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• Definition of problem:
  • Primary hyperparathyroidism (PHPT):
    • Is the unregulated overproduction of parathyroid hormone (PTH) resulting in abnormal calcium homeostasis
• Frequency:
  • Primary hyperparathyroidism is more common in women:
    • The incidence being:
      • 66 per 100,000 person-years in females
      • 25 per 100,000 person-years in males
  • In a large study of 3.5 million enrollees in Kaiser Permanente of Southern California:
    • The incidence fluctuated over time but was not seen to decrease substantially​
    • On the contrary, the prevalence of primary hyperparathyroidism saw a substantial increase in this population
  • The mean age at diagnosis has remained between:
    • 52 and 56 years
• Etiology:
  • In approximately 85% to 90% of cases:
    • Primary hyperparathyroidism is caused by:
      • A single adenoma
  • In 15% of cases:
    • Multiple glands are involved:
      • Multiple adenomas:
        • Doble adenomas
        • Triple adenomas
      • Hyperplasia (4 glands)
  • Rarely, primary hyperparathyroidism is caused by parathyroid carcinoma
  • The etiology of adenomas or hyperplasia:
    • Remains unknown in most cases
  • Familial cases can occur as either part of the:
    • Multiple endocrine neoplasia syndromes (MEN 1 or MEN 2a)
    • Hyperparathyroid-jaw tumor (HPT-JT) syndrome
    • Familial isolated hyperparathyroidism (FIHPT)
    • Familial hypocalciuric hypercalcemia and neonatal severe hyperparathyroidism also belong to this category
  • The molecular genetic basis of MEN 1 (Wermer Syndrome):
    • Is an inactivating mutation of the MEN1 gene:
      • Located on chromosome band 11q13
  • MEN 2a is caused by a:
    • Germline mutation of the Ret proto-oncogene on chromosome 10. 
  • Germline mutation of HRPT2 localized on chromosome arm 1q:
    • Is responsible for HPT-JT
• While FIHPT is genetically heterogeneous

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• Incidence:
  • The incidence of PHPT has remained relatively stable in the last couple of decades
  • PHPT is more common in women than in men:
    • Two to three times higher in incidence rate in women
  • PHPT is more common in the elderly population:
    • The incidence increases with age
    • The incidence starts to increase at age 50:
      • 1 in 500 postmenopausal women will have PHPT
      • 1 in 1000 men over 50 will have PHPT
  • Incidence rates in the USA:
    • 60 cases per 100, 000 women
    • 20 cases per 100,000 men
• Prevalence
  • In the USA:
    • 1% of the postmenopausal female population will have PHPT
  • International prevalence rates:
    • 3% of the postmenopausal female population will have PHPT
  • The prevalence PHPT has risen in the last couple of decades:
    • From 1995 and 2010 it has tripled:
      • Women:
        • 76 to 233 cases per 100,000 women
      • Men:
        • 30 to 85 cases per 100,000 men
  • Gender:
    • African Americans have the highest prevalence of PHPT:
      • Followed by caucasians followed by Asians
    • Hispanics have a lower prevalence rate
  • Reason for the higher prevalence compared to incidence in PHPT:
    • Is that only 20% to 25% of patients with PHPT in the USA will end up having surgery
    • Only 50% of patients in the USA with nephrolithiasis and PHPT have surgery
    • Only 20% of patients with osteoporosis and PHPT in the USA go onto have surgery
    • The probability of having surgery decreases with age:
      • The older one gets the less likely they will be offered an intervention
• Genetics of PHPT:
  • Six primary conditions associated with an inherited predisposition for the development of PHPT:
    • MEN Type 1:
      • Incidence:
  • The incidence of PHPT has remained relatively stable in the last couple of decades
  • PHPT is more common in women than in men:
    • Two to three times higher in incidence rate in women
  • PHPT is more common in the elderly population:
    • The incidence increases with age
    • The incidence starts to increase at age 50:
      • 1 in 500 postmenopausal women will have PHPT
      • 1 in 1000 men over 50 will have PHPT
  • Incidence rates in the USA:
    • 60 cases per 100, 000 women
    • 20 cases per 100,000 men
• Prevalence
  • In the USA:
    • 1% of the postmenopausal female population will have PHPT
  • International prevalence rates:
    • 3% of the postmenopausal female population will have PHPT
  • The prevalence PHPT has risen in the last couple of decades:
    • From 1995 and 2010 it has tripled:
      • Women:
        • 76 to 233 cases per 100,000 women
      • Men:
        • 30 to 85 cases per 100,000 men
  • Gender:
    • African Americans have the highest prevalence of PHPT:
      • Followed by caucasians followed by Asians
    • Hispanics have a lower prevalence rate
  • Reason for the higher prevalence compared to incidence in PHPT:
    • Is that only 20% to 25% of patients with PHPT in the USA will end up having surgery
    • Only 50% of patients in the USA with nephrolithiasis and PHPT have surgery
    • Only 20% of patients with osteoporosis and PHPT in the USA go onto have surgery
    • The probability of having surgery decreases with age:
      • The older one gets the less likely they will be offered an intervention
• Genetics of PHPT:
  • Only 5% to 10% of patients with PHPT will with have an underlying genetic predisposition
  • Six primary conditions associated with an inherited predisposition for the development of PHPT:
    • MEN Type 1:
      • Pituitary Tumors
      • PHPT:
        • Has almost 100% penetrance
        • It is the first endocrine disease to manifest
        • It manifests at a young age
      • Pancreatic neuroendocrine tumors:
        • Duodenal and gastronomes
      • Foregut carcinoid tumors:
        • Lung
        • Thymus
      • Adrenal adenomas
    • MEN Type 2A:
      • Medullary thyroid carcinoma:
        • 100% penetrance
        • First endocrinopathy to manifest
      • Pheochromocytoma
      • PHPT:
        • Only 20% to 30% develop PHPT
        • Will depend on the RET mutation (codon)
        • They develop mild hypercalcemia
        • More common to see multi gland disease but you can also get one gland disease
        • Age of onset is younger:
          • Two decades earlier than sporadic PTHP
    • MEN Type IV:
      • Phenotypically similar to MEN type 1
      • Mutation CDKNIB gene
    • Hyperparathyroidism jaw tumor syndrome (rare):
      • Ossifying fibromas
      • Mixture of renal tumors, uterine fibroids
    • Familial hypocalciuric hypercalcemia (FHH – predisposes to hypercalcemia):
      • FHH is mainly classified into three different types depending on the genetic cause
      • FHH type 1:
        • Is the most common type of FHH and is caused by changes (also known as pathogenic variants or mutations) in the CASR gene
        • The protein made from the CaSR gene:
          • The calcium-sensing receptor (CaSR protein), monitors and regulates the level of calcium in the blood
      • FHH type 2:
        • Is caused by changes in the GNA11 gene
      • FHH type 3:
        • Is caused by changes in the AP2S1 gene
      • All three types of FHH are inherited in:
        • An autosomal dominant manner
      • In rare cases, FHH may be caused when a person’s immune system mistakenly makes antibodies that attack the CaSR protein:
        • The autoimmune form of FHH is not known to be caused by changes in a specific gene
      • Diagnosis of FHH:
        • Is suspected by high levels of calcium in the blood:
          • Especially when there are no other symptoms present
        • Further blood and urine tests may be used to rule out other possible causes
        • Genetic testing can confirm the diagnosis of FHH, except in rare autoimmune cases
      • Treatment:
        • Is typically considered unnecessary because most people with FHH do not have symptoms
        • If pancreatitis occurs, removal of the parathyroid gland may be recommended
    • Isolated familial PHPT
• Management of inherited PHPT:
  • In many cases PHPT is the first manifestation of a hereditary syndromic disease:
    • Goal of surgery is to normalize PTH and provide best chances for long term disease free outcome
  • Pitfalls in imaging in patients with MEN type 1:
    • Present with parathyroid gland asymmetry:
      • Most of this cases are secondary to hyperplasia not adenoma
  • The gold standard for the management of MEN type 1 is:
    • Bilateral neck exploration with a subtotal parathyroidectomy or total parathyoidectomy with autotransplantation (to the sternocleidomastoid muscle of the neck or the brachioradialis muscle of the forearm):
      • Biochemical cure are very similar between both approaches
      • With autotransplantation there is a 3% to 10% risk that the autotransplanted gland does not take leading to hypoparathyroidism:
        • For this reason cryopreservation might be a good option (they can be kept in this state for up to 2 years)
    • Remember that 3% to 5% of the cases of MEN type 1 might have super numerary glands:
      • This glands might hide in the thymus / thryothymic ligament or other ectopic locations
  • Intraoperative PTH measuring:
    • Allows us to decide how much of a gland remnant can be left behind to achieve longterm cure:
      • Achieving a intact PTH less that 40 pg/dl supports a longer long term free of recurrence
    • If the intraoperative PTH is very low it can helps us decide to autotransplant a gland to decrease that incidence of postoperative permanent hypoparathyroidism
  • Management of MEN type IIa:
    • All of this patients will have manifested with medullary thyroid cancer (MTC) or will be diagnosed with MTC and PHPT at the same time
    • The operative report of the thyroid cancer case is required along with the pathology report:
      • Talking with the surgeon that performed the thyroidectomy will be beneficial
    • At least two localizing studies that are concordant
    • Use cryopreservation in re due cases:
      • Because we might not have the information of how many glands were removed or injured during the thyroid surgery
    • Autotransplantation might be a good option when managing PHPT because MTC commonly recurs in the neck
    • If operating for the MTC and PHPT at the same time:
      • The surgery for PHPT remove the abnormal gland check intraoperative PTH (make sure it is normal) and leave the rest of the normal glands in situ
    • If subtotal thyroidectomy is performed:
      • Leave a portion of a gland that is about the same size as a normal gland
      • Make sure it is well vascularized
      • If possible leave an inferior gland:
        • They are easier to localize than a superior gland in re due cases
        • Prevents deep dissection close to the RLN in re due cases

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• Toxic Nodular Goiter (TNG):
  • Generally causes milder symptoms than Graves’ disease
• In the absence of contraindications:
  • Beta-blockers may be used for symptomatic relief:
    • While awaiting results of definitive treatment
  • Beta-blockers may also be appropriate for patients with:
    • Atrial fibrillation and rapid ventricular response
  • Propranolol has been widely used to block T4 to T3 conversion:
    • A theoretic benefit
  • A selective beta-blocker:
    • Such as atenolol:
      • May be used in patients who cannot tolerate propranolol
  • If beta-blockers are contraindicated:
    • A calcium channel blocker may be useful
• Definitive Treatment:
  • Toxic Nodular Goiter:
    • RAI therapy (with ¹³¹I) and surgery:
      • Are effective options for the definitive treatment for TNG
    • The long-term use of thionamide antithyroid drugs (ATDs):
      • Is not favored:
        • Unless either ¹³¹I therapy or surgery is contraindicated
    • Thionamides, however, may be used before surgery:
      • Especially in older patients:
        • Until euthyroidism is restored
    • Radioactive iodine:
      • The clinical utility of RAI therapy in the management of TNG:
        • Is well established
      • If radioactive iodine uptake (RAIU) is adequate and the patient is not a good surgical candidate:
        • RAI is the treatment of choice 
      • Although the dose of ¹³¹I may be calculated on the basis of uptake determinations and gland weight:
        • TNGs are relatively resistant to ¹³¹I:
          • Because of their larger size and relatively lower uptake of iodine:
            • For these reasons, some clinicians increase the standard dose:
              • By 20% to 50%
      • Frequently, RAI doses between:
        • 15 and 50 mCi (555 and 1850 MBq) are administered
      • In a report from Mayo Clinic, Jensen et al:
        • Treated their patients with a mean dose of 37 mCi (1370 MBq) (range, 6.3 to 150 mCi [233 to 5550 MBq]):
          • After 1 year of follow-up:
            • 16% of patients were hypothyroid
      • Danaci et al. treated TNGs with a fixed dose of 16.6 mCi (631 MBq) ¹³¹I and reported:
        • A cumulative relapse rate of:
          • 39% at 5 years
        • Cumulative incidence of hypothyroidism of:
          • 24% at 5 years
      • In a large prospective study involving 130 consecutive patients with TNGs and a mean follow-up of 6 years:
        • 92% of patients were cured after one or two treatments with ¹³¹I
        • Thyroid volume was reduced by a mean of 43%, and adverse effects were few
        • Patients were treated with a median dose of 10 mCi (370 MBq)

• Generally, after RAI most patients are euthyroid within 2 to 4 months:
  • Although sometimes achieving euthyroidism may take longer
• Although most patients treated with RAI achieve long-term euthyroidism:
  • 10% to 24% of these patients eventually become hypothyroid:
    • Regardless of the dose used
  • RAI is associated with a 20% chance of recurrence:
    • In which case patients may receive a second dose of ¹³¹I or opt for thyroidectomy
    • These patients should not be given iodide preoperatively:
      • Because of the risk of exacerbating thyrotoxicosis
• Surgery:
  • Total thyroidectomy:
    • Is recommended for patients with:
      • Large goiters causing obstructive symptoms such as:
        • Choking
        • Dyspnea
        • Dysphagia:
          • Hoarsness
    • For those who refuse RAI therapy
    • Surgery may also be indicated when a suspicious cold or growing nodule is identified in a TNG
    • Surgery is an excellent option for patients who:
      • Decline RAI therapy and also for pregnant women 
  • Two issues with the operation:
    • The extent of thyroidectomy remains somewhat controversial
    • In the past, some clinics have preferred subtotal thyroidectomy to minimize complications such as:
      • Recurrent laryngeal nerve damage and hypoparathyroidism
    • In current practice, most surgeons perform:
      • A total thyroidectomy for bilateral benign nodular goiters:
        • This is what I recommend
    • Also, the trend in recent decades:
      • Suggests that RAI is being increasingly considered as:
        • An attractive, effective alternative to surgery in TNG
      • For example, a study from Mayo Clinic showed that between 1950 and 1974:
        • 83% of patients had surgical treatment
        • 17% had RAI treatment
      • Between 1990 and 1999, the figures were:
        • 53% for surgery and 47% for RAI
• Thionamide antithyroid drugs:
  • Thionamide antithyroid drugs are the preferred transient treatment:
    • During pregnancyuntil delivery
  • They should also be considered for patients who are not candidates for or who decline definitive treatment
  • Treatment is generally indefinite with thionamide ATDs:
    • Generally because permanent remission is never achieved in TNG
• Graves’ Disease:
  • In the management of Graves’ disease:
    • Treatment preferences vary substantially by geographic region
  • This was suggested by the outcome of an international survey of endocrinologists from the United States, Europe, and Japan:
    • Among physicians in the United States:
      • Thionamide ATDs were selected as the primary form of therapy for a “typical 43-year-old healthy woman” by only approximately 30%, whereas 69% chose RAI treatment and 1% opted for surgery
    • By contrast, 77% of European physicians and 88% of Japanese physicians selected thionamide ATDs as the preferred primary treatment, with RAI therapy as the second choice.
  • Thionamide antithyroid drugs:
    • Thionamide ATDs inhibit biosynthesis of thyroid hormones:
      • Biochemical euthyroidism is usually achieved within 6 to 8 weeks after initiation of therapy
    • Currently, three thionamide ATDs are available:
      • Methimazole
        • Available in the United States
        • Half-life of methimazole in plasma is:
          • 3 to 5 hours
      • Propylthiouracil
        • Available in the United States
        • Half-life of  in plasma of propylthiouracil is 1 to 2 hours
      • Carbimazole:
        • Which is metabolized to methimazole:
          • Is sometimes used in Europe and Asia
    • Methimazole has a longer duration of action:
      • Although both drugs are effective for more than 5 hours because they accumulate in thyroid cells
    • Initial daily doses range from:
      • 10 mg to 40 mg of methimazole usually once daily
      • 100 to 150 mg of propylthiouracil every 6 to 8 hours daily
      • 15 to 45 mg daily of carbimazole usually in one dose up to three divided doses
    • The decision to use methimazole / carbimazole or propylthiouracil:
      • Is a matter of physician preference:
        • Because both agents are equally effective
      • However, observations over several decadeshave shown that methimazole and its prodrug carbimazole are better than propylthiouracil in controlling more severe hyperthyroidism;
        • But propylthiouracil should not be routinely used because of potential fatal hepatotoxicity
    • This has led to the recommendation that methimazole / carbimazole:
      • Be the first-line drug when ATD therapy is initiated:
        • Either for primary treatment or to prepare a patient for RAI therapy or surgery
      • An exception to this rule has been pregnancy:
        • During which propylthiouracil has been preferred:
          • Because of rare reports of birth defects associated with methimazole
        • Propylthiouracil has also been used in patients with:
          • Minor reactions to methimazole but who, nonetheless, prefer to continue ATD therapy 
        • Propylthiouracil may also be preferable in patients with:
          • Life-threatening thyrotoxicosis:
            • Because of its additional inhibition of T4 to T3 conversion
    • It is crucial to evaluate patients clinically and biochemically (with serum T4 and TSH measurements) regularly:
      • From 6 to 8 weeks after the initiation of ATD treatment:
        • Until the patient is biochemically euthyroid and every 8 to 12 weeks thereafter
      • Once the patient is euthyroid, the ATD dose may be reduced
    • Some clinicians favor adding levothyroxine to the ATD regimen as part of a block-replacement regimen:
      • Without reducing the original ATD dose:
        • To minimize the number of patient visits and maintain a more normal stable TSH:
          • This addition to the regimen causes no difference in the remission outcome compared with titration of ATD alone
        • The concern about compliance and the advantages of ATD alone have ensured that combination treatment (thyroxine and ATD) has not been widely adopted
    • It has been determined from various reports that treatment with thionamide ATDs for 12 to 18 months is optimal:
      • Resulting in long-term remission in 40% to 60% of patients with Graves’ disease:
        • With higher remission rates in women than in men
      • The likelihood of sustained remission:
        • Is greater in patients with:
          • Mild hyperthyroidism
          • Small goiter
          • Low or undetectable TSHR-Ab titers:
            • Than in those with moderate to severe hyperthyroidism or T3 toxicosis, large goiter, and high TSHR-Ab titers
      • If hyperthyroidism recurs:
        • Other modes of therapy (RAI or surgery) are considered
      • Most relapses following cessation of thionamide ATDs;
        • Occur shortly after the ATDs are discontinued:
          • Generally within the first few months:
            • Although they may occur several years later:
              • Therefore, clinical and biochemical evaluation is necessary 2 months after ATD withdrawal and periodically at regular intervals thereafter
    • As with all other drugs, thionamide ATDs may cause adverse effects:
      • As early as 2 weeks after initiation of therapy or later in the course of therapy:
        • It is essential to instruct patients on how to deal with these adverse reactions
    • The most serious and rare complication:
      • Agranulocytosis:
        • Should be ruled out:
          • By obtaining white blood cell and differential counts:
            • If fever and signs of infection such as sore throat occur while the patient is on thionamide ATD therapy

Adverse Effect	Propylthiouracil (100 to 150 mg/day)	Methimazole (10 to 40 mg/day)
Minor reactions
—Fever, rash, arthralgia	5% to 20%	5% to 20% (dose related)
Major reactions
—Agranulocytosis	0.2%-0.5% (not clearly dose related)	0.2%-0.5% (dose related)
—Hepatotoxicity (hepatitis)	30% (< 1% severe)	Cholestatic (usually reversible, with few deaths reported)
—Vasculitis	ANCA +	Rare
ANCA, antineutrophil cytoplasmic antibody

• Inorganic Iodine:
  • Iodine given in pharmacologic doses (as Lugol solution or as a saturated solution of potassium iodide):
    • Inhibits the release of thyroid hormones for a few days or weeks:
      • After which its antithyroid action is lost
    • For this reason it is not used routinely:
      • But short-term iodine therapy is useful in:
        • The preparation of patients for surgery
        • After RAI therapy to hasten the fall in serum T3 and T4 concentrations to normal:
          • Although this is not a routine indication
      • In the treatment of thyrotoxic crisis
    • The usual dose of Lugol solution (5% iodine and 10% potassium iodide in water) is:
      • 0.1 to 0.3 mL three times daily
    • The usual dose of potassium iodide is:
      • 60 mg (1 drop) three times daily
• Radioactive iodine therapy:
  • In use for more than 60 years:
    • RAI therapy is established as an effective, relatively inexpensive, and safe treatment option for Graves’ disease
  • The objective of RAI therapy is to:
    • Destroy sufficient thyroid tissue to cure hyperthyroidism
  • The goal of treatment is to:
    • Render the patient either euthyroid or hypothyroid:
      • Depending on the willingness of the physician to risk the possibility of persistent hyperthyroidism
  • Much attention has focused on achieving euthyroidism:
    • By adjusting the RAI dose:
      • But there is little consensus regarding the most appropriate dose schedule
  • The regimens used include the traditional method of:
    • Repeated low doses (2 mCi)
    • Fixed doses
    • Doses calculated on the basis of:
      • The size of the thyroid
      • The RAIU
      • The turnover of ¹³¹I
  • Because it has proved impossible to titrate doses for individual patients accurately to guarantee a euthyroid state:
    • The majority of physicians in the United States:
      • Prefer to administer a single, relatively large dose:
        • 10 to 20 mCi initially with the intent of:
          • Inducing thyroid ablation and the development of hypothyroidism
      • Thyroid function is then assessed 6 to 8 weeks after RAI administration and possibly every month thereafter:
        • To monitor the development of hypothyroidism:
          • Especially during the first 6 months after RAI treatment
      • When hypothyroidism is detected by TSH elevations:
        • Levothyroxine treatment should be initiated:
          • To maintain the TSH level in the normal range (0.5 to 3 mIU/L)
      • However, if hyperthyroidism persists:
        • Another RAI dose may be delivered:
          • But should not be given until at least 6 months after the first dose
  • Before RAI treatment is started:
    • Patients should be informed of the precautions needed after RAI
    • Rarely patients may experience:
      • Mild anterior neck pain after RAI
      • A short-lived exacerbation of hyperthyroid symptoms:
        • Caused by the leakage of preformed thyroid hormones from a damaged thyroid gland
      • Worsening of Graves’ ophthalmopathy:
        • Especially among smokers:
          • May be observed after ¹³¹I treatment
        • Risk is reduced by:
          • Cessation of smoking and the administration of glucocorticoids, namely, prednisone:
            • Different regimens are available, but most agree on the regimen of oral prednisone:
              • Administration 1 to 3 days after RAI treatment at 0.3 to 0.5 mg/kg daily, and the dose is tapered until withdrawal about 3 months later
  • Whether to pretreat patients with thionamide ATDs:
    • Until they are euthyroid before ¹³¹I administration is a matter of debate:
      • Retrospective studies have shown that the efficacy of treatment with ¹³¹I:
        • Is decreased after propylthiouracil:
          • It is best to discontinue ATDs a few days before RAI is given
    • Previously RAI was reserved for adults because of the lack of long-term data in children and adolescents:
      • More recently, in properly administered doses, data have shown that RAI is the ideal form of therapy for Graves’ disease in children
    • It remains absolutely contraindicated:
      • During pregnancy and lactation
• Surgery:
  • Because of the higher relapse rates seen with subtotal thyroidectomy, or near-total thyroidectomy:
    • Total thyroidectomy:
      • Is the recommended surgical procedure for the treatment of Graves’ hyperthyroidism
  • It usually results in postoperative hypothyroidism:
    • Requiring lifelong levothyroxine replacement
  • Thyroidectomy is preferred in patients with:
    • Large goiters:
      • Especially those with tracheoesophageal compression symptoms)
    • Coincidental suspicious thyroid nodules
    • Contraindications to ¹³¹I or ATDs
    • In those who refuse RAI treatment or are pregnant when hyperthyroidism is difficult to control
  • Surgical morbidity, including:
    • Permanent hypoparathyroidism
    • Vocal cord dysfunction caused by recurrent laryngeal nerve injury,
    • Infection
    • Hematoma
      • Is low in experienced centers
  • Any patient with hyperthyroidism scheduled to undergo surgery:
    • Should be treated with thionamide ATDs:
      • To restore euthyroidism
  • Alternative methods of preoperative therapy include:
    • Thionamide ATDs combined with beta-blockers:
      • Propranolol:
        • 40 to 80 mg three times a day or
      • A longer-acting beta-adrenergic antagonist:
        • Atenolol, 50 mg/day
    • Potassium iodide:
      • 40 mg three times a day for 10 days
    • Potassium iodide (several drops per day for 10 days) in combination with propranolol (40 to 120 mg per day):
      • May be another alternative:
        • Any of these regimens virtually eliminates the risk of postoperative thyrotoxic crisis
  • Indefinite follow-up is essential after thyroidectomy:
    • With an adequate replacement dose of levothyroxine that maintains TSH within the range of normal
• Pregnancy:
  • Appropriate management of hyperthyroidism during pregnancy is important for the mother’s health and for the course of the pregnancy
  • Moreover, the quality of management may have considerable impact on the progeny:
    • Both in fetal and in neonatal life and on the long-term health of the child
  • The most common form of hyperthyroidism during pregnancy:
    • Is mostly the result of Graves’ disease:
      • Its adequate control is essential
  • Pregnant hyperthyroid women should be treated with:
    • Thionamide ATDs:
      • Most clinicians prefer propylthiouracil:
        • Although both propylthiouracil and methimazole:
          • Are shown to cross the placenta equally
      • As noted previously, rare reports of birth defects associated with methimazole exist
      • The minimum dose of ATD that keeps maternal thyroid function around or slightly above the upper limit of normal should be used:
        • To avoid fetal hypothyroidism and fetal goiter:
          • Therefore, frequent monitoring of the mother and the fetus is necessary
      • Mothers may experience:
        • Exacerbation of thyrotoxicosis after delivery
      • Newborns may have:
        • Transient thyroid dysfunction when exposed to ATDs or may develop transient neonatal hyperthyroidism resulting from the passage of TSHR antibodies through the placenta
  • Postpartum propylthiouracil:
    • Is also preferred for nursing mothers:
      • Because less drug appears in breast milk than with methimazole
  • Surgical thyroidectomy:
    • In the second trimester of a pregnant woman with Graves’ disease:
      • Is performed only in the case of uncontrollable hyperthyroidism:
        • That threatens the health of the woman or when ATDs are not tolerated
    • If thyroidectomy is performed, this should be followed by a systematic and a careful follow-up evaluation of the thyroid state of the fetus

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• Serum total T4 (TT4) and total T3 (TT3) concentrations:
  • Are a measure of both the bound and free hormone levels of these two hormones
• TT4 or TT3 levels should be interpreted in the context of the clinical situation:
  • Because many clinical conditions and medications alter the concentrations of thyroid hormone binding proteins and / or compete with the binding of thyroid hormones to the binding proteins:
    • As such, measured TT4 and TT3 levels may be affected, even though the bioactive free levels and thus, the thyroidal status, remain unchanged
• T3 is the active thyroid hormone:
  • It is primarily useful in the diagnosis and management of patients with hyperthyroidism
  • It occasionally can be used to differentiate stimulation induced thyrotoxicosis / Graves’ disease (TT3 / TT4 ratio > 20) from destruction induced thyrotoxicosis / subacute thyroiditis (TT3 / TT4 ratio < 12):
    • This assessment can be further augmented when TSH is considered as serum levels of TSH are generally suppressed in most untreated Graves’ patients, whereas they usually were not completely suppressed in patients with painless thyroiditis or subacute thyroiditis
  • Measurement of serum TT3 is not usually helpful if hypothyroidism is suspected:
    • Because the activity of 5’deiodinas type 2 enzyme (Dio2):
      • Which converts T4 to the biologically active T3:
        • Increases while serum T4 falls:
          • Thus maintaining normal T3 levels until the overall thyroid hormone levels are very low
• rT3, which may be elevated during nonthyroidal illness:
  • Is not biologically active:
    • As such, the utility of measuring it and other forms of inactive iodothyronine are limited during the evaluation of thyroid status
• Finally, the human anti-mouse antibodies (HAMAs) that interfere with TSH testing:
  • Can also interfere with the thyroid hormone assays
  • HAMA positivity:
    • May result in artificially elevated or reduced TT4, TT3, FT4, and FT3 levels
  • Patients who have received therapeutic monoclonal antibody treatment may be at increased risk of develop interfering positive HAMA titers

• Oral cavity SCC is staged using the AJCC 8th edition TNM system:
  • Which uniquely incorporates:
    • Depth of invasion (DOI) into the T classification and extranodal extension (ENE) into the N classification:
      • Two major changes from prior editions
• The following summarizes the complete staging system per the NCCN Head and Neck Cancer Guidelines
• Primary Tumor (T) Classification:
  • The T category is determined by both tumor size and DOI (measured from the basement membrane of adjacent normal mucosa, not tumor thickness):
    • Tis — Carcinoma in situ
    • T1 — Tumor ≤2 cm, DOI ≤5 mm
    • T2 — Tumor ≤2 cm with DOI >5 mm, OR tumor >2 cm and ≤4 cm with DOI ≤10 mm
    • T3 — Tumor >2 cm and ≤4 cm with DOI >10 mm, OR tumor >4 cm with DOI ≤10 mm
    • T4a — Tumor >4 cm with DOI >10 mm, OR invasion of adjacent structures (through cortical bone of mandible/maxilla, maxillary sinus, skin of face):
      • Superficial erosion of bone/tooth socket alone by a gingival primary does not qualify
    • T4b — Invasion of masticator space, pterygoid plates, skull base, and/or encasement of internal carotid artery
• Regional Lymph Nodes (N) — Clinical (cN):
  • N0 — No regional lymph node metastasis
  • N1 — Single ipsilateral node ≤3 cm, ENE(−)
  • N2a — Single ipsilateral node >3 cm but ≤6 cm, ENE(−)
  • N2b — Multiple ipsilateral nodes, none >6 cm, ENE(−)
  • N2c — Bilateral or contralateral nodes, none >6 cm, ENE(−)
  • N3a — Any node >6 cm, ENE(−)
  • N3b — Any node(s) with clinically overt ENE(+)
• Regional Lymph Nodes (N) — Pathological (pN):
  • The key difference from clinical N staging is that ENE now upstages nodal disease:
    • pN1 — Single ipsilateral node ≤3 cm, ENE(−)
    • pN2a — Single ipsilateral node ≤3 cm with ENE(+), OR single ipsilateral node >3–6 cm and ENE(−)
    • pN2b — Multiple ipsilateral nodes, none >6 cm, ENE(−)
    • pN2c — Bilateral/contralateral nodes, none >6 cm, ENE(−)
    • pN3a — Any node >6 cm, ENE(−)
    • pN3b — Single ipsilateral node >3 cm with ENE(+), OR multiple nodes any with ENE(+), OR single contralateral node of any size with ENE(+)
• Key Points on the 8th Edition Changes
  DOI vs. tumor thickness:
  • DOI is measured from the horizon of the basement membrane of adjacent uninvolved mucosa perpendicularly to the deepest point of invasion — distinct from tumor thickness, which is measured from the surface:
    • For every 5 mm increase in DOI, the T category increases by one level (cutoffs at 5 mm and 10 mm)
  • Upstaging impact:
    • Incorporation of DOI led to upstaging of approximately:
      • 29% to 36% of patients in the T category
    • ENE led to upstaging in:
      • ~13% for the N category
  • The 8th edition demonstrates improved prognostic discrimination compared to the 7th edition (Harrell’s C-index 0.70–0.74 vs. 0.65–0.69 for OS and DSS)
  • Clinical implications:
    • Patients with small tumors (formerly T1) upstaged to T3 based on DOI >10 mm may benefit from postoperative radiotherapy, even in the N0 setting
    • DOI is an independent predictor of regional nodal metastasis and disease-specific survival

The final 15-year analysis of the landmark SOFT and TEXT phase III trials provides the longest follow-up to date for endocrine therapy in premenopausal women with hormone receptor-positive early breast cancer.

These data reinforce that treatment intensity should be tailored according to recurrence risk. 

Key takeaways:

• Ovarian function suppression (OFS) significantly reduces breast cancer recurrence compared with tamoxifen alone.

• Exemestane + OFS provides the greatest reduction in recurrence and distant metastases, particularly in HER2-negative disease.

• The largest overall survival benefit was observed in high-risk patients, especially:

• Women < 35 years old
• High-grade tumors
• Patients requiring adjuvant chemotherapy

• For lower-risk patients who did not require chemotherapy, long-term survival remained excellent regardless of the endocrine regimen, emphasizing the importance of individualized treatment decisions.

Clinical Message

This landmark study confirms that not every premenopausal patient requires the same endocrine therapy. Careful risk stratification allows us to maximize oncologic outcomes while minimizing unnecessary toxicity. Personalized, multidisciplinary breast cancer care remains essential for achieving the best long-term results. 

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Rodrigo Arrangoiz, MS, MD, FACS, FSSO
Breast Surgeon | Head & Neck Surgical Oncologist | Thyroid & Parathyroid Surgeon
Assistant Professor of Surgery, New York Medical College School of Medicine
Division of Surgical Oncology
Braman Comprehensive Cancer Center
Mount Sinai Medical Center – Miami, Florida

#BreastCancer #BreastSurgery #SurgicalOncology #BramanCancerCenter #MountSinaiMiami #HormonePositiveBreastCancer #PremenopausalBreastCancer #SOFTTrial #TEXTTrial #EvidenceBasedMedicine #CancerCare

👉The combination of 123I/99mTc-sestamibi subtraction planar pinhole scintigraphy with SPECT/CT and ultrasound improves the specificity of gland localization for minimally invasive parathyroidectomy.

👉https://doi.org/10.1016/j.amjsurg.2018.06.027

👉Rodrigo ARRANGOIZ MS, MD, FACS miembro de Sociedad Quirúrgica SC y pionero en MEXICO de la paratiroidectomia mínimamente invasiva radioguiada

👉For more information: http://www.hiperparatiroidismo.info

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