other cancers that occur in the neck. All thyroid cancers spread to particular areas of the neck called levels. Removing just some of the lymph nodes has been called “cherry picking” and is the wrong surgery! A thyroid cancer expert surgeon trained and experienced to perform modified neck dissections specifically for thyroid cancer is needed to prevent recurrent or persistent disease.
- The anterolateral neck dissection, in skilled hands, spares all critical nerves, muscles, and blood vessels which are not directly involved with cancer (very rarely are critical structures involved by hurthle cell cancers). It is an approximately 40 minute surgery that removes lymph nodes and fatty tissue.
- In rare circumstances, hurthle cell cancers may show extensive growth into the the soft tissues of the neck. In such circumstances, a special surgery that can “get around” the hurthle cell cancer can be safely performed to remove all of the cancer.
Hurthle Cell Cancer Surgery in Sites Other Than The Neck
Hurthle cell cancer surgery is uncommonly proposed as a treatment approach when disease has spread to distant sites. Although surgery is not commonly proposed for distant spread of hurthle cell cancer, consideration for surgery for distant disease is based upon the expert thyroid cancer team evaluation and considers the following issues:
- Where is the hurthle cell cancer distant disease located?
- What are the risks and benefits of surgery?
- Are there other sites of distant spread?
- What hurthle cell cancer treatments have already been used?
- What were the outcomes of other treatments for the hurthle cell cancer?
- How fast is the hurthle cell cancer growing?
- What are the patient’s treatment desires?
- What are the other treatment options?
- What is the hurthle cell cancer pathologic type (what do the cells look like under the microscope?
- What are the hurthle cell cancer genetic mutations found?
Hurthle Cell Cancer/ or Hurthle Cell Neoplasm Robotic Surgery
Robotic surgery for the thyroid was developed largely in South Korea and brought to the United States several years ago as a “tool” in thyroid surgery. Its proposed benefits were to be the following:
- Absent or less noticeable neck incisions
- Improved visualization
- Less Surgeon Fatigue
Although we have been trained and performed robotic thyroid surgery, the following is the reality of robotic thyroid surgery:
- Incisions are tremendously longer but just not located on the front of the neck
- In hurthle cell cancer, it is a one sided surgery approach to a frequently required two-sided surgery!
- The instruments used to perform the surgery are not as refined or delicate as the instruments used to perform the minimally invasive neck surgeries. (think of all the delicate structures that we have shown you here)
- Multiple surgeons are required
- The surgeon has no ability to “feel” in the neck. The fingers are the surgeon’s third eye. Subtle changes in feel, hardness or extension of cancer can be totally unappreciated.
- It is not minimally invasive by any measure. It is maximally invasive but just at a distance from where the surgery is focusing.
- It is a much longer surgical procedure by any measure (the set up of the robot is longer than the average thyroid lobectomy).
- It is an inferior surgical approach to manage hurthle cell cancer or a hurthle cell neoplasm
- Unanticipated findings during surgery may not be able to be adequately addressed robotically.
- It may be an acceptable surgical approach for clearly known benign thyroid surgery.
Most importantly, the ability to perform a surgery well, is not an indication for a surgery!!! Robotic thyroid surgery is an inferior surgical approach in managing hurthle cell cancer, any other type of thyroid cancer, or any thyroid lesion at risk of being a potential thyroid cancer, especially a hurthle cell neoplasm or lesion.
Hurthle Cell Cancer Treatment with Radioactive Iodine (RAI)
Hurthle cell cancer, itself, is not an indication for RAI treatment. RAI treatment is a type of internal radiation therapy. RAI treatment was the first true “targeted therapy” developed in the treatment of cancer. The hurthle cell cancer patient swallows a radioactive iodine form of iodine called iodine 131 (I-131) in a liquid or pill (capsule) form. The RAI is absorbed through digestion and circulated throughout the body in bloodstream. The hurthle cell cancer cells can pick up the radioactive iodine wherever they are located in the body.
If you had almost any type of thyroid cancer, 25 years ago, you would have almost certainly been treated with surgery and RAI. Today, only a small percentage of hurthle cell cancer patients undergo post-0perative RAI treatment. RAI therapy is primarily beneficial only when the hurthle cell cancer patient has undergone a total thyroidectomy (complete removal of the thyroid gland) for their thyroid cancer.
Hurthle cell cancer should only undergo RAI treatment (therapy) in instances where the risk of the hurthle cell cancer coming back is greater than the potential risks of RAI therapy itself. In hurthle cell cancer treatment, there is no urgency for the rapid delivery of RAI. RAI can be given as early as 4-5 weeks following total thyroidectomy but can be delayed for months or even years following surgery.
- The Hurthle cell cancer had evidence of invasion (or extension) outside of the thyroid gland capsule (called soft tissue extension)
- Hurthle cell cancer has grown into blood vessels
- The hurthle cell cancer cells look angry/aggressive microscopically
- Older patients above 50 years of age
- The Hurthle cell cancer that has spread to any lymph nodes in the neck (in any area of the neck)
- The hurthel cell cancer team desire to destroy any additional thyroid tissue
- Hurthle cell cancer that has spread to distant sites (lungs, bones, and liver)
- The hurthle cell cancer takes up the iodine
Preparation for Radioactive Iodine Treatment
Thyroid hurthle cell cancer patients must be taken off of levothyroxine thyroid hormone (T4 hormone) for a minimum of four weeks, taken off of liothyrionine thyroid hormone (T3 hormone) for a minimum of two weeks, or receive a medication which is TSH (which is a pharmaceutical production of the Thyroid Stimulating Hormone [TSH] produced as a recombinant protein which is identical to the TSH normally produced by the pituitary gland). Additionally, hurthle cell cancer patients must be on a low iodine diet for a minimum of four weeks to starve their body of iodine. Those patients which have undergone CAT scans with intravenous contrast must wait until their blood iodine levels have been adequately decreased (usually at least two months). Note, a desire to treat with radioactive iodine should never prevent the use of necessary CAT scans for the evaluation of a hurthle cell cancer patient.
What are the potential risks of RAI treatment?
- Dry mouth and or eyes
- Narrowing of the drainage duct of the eye’s tears leading to excessive tearing down the cheek
- Decreased production of blood cells by the bone marrow (with very high RAI doses)
- Swelling in your cheeks from inflammation or damage to the saliva producing glands (the spit glands)
- Short term changes to taste and smell (usually resolve in 4-8 weeks)
- Lowered testosterone levels in males (usually resolves within the first year)
- Change in periods (menstruation) in women (usually resolves within the first year)
- Second tumors (these are rare and can be discussed with your thyroid cancer treatment team)
Hurthle Cell Cancer Treatment With RAI (Radioactive Iodine): How and How Much Treatment?
Hurthle cell cancer guidelines for post operative treatment with radioactive iodine were last updated in the American Thyroid Association 2015 edition. After your doctor has prepared your body for RAI by either stopping your use of thyroid hormone pills or giving injections of recombinant TSH (Thyrogen), they may choose to give you a small dose of RAI and perform a special nuclear scan called a Thyroid Cancer Uptake Study. In this scan, the image will determine if there is any evidence of iodine uptake in the body. Approximately 90% of patients will have some uptake of iodine following a total thyroidectomy. Hurthle cell cancer is not the only reason that iodine can be taken up by tissue. One such issue is retained thyroid tissue. How much retained thyroid tissue is related to the thoroughness of your thyroid surgeon in performing a total thyroidectomy. The amount of RAI chosen to treat the hurthle cell cancer is based upon:
- The level of thyroglobulin while the TSH is elevated for the scan (this is called a stimulated thyroglobulin)
- The percent uptake of RAI in the Thyroid Cancer Uptake Scan
- The hurthle cell cancer locations of disease (uptake)
- Is there evidence of distant spread of the hurthle cell cancer?
- Prior RAI treatment doses
As an alternative to a thyroid cancer uptake study of a small dose of RAI, some doctors may choose to give you their prescribed dose of RAI as a definitive treatment. Following either of the above approaches to treat a hurthle cell cancer with RAI, a scan is obtained following the therapeutic dose in 48 to 72 hours to determine the location and percent uptake of the radioactive iodine. The strength of radioactive iodine is described in millicuries. The hurthle cell cancer treatment dose of radioactive iodine ranges from about 30 millicuries to up to 200 millicuries. Low risk hurthle cell cancers and eradication of small amounts of retained thyroid tissue are treated with lower doses of RAI in the 30-50 range. Intermediate risk hurthle cell cancers such as patients above 50 years of age with lymph node spread are treated in the middle ranges. Hurthle cell cancers with high risk features (vascular invasion, soft tissue invasion, angry looking microscopic cells) or distant spread of disease are treated with higher doses up to the 200 millicurie range.
Hurthle cell cancers can also be treated with radioactive iodine based upon a method called dosimetry. This is a radiation physics determination utilizing complex mathematical methods to determine the actual dose of radiation that will be delivered to a particular area of hurthle cell cancer. In some circumstances, dosimetry can allow much higher doses of radioactive iodine to be prescribed when hurthle cell cancers effectively take up the treatment. Hurthle cell cancers, however, rarely require dosimetry for definitive treatment.
Thyroid Hormone Suppressive Therapy for Hurthle Cell Cancer
Thyroid hormone is a necessary hormone for life. The thyroid gland normally produces thyroid hormone to adequate levels. The amount of thyroid hormone produced by the body is strictly controlled by a portion of the brain called the pituitary gland. When the body has too little thyroid hormone, the pituitary gland senses the low levels and produces TSH (thyroid stimulating hormone). When thyroid hormone levels are elevated (too high), the pituitary does the opposite and lowers its production of TSH. This is called an endocrine feedback loop.
Most hurthle cell cancer cells and all normal thyroid cells have a site on the surface of the cell that can stimulate their growth. This site is called a “receptor” and when stimulated by TSH (thyroid stimulating hormone) in normal thyroid cells it causes increased production of thyroid hormone. In hurthle cell cancer cells, this same TSH receptor can stimulate the growth of these cancer cells. Obviously, it is undesirable concept to have TSH stimulate your hurthle cell cancer cells to grow. Therefore the goal in the hurthle cell cancer patient is to keep TSH levels low. So how is this done?
When hurthle cell cancer patients take thyroid hormone pills, the body does not tell the difference between this medication and what the thyroid gland produces. The more thyroid hormone circulating in your body causes the TSH production to drop. Therefore, hurthle cell cancer patients are usually given thyroid hormone to decrease TSH levels to prevent the growth of the cancer cells. Giving thyroid hormone to hurthle cell cancer patients is called thyroid hormone suppressive therapy when the goal is to decrease the pituitary production of TSH. Hurthle cell cancer patients that have thyroid suppressive therapy will have TSH levels that are below the “normal range”. To those that are caring for hurthle cell cancer patients but unfamiliar with the concept of thyroid suppressive therapy, they may mistake the dose of thyroid hormone for being “too high”. Thyroid suppressive therapy is a delicate balance between elevated but not “too high” thyroid hormone doses. It is therefore important that only your skilled thyroid hurthle cell cancer specialist manage your thyroid hormone. But it is also important that communication be open between your thyroid hurthle cell cancer specialist and those that are caring for your primary care needs.
When is External Beam Radiation Therapy Indicated for Hurthle Cell Cancer?
Thyroid hurthle cell cancer treatment with external beam radiation therapy is not commonly required or indicated. The planning and implementation of radiation therapy is beyond the goals for this website. However certain principles must be emphasized. Radiation therapy is not a substitute for incomplete surgery. What is meant by that is all the thyroid hurthle cell cancer in the neck must be completely and effectively removed. Whenever feasible, hurthle cell cancer patients should be reduced down to microscopic remaining neck disease, at most, also sparing voice box and swallowing tube function. Radiation therapy should not be given as a substitute for incomplete surgery. As a general rule, choosing to treat a hurthle cell cancer with external beam radiation is a commitment that the surgeon believes that no meaningful re-operation will be feasible in the future and therefore radiation therapy is required to help control the hurthle cell cancer (microscopic disease) remaining in the neck. In these circumstances, external beam radiation therapy is quite effective. Hurthle cell cancer radiation therapy is also associated with significant short term and long term complications and effects that should not be taken lightly.
- Invade (grow into) the voice box (larynx), breathing tube (trachea) or swallowing tube (esophagus)
- Directly grow into the skin or deep structures in the neck
- Invade the tissues underneath the breast bone (sternum)
- are deemed unable to undergo another surgery if their cancer should return.
- Have spread to the spinal column and risk the spinal cord itself
- Have spread to the brain
- Have spread to bone and are causing pain or growth would place the bone at risk for fracture.
Hurthle Cell Cancer Treatment for Persistent or Recurrent Disease:
Follicular thyroid cancer treatment for recurrences (cancer that has come back) or persistence (cancer that remains after initial therapy) depends mainly on where the cancer is, although other factors may be important as well. The recurrence may be found by either thyroglobulin blood tests or imaging studies such as ultrasounds, radioiodine scans, CAT scan or PET imaging.
If there is concern that the hurthle cell cancer has come back in the neck, an ultrasound-guided biopsy is first done to confirm that it is really cancer. Remember, that the FNA of a mass in the neck may be called “hurthle cell lesion” or “hurthle cell neoplasm” and not recurrent or persistent hurthle cell cancer (because the cells cannot be called cancer just by looking at them) !!! Thus the thyroid cancer surgery expert must be able to put together all the important information together to determine the site(s) and diagnosis of the recurrent or persistent hurthle cell cancer.
Then, if the hurthle cell cancer appears to be resectable (removable), surgery is often used. The extent of surgery would depend upon the location or locations of the persistent or recurrent hurthle cell cancer and the prior surgeries and quality of surgeries that the patient has undergone. The sections of complicated thyroidectomy, central compartment surgery, and lateral neck dissection have been written for you and are appropriate for persistence or recurrent hurthle cell cancer in any of these locations. We have examples of surgeries for just these types of circumstances for you to watch. Thyroid hurthle cell cancer surgery very effectively manages neck disease, sparing function and cosmetic appearance but should only be performed by very high volume and experienced thyroid cancer surgeons. We have publications establishing our ability to control thyroid cancer recurrences or persistence in the neck approaching 98% when the thyroid cancer recurs in the thyroid location (central neck) or lateral neck (side of the neck).
Persistent or recurrent hurthle cell cancer in residual thyroid tissue is much more concerning for the potential for the cancer to extend directly into the breathing tube or voice box. Only the most skilled and experience thyroid cancer surgeons should manage such circumstances. The purpose of this specific thyroid hurthle cell cancer surgery is to maintain vocal and swallowing function, parathyroid function, and airway control. These are the most complicated and complex of all thyroid surgeries.
If the hurthle cell cancer shows up on a radioiodine scan (meaning the cells are taking up iodine), radioactive iodine (RAI) therapy may be used, either alone or with surgery. If the hurthle cell cancer does not show up on the radioiodine scan but is found by other imaging tests such as a, ultrasound, CAT scan, or PET scan, the hurthle cell cancer is termed non-radioiodine avid. The thyroid hurthle cell cancer treatment will be based upon interdisciplinary evaluation, disease locations and extent of disease.
Targeted Therapy and/or Chemotherapy
For hurthle cell cancer patients who have spread of their cancer to several places outside of the neck area and RAI and other treatments are not helpful or the cancer sites are getting bigger, new therapies have been developed and approved by the FDA (Food and Drug Administration). Although these FDA approved thyroid cancer targeted medications have been shown to be effective, none of these treatments are curative. Skilled physicians in prescribing these medications are required because of the necessity for close monitoring of symptoms, toxicities, and monitoring of the patient’s hurthle cell cancer.
The two approved targeted therapies (medication pills) in the management of thyroid cancer are Lenvima and Sorafenib. These medications are taken by mouth and frequently cause weight loss, fatigue, muscle wasting, hand and foot pain, changes in blood pressure and skin symptoms. The toxicities are directly related to the dose and frequency the medication is taken. Again, these medications cannot be taken indefinitely and do not cure thyroid hurthle cell cancer.
Hurthle cell cancer chemotherapy is rarely indicated except when used in combination with radiation therapy for the worst of the worst types of thyroid cancers growing into the breathing tube or swallowing tube. Experimental therapies such as new targeted therapies, immune therapy based treatments, and other novel approaches for hurthle cell cancer should be developed in institutions directed and capable of performing such investigational studies.