A Prospective Study of Publicly Funded Molecular Testing of Indeterminate Thyroid Nodules: Canada's Experience.

CONTEXT: Indeterminate thyroid nodules (ITNs) lead to diagnostic surgeries in many countries. Use of molecular testing (MT) is endorsed by several guidelines, but costs are limitative, especially in public healthcare systems like in Canada. OBJECTIVES: Primary objective: evaluate the clinical value of Thyroseq® v3 (TSv3) using benign call rate (BCR) in a real-world practice. Secondary objective: assess cost-effectiveness of MT. DESIGN: This is a multicentric prospective study. SETTING: This study was conducted in 5 academic centers in Quebec, Canada. PATIENTS OR OTHER PARTICIPANTS: 500 consecutive patients with Bethesda III (on 2 consecutive cytopathologies) or IV and TIRADS 3 or 4 nodules measuring 1 to 4 cm were included. INTERVENTION: MT was performed between November 2021 and November 2022. Patients with a positive TSv3 were referred to surgery. Patients with a negative TSv3 were planned for follow-up by ultrasonography for a minimum of 2 years. MAIN OUTCOME MEASURE: The BCR, corresponding to the proportion of ITNs with negative TSv3 results, was assessed. RESULTS: 500 patients underwent TSv3 testing, with a BCR of 72.6% (95% CI: 68.5-76.5; p<0.001). 99.7% of patients with a negative result avoided surgery. The positive predictive value of TSv3 was 68.2% (95% CI: 58.5-76.9). The cost-benefit analysis identified that the implementation of MT would yield cost savings of $6.1 million over the next 10 years. CONCLUSIONS: Use of MT (TSv3) in a well-selected population with ITNs led to a BCR of 72.6%. It is cost-effective and prevents unnecessary surgeries in a public healthcare setting.

Lenvatinib Therapy for Advanced Thyroid Cancer: Real-Life Data on Safety, Efficacy, and Some Rare Side Effects.

Context: The SELECT trial led to the approval of lenvatinib for the treatment of advanced radioiodine-refractory differentiated thyroid carcinomas (DTCs) but also revealed an important adverse event (AE) profile which may limit its use in clinical practice. Objective: We aim to describe the efficacy and toxicity profiles of lenvatinib in real life. Methods: We included all patients who received lenvatinib for an advanced DTC at our institution, enrolling 27 patients. We reviewed retrospectively electronic medical records to assess efficacy and AEs. Results: Among the 24 patients with evaluation of tumor response during treatment, overall response rate (ORR) was 37.0% (95% CI, 19.4%-57.6%), and disease control rate was 85.2% (95% CI, 66.3%-95.8%). The median progression-free survival (PFS) was 12 months (95% CI, 7.5-16.5]. The most prevalent AEs were hypertension (77.8%), fatigue (55.6%), and weight loss (51.9%). At least one grade ≥ 3 AE was experienced by 25/27 patients (92.6%), mostly hypertension (59.3%). Lenvatinib was discontinued due to AEs in 13/27 patients (48.1%). Interestingly, 1 patient experienced a grade 4 posterior reversible encephalopathy syndrome, and another developed a Takotsubo cardiomyopathy. Conclusion: The safety profile of lenvatinib in our cohort was similar to that reported in the literature, with a predominance of hypertension. Rigorous blood pressure control is therefore essential to avoid discontinuing therapy. We also report 2 severe and rarely described AEs that physicians should watch for. As for efficacy, although less than in the SELECT trial, ORR and PFS were similar to other real-life studies.

A risk-adapted approach to the use of radioactive iodine and external beam radiation in the treatment of well-differentiated thyroid cancer.

BACKGROUND: Both radioactive iodine (RAI) and external beam radiation therapy (EBRT) offer important clinical benefits in properly selected patients with differentiated thyroid cancer. With the increased emphasis on a risk-adapted model for the management of thyroid cancer, it is important to identify which patients are most likely to benefit from radiation therapies given in the adjuvant setting and as treatment of gross residual disease. METHODS: This review compares the authors' current management practices with the recommendations of published guidelines from both the National Comprehensive Cancer Network and the American Thyroid Association. RESULTS: Because of the lack of prospective randomized studies on either RAI or EBRT in differentiated thyroid cancer, recommendations must be based on retrospective cohort studies that vary in selection criteria, histologies, sample size, inclusion criteria, and follow-up. CONCLUSIONS: RAI has an important adjuvant therapy and treatment function in properly selected patients. Likewise, EBRT is associated with increased locoregional control and palliative therapeutic effects in high-risk patients.

Isolated Pheochromocytoma in a 73-Year-Old Man With No Clinical Manifestations of Type 1 Neurofibromatosis Carrying an Unsuspected Deletion of the Entire NF1 Gene.

Pheochromocytomas (PHEOs) are a rare cause of endocrine hypertension that requires genetic counseling since at least 30% of PHEOs are associated with a germline mutation in a susceptibility gene. Neurofibromatosis type 1, NF1 is amongst the 16 known causing genes for pheochromocytomas/paragangliomas. We report a case of a 73-year-old man with PHEO in whom genetic testing revealed a large pathogenic heterozygous deletion of 1.14 Mb encompassing the entire coding sequence of the NF1 gene while the patient showed no signs of clinical NF1.This case illustrates that the diagnosis of NF1 should not be excluded in patients with PHEO in the absence of clinical diagnosis of the disease and support that older patients with PHEO should also be offered genetic counseling.

Serum calcitonin nadirs to undetectable levels within 1 month of curative surgery in medullary thyroid cancer.

OBJECTIVE: Because serum calcitonin (CT) is a reliable marker of the presence, volume, and extent of disease in medullary thyroid cancer (MTC), both the ATA and NCCN guidelines use the 2-3 month post-operative CT value as the primary response to therapy variable that determines the type and intensity of follow up evaluations. We hypothesized that the calcitonin would nadir to undetectable levels within 1 month of a curative surgical procedure. SUBJECTS AND METHODS: This retrospective review identified 105 patients with hereditary and sporadic MTC who had at least two serial basal CT measurements done in the first three months after primary surgery. RESULTS: When evaluated one year after initial surgery, 42 patients (42/105, 40%) achieved an undetectable basal calcitonin level without additional therapies and 56 patients (56/84, 67%) demonstrated a CEA within the normal reference range. In patients destined to have an undetectable CT as the best response to initial therapy, the calcitonin was undetectable by 1 month after surgery in 97% (41/42 patients). Similarly, in patients destined to have a normalize their CEA, the CEA was within the reference range by 1 month post-operatively in 63% and by 6 months in 98%. By 6 months after curative initial surgery, 100% of patients had achieved a nadir undetectable calcitonin, 98% had reached the CEA nadir, and 97% had achieved normalization of both the calcitonin and CEA. CONCLUSION: The 1 month CT value is a reliable marker of response to therapy that allows earlier risk stratification than the currently recommended 2-3 month CT measurement.

Rapid and Complete Remission of Metastatic Adrenocortical Carcinoma Persisting 10 Years After Treatment With Mitotane Monotherapy: Case Report and Review of the Literature.

Mitotane has been used for more than 5 decades as therapy for adrenocortical carcinoma (ACC). However its mechanism of action and the extent of tumor response remain incompletely understood. To date no cases of rapid and complete remission of metastatic ACC with mitotane monotherapy has been reported. A 52-year-old French Canadian man presented with metastatic disease 2 years following a right adrenalectomy for stage III nonsecreting ACC. He was started on mitotane which was well tolerated despite rapid escalation of the dose. The patient course was exceptional as he responded to mitotane monotherapy after only few months of treatment. Initiation of chemotherapy was not needed and he remained disease-free with good quality of life on low maintenance dose of mitotane during the following 10 years. A germline heterozygous TP53 exon 4 polymorphism c.215C>G (p. Pro72Arg) was found. Immunohistochemical stainings for IGF-2 and cytoplasmic ß-catenin were positive. Advanced ACC is an aggressive disease with poor prognosis and the current therapeutic options remain limited. These findings suggest that mitotane is a good option for the treatment of metastatic ACC and might result in rapid complete remission in selected patients.

Serum calcitonin nadirs to undetectable levels within 1 month of curative surgery in medullary thyroid cancer

ABSTRACT Objective: Because serum calcitonin (CT) is a reliable marker of the presence, volume, and extent of disease in medullary thyroid cancer (MTC), both the ATA and NCCN guidelines use the 2-3 month post-operative CT value as the primary response to therapy variable that determines the type and intensity of follow up evaluations. We hypothesized that the calcitonin would nadir to undetectable levels within 1 month of a curative surgical procedure. Subjects and methods: This retrospective review identified 105 patients with hereditary and sporadic MTC who had at least two serial basal CT measurements done in the first three months after primary surgery. Results: When evaluated one year after initial surgery, 42 patients (42/105, 40%) achieved an undetectable basal calcitonin level without additional therapies and 56 patients (56/84, 67%) demonstrated a CEA within the normal reference range. In patients destined to have an undetectable CT as the best response to initial therapy, the calcitonin was undetectable by 1 month after surgery in 97% (41/42 patients). Similarly, in patients destined to have a normalize their CEA, the CEA was within the reference range by 1 month post-operatively in 63% and by 6 months in 98%. By 6 months after curative initial surgery, 100% of patients had achieved a nadir undetectable calcitonin, 98% had reached the CEA nadir, and 97% had achieved normalization of both the calcitonin and CEA. Conclusion: The 1 month CT value is a reliable marker of response to therapy that allows earlier risk stratification than the currently recommended 2-3 month CT measurement.

Role of vandetanib in the management of medullary thyroid cancer.

Traditionally available treatments, like cytotoxic chemotherapy and external-beam radiation therapy, are limited and essentially ineffective for metastatic medullary thyroid carcinoma (MTC). In the last decade, small-molecule tyrosine kinase inhibitors (TKI) have been introduced in the field of thyroid cancer, after having been shown effective in a wide variety of other tumors. This review focuses on vandetanib (ZD6474, Zactima™; AstraZeneca) and its role in the treatment of MTC. Vandetanib is an oral TKI that targets VEGF receptors 2 and 3, RET, and at higher concentrations, the epidermal growth factor (EGF) receptor. This drug has been tested in two important phase II studies which demonstrated that both the 100 and 300 mg/day dosage of vandetanib have antitumor activity on advanced MTC. A phase III trial (ZETA trial) evaluating vandetanib in 331 patients with locally advanced or metastatic MTC showed a significant prolongation of PFS for patients receiving vandetanib compared with placebo. Toxicity surveillance in all studies reported high rates of adverse effects with diarrhea, rash, fatigue and nausea being the most commonly experienced by patients. Vandetanib is currently approved in the United States for unresectable locally advanced or metastatic MTC and has become a new standard of care in this rare and indolent pathology.

Similarities and differences in follicular cell-derived thyroid cancer management guidelines used in Europe and the United States.

The management of thyroid cancer has become more refined and complex over the last thirty years. In an effort to provide guidance to both clinicians and patients, several organizations have developed clinical management guidelines that provide specific advice regarding the diagnosis, treatment and follow-up of differentiated thyroid cancer. In this review, we compare and contrast the major management recommendations provided in the guidelines of the European Thyroid Association with those published by thyroid cancer specialty organizations in the United States (American Thyroid Association and National Comprehensive Cancer Network). By carefully examining treatment and management approaches that are applied in other areas of the world, we can identify equally effective alternative treatment or follow-up options that may find applicability to specific patients in our own practice. Despite significant difference in cultures, economies, and health care delivery systems, thyroid cancer management recommendations from the European experts and the American experts are far more similar than they are different. Each of the guidelines strongly endorses an initial management approach that is guided by individualized estimates of risk of recurrence and risk of death. Furthermore, follow up and additional therapeutic recommendations are based on revised risk estimates that reflect an individual patient's response to therapy.

Ultrasonographically detected small thyroid bed nodules identified after total thyroidectomy for differentiated thyroid cancer seldom show clinically significant structural progression.

BACKGROUND: High-resolution ultrasound (US) is the primary tool used to identify locoregional recurrences in differentiated thyroid cancer. Although small thyroid bed (TB) nodules are a commonly reported sonographic finding, their natural history, regardless of whether they are benign or malignant, has not been well characterized. This study was designed to determine the likelihood, magnitude, and rate of growth of small TB nodules identified on routine surveillance neck US after thyroidectomy for differentiated thyroid cancer as well as to identify ultrasonographic and clinical predictors of growth. METHODS: This retrospective review identified 191 patients with at least one TB nodule (≤ 11 mm) on the first postoperative US performed at a comprehensive cancer center. Change in size of each TB nodule was determined using serial US studies over time. Clinicopathologic and sonographic characteristics were analyzed as possible predictors for growth of the TB nodules. RESULTS: Over a median clinical follow-up of 5 years, 9% (17/191) of patients had increase in size of at least one TB nodule. Median size of the TB nodules was 5 mm (range: 2-11 mm). Suspicious US features were seen in 63% (121/191) of patients with TB nodules identified on initial US and in 31% (21/67) of those with TB nodules detected on subsequent follow-up US. The rate of growth was 1.3 mm/year in those nodules showing an increase in size and thus demonstrated a significant increase in size only after several years of follow-up. The negative predictive values associated with the absence of any suspicious US features (0.97), the absence of abnormal cervical lymph nodes (0.94), and the lack of a rising serum thyroglobulin (0.93) provided clinically useful information regarding the likelihood that nodules would not increase in size. CONCLUSION: Most TB nodules do not show clinically significant growth over several years of follow-up. Thus, TB nodules can be followed up with cautious observation and serial ultrasonography using an approach similar to that recommended by the American Thyroid Association thyroid cancer guidelines for the management of small abnormal cervical lymph nodes.

Serum prolactin levels in a uremic child: effects of bilateral nephrectomy and kidney transplantation.

Elevated levels of serum prolactin (PRL) are common and well described in patients with chronic renal failure. We report the case of a 4-year-old girl who also presented with premature thelarche and transient galactorrhea. Neither peritoneal dialysis nor hemodialysis reduced her extremely elevated levels of PRL, which fluctuated from time to time, probably reflecting variations in lactotroph secretion rate. Bilateral nephrectomy (BN) was eventually followed by a progressive and significant rise in PRL levels, suggesting that even uremic kidneys can eliminate PRL through tubular breakdown. Kidney transplantation was responsible for a very abrupt normalization of PRL serum levels, much faster than that observed for creatinine. This confirms animal studies suggesting that elimination of PRL occurs both through glomerular filtration and tubular breakdown. We hypothesized that the seemingly precocious puberty may have resulted from a combination of growth hormone therapy, elevated PRL and a rise in estrogens through the aromatization of adrenal androgens. This case illustrates the impact of dialysis, BN and kidney transplantation on PRL, providing new knowledge on renal PRL metabolism.

Reference range thyroid-stimulating hormone is associated with physical activity energy expenditure in overweight and obese postmenopausal women: a Montreal-Ottawa New Emerging Team Study.

Clinical and, to a lesser extent, subclinical hypothyroidism is associated with a variety of metabolic abnormalities, including increased body mass index, unfavorable lipoprotein profile, and increased biomarkers for atherosclerosis. Energy expenditure could act as a confounding factor in the association reported between thyroid-stimulating hormone (TSH) levels and cardiometabolic risk factors. The objective of the study was to investigate the relationship between reference range plasma TSH and energy expenditure as well as blood pressure, lipid, and inflammation parameters in women. One hundred four postmenopausal, overweight and obese, spontaneously euthyroid women were included in the study. We evaluated total energy expenditure by doubly labeled water, resting energy expenditure by indirect calorimetry, physical activity energy expenditure (PAEE = [total energy expenditure × 0.90] - resting metabolic rate), body weight, and percentage of fat mass by dual-energy x-ray absorptiometry. Blood pressure, plasma lipoproteins profile, and high-sensitivity C-reactive protein levels were also measured. Mean TSH was 2.39 ± 1.09 mIU/L. We observed that high-density lipoprotein cholesterol (r = -0.20, P ≤ .05) was negatively associated with TSH, whereas systolic blood pressure (r = 0.21, P ≤ .05) and apolipoprotein B (r = 0.22, P ≤ .05) were positively correlated with TSH. However, these correlations were no longer significant after controlling for PAEE. A significant negative correlation was found between TSH and PAEE (r = -0.23, P ≤ .05). Our results suggest that, although TSH in the reference range is associated with some cardiometabolic risk factors, this is in large part explained by lower PAEE. In turn, lower PAEE could increase the cardiometabolic risk.