Cabergoline treatment for surgery-naïve non-functioning pituitary macroadenomas.

PURPOSE: The treatment strategy of non-functioning pituitary adenomas (NFPAs) includes surgery, radiotherapy, medical therapy, or observation without intervention. Cabergoline, a dopaminergic agonist, was suggested for the treatment of NFPA remnants after trans-sphenoidal surgery. This study investigates the efficacy of cabergoline in surgery-naive patients with NFPA. METHODS: Retrospective cohort study including surgery-naive patients with NFPA ≥ 10 mm, treated with cabergoline at a dose of ≥ 1 mg/week for at least 24 months. Patients with chiasmal damage were excluded. Data collected included symptoms, in particular visual disturbances, hormonal levels, tumor characteristics and size evaluated by MRI. Tumor growth was defined as an increase in maximal diameter of ≥ 2 mm, and shrinkage as reduction of ≥ 2 mm. RESULTS: Our cohort included 25 patients treated with cabergoline as primary therapy. Mean age was 63.3 ± 17.3 years, 56% (14/25) were males. Mean tumor size at diagnosis was 18.6 ± 6.3 mm (median 17 mm, range 10-36), and the average follow-up period with cabergoline was 4.6 ± 3.4 years. Out of the 25 tumors, five tumors (20%) decreased in size (mean decrease of 5.0 ± 3.0 mm), 12 tumors (48%) remained stable, and eight (32%) increased in size (mean growth of 5.0 ± 3.3 mm) with cabergoline treatment. During the first two years of cabergoline treatment, the median tumor size exhibited a reduction of 0.5 mm. Patients with an increase in tumor size had larger adenomas at diagnosis and a longer follow-up. Two patients (8%) underwent surgery due to tumor enlargement. CONCLUSION: Primary treatment with cabergoline is a reasonable approach for selected patients with NFPAs without visual threat.

Clinical characteristics of a large familial cohort with Medullary thyroid cancer and germline Cys618Arg RET mutation in an Israeli multicenter study.

Objective: To determine genealogical, clinical and pathological characteristics of a cohort with Cys618Arg mutation from an Israeli multicenter MTC study. Methods: Retrospective database analysis examining RET mutations and comparing Cys618Arg and Cys634Arg/Thr/Tyr subgroups. Results: Genetic testing was performed in 131/275 MTC patients (47.6%). RET mutations were found in 50/131 (38.2%), including Cys618Arg (28/50 cases,56%), and Cys634Arg/Thr/Tyr (15/50,30%). Through genealogical study, 31 MTC patients were found descendants of one family of Jewish Moroccan descent, accounting for 27/28 patients with documented Cys618Arg mutation and 4 patients without available genetic testing. Familial Cys618Arg cases (n=31) and Cys634Arg/Thr/Tyr cases (n=15, from 6 families) were compared. Although surgical age was similar (25.7 vs 31.3 years, p=0.19), the Cys618Arg group had smaller tumors (8.9mm vs 18.5mm, p=0.004) and lower calcitonin levels (33.9 vs 84.5 X/ULN, p=0.03). Youngest ages at MTC diagnosis were 8 and 3 years in Cys618Arg and Cys634Arg/Thr/Tyr cohorts, respectively. Long-term outcome was similar between groups. The Cys618Arg cohort had lower rates of pheochromocytoma (6.5% vs 53.3%, p=0.001) and primary hyperparathyroidism (3.2% vs 33.3%, p=0.01). Conclusion: This is the first description of RET mutation distribution in Israel. Of 131 tested MTC patients, Cys618Arg was the predominant mutation. To the best of our knowledge, this is the largest cohort of Cys618Arg mutation described. For Cys618Arg and Cys634Arg/Thr/Tyr cohorts, MTC was diagnosed earlier than expected, likely due to familial genetic screening, and MTC outcomes were similar between groups. International studies are necessary to further characterize the clinical features of Cys618 mutations due to their relative rarity.

A Comparison of Outcomes in Medullary Thyroid Carcinoma Patients With and Without a Preoperative Diagnosis: A Multicenter Retrospective Cohort Study.

Background: Cytological limitations pose a challenge to preoperative diagnosis of medullary thyroid carcinoma (MTC) and therefore, a significant subset of patients is only diagnosed postoperatively. The objective of this study was to investigate the impact of knowledge of a preoperative MTC diagnosis on disease management and outcomes. Methods: Multicenter, retrospective, cohort study of MTC patients treated in Israel from January 2000 to June 2021. We compared cohorts of patients according to the presence or absence of a preoperative MTC diagnosis. Results: Ninety-four patients with histologically confirmed MTC were included (mean age 56.2 ± 14.3 years, 43% males). Fifty-three patients (56%) had a preoperative MTC diagnosis (preop-Dx group), and 41 (44%) were confirmed only postoperatively (no-Dx group). The extent of surgical resection, including completion procedures, was as follows: total thyroidectomy in 83% versus 100% (p = 0.002), central lymph node dissection (LND) in 46% versus 98% (p < 0.001), ipsilateral lateral LND in 36% versus 79% (p < 0.001), and contralateral lateral LND in 17% versus 28% (NS), in the no-Dx versus the preop-Dx group, respectively. Pathology confirmed a smaller median tumor size of 16 ± 17.4 mm versus 23 ± 14.0 mm (p = 0.09), a higher proportion of micro-MTC (size ≤10 mm) 32% versus 15% (p = 0.03), and a higher rate of co-occurrence of follicular cell-derived carcinoma 24% versus 4% (p = 0.003), in the no-Dx compared to the preop-Dx group, respectively. The rates of extrathyroidal and extranodal tumor extension were not significantly different between the groups. At the last follow-up, the biochemical cure was attained in 55% [CI 0.38-0.71] compared to 64% [CI 0.50-0.77] of the no-Dx and the preop-Dx group, respectively (p = 0.41). After the exclusion of patients with micro-MTC, biochemical cure was more commonly achieved in the preop-Dx group (33% [CI 0.14-0.52] vs. 62% [CI 0.46-0.77], p = 0.04). Preop-Dx patients had improved overall survival compared to the no-Dx group (log-rank p = 0.04) over a median follow-up of 82 months (interquartile range [IQR] 30-153). Conclusions: Preoperatively, the diagnosis of MTC is often missed. An accurate preoperative diagnosis of MTC may enable guideline-concordant surgical treatment and ultimately contribute to an overall survival benefit in MTC patients.

Infertility and Pregnancy Rates in Female Thyroid Cancer Survivors: A Retrospective Cohort Study Using Health Care Administrative Data from Israel.

Background: Thyroid cancer (TC) is one of the most common carcinomas in young women. Concerns have been raised regarding the impact of the disease and its treatment on reproductive function. The aim of the study was to investigate the association of TC diagnosis and radioactive iodine (RAI) treatment on infertility and pregnancy rates in women. Methods: The comprehensive computerized database of a health management organization in Israel was screened for all female patients who were diagnosed with TC at age ≤40 years in 2000-2020. Rates of infertility (based on a documented diagnosis or purchase of fertility medications in the patient files) and pregnancy were compared with healthy age-matched controls. Results: The cohort included 1164 patients with TC (median age at diagnosis 31.6 years; interquartile range [IQR]: 26.7-35.4) and 5030 controls, followed for a median period of 10 years (IQR: 5.0-15.0). The infertility rate was higher in the TC group than in the control group (23.9% vs. 20.4%, p = 0.008). Still, the postdiagnosis/referent date pregnancy rates were comparable in the whole cohort (46.9/47.7%, p = 0.625) and across all age quartiles. The median time to the first pregnancy postdiagnosis/referent date was longer in TC patients than in controls (37 vs. 31 months, p < 0.001). Within the TC group, women who received repeated radioactive iodine treatment (n = 611, 52.5%) had comparable rates of infertility and pregnancy as those who did not. However, their time to the first postdiagnosis pregnancy was longer (median 45 vs. 29 months, p = 0.020). Conclusions: Our study provides reassuring evidence about the reproductive characteristics of women treated for TC. Pregnancy rates in TC survivors were comparable with controls. However, a higher infertility rate and a longer time to conceive were observed in the TC group compared with the control group. These findings were consistent in women who received single or repeated RAI treatments.

Cushing's syndrome in women: age-related differences in etiology and clinical picture.

OBJECTIVE: To evaluate the clinical presentation, biochemical profile, and etiology of Cushing's syndrome (CS) in women stratified by age. METHODS: Retrospective study of patients with CS, treated at Rabin Medical Center from 2000 to 2020, or Maccabi Healthcare Services in Israel from 2005 to 2017. Disease etiology, presentation and biochemical profile were compared according to age at diagnosis: ≤ 45, 46-64, or ≥ 65 years. Study was approved by the Ethics Review Boards of both facilities with waiver of consent. RESULTS: The cohort included 142 women (mean age, 46.0 ± 15.1 years):81 (57.0%) with Cushing's disease (CD), and 61 (43.0%) with adrenal CS. Pituitary etiology was more common among women < 45 (70.6%), compared with patients ≥ 65 years (31.6%) (P < 0.05). Among CS patients, hypercortisolism was diagnosed in the context of screening after an adrenal incidentaloma detection in 15.0% of patients < 45 and 53.8% of ≥ 65 years (P < 0.001). Weight gain was evident in 57.4% of women < 45 (56.3% CD, 60.0% CS), and 15.8% of women ≥ 65 years (50% CD, 0% CS) (P = 0.011). Mean UFC levels were highest for women < 45 (3.8 × ULN) and lowest for ≥ 65 years (2.3 × ULN) (P < 0.001). CONCLUSION: We have shown for the first time that women with CS ≥ 65 years of age more commonly have adrenal etiology. The initial presentation of CS also differs between age groups, where women < 45 years are likely to present with weight gain, while those ≥ 65 years are frequently diagnosed incidentally, when screening for hypercortisolism in the presence of an adrenal incidentaloma.

Subclinical acromegaly: to treat or not to treat?

Patients with acromegaly usually present with the classical signs of acromegaly, whereas patients without the specific signs or symptoms are rarely diagnosed. This unique entity can be named "subclinical acromegaly". This was a retrospective study. Our study group consisted of 6 patients (4 females) with incidentally diagnosed acromegaly, most following head MRI for unrelated reasons and without the specific signs of acromegaly. Mean age at diagnosis was 48.8 ± 19.2 years. Baseline IGF-1 ranged between 1.3-2.0 × upper limit of normal (ULN). MRI depicted a pituitary microadenoma in 5 patients, and one patient presented with a 12 mm intra-sellar macroadenoma. Mean calculated SAGIT clinical score was 4.8. Three patients underwent trans-sphenoidal resection; two achieved hormonal remission and one improved but did not normalize IGF-1 following surgery. Four patients (including one following surgery) were given somatostatin analogs, and three normalized IGF-1. Several patients improved clinically following treatment, reporting improvement in snoring, hypertension, or weight loss, and pituitary adenoma decreased in size in 2 patients that responded to medical treatment. We report a series of 6 patients with very mild and subclinical acromegaly. It is uncertain whether all such patients will gain clinical benefit from treatment, but most experienced clinical improvement due to treatment.

Quality of life following lobectomy versus total thyroidectomy is significantly related to hypothyroidism.

OBJECTIVE: The aim of the present study was to investigate the differences in quality of life (QOL) following complete or partial thyroidectomy and with regard to thyroid hormone replacement (LT4) therapy. STUDY DESIGN: Patients who underwent thyroidectomy were asked to complete the validated thyroid-specific ThyPRO QOL questionnaire at least 6 months following surgery. SETTING: Tertiary medical center. METHODS: Thyroid specific QOL questionnaire analysis. RESULTS: A total of 190 patients completed the ThyPRO questionnaire. Of them 89 patients had complete thyroidectomy and 101 patients had unilateral thyroid lobectomy. The total thyroidectomy group had significantly worse overall QOL self-assessment score than the lobectomy patients (p < 0.0001). Patients receiving LT4 therapy regardless of the extent of surgery, reported worse QOL compared to patients not receiving LT4. CONCLUSIONS: Quality of life following thyroid surgery is significantly related to hypothyroidism and the requirement for LT4 therapy, rather to the extent of surgery. The best QOL was reported in patients treated with lobectomy who did not require LT4 therapy.

Clinical Study and Systematic Review of Pituitary Microadenomas vs. Macroadenomas in Cushing's Disease: Does Size Matter?

Background: Reports on clinical and biochemical differences between adrenocorticotropic hormone (ACTH)-secreting pituitary microadenomas and macroadenomas are limited and inconsistent. Objective: Compare clinical and biochemical characteristics of patients with corticotroph microadenomas and macroadenomas and assess predictive factors for biochemical response to dynamic testing for Cushing's disease (CD) in a clinical trial and a systematic review. A second aim was to evaluate differences between macroadenomas with and without cavernous and sphenoid sinus invasion. Methods: Retrospective charts review of patients with CD, treated at Rabin Medical Center between 2000 and 2020 or at Maccabi Healthcare Services in Israel between 2005 and 2017. Clinical and biochemical factors were compared between patients with corticotroph microadenomas and macroadenomas. We have also performed a systematic review of all studies (PRISMA guidelines) comparing corticotroph microadenomas with macroadenomas up to 31 November 2021. Results: The cohort included 105 patients (82 women, 78%; mean age, 41.5 ± 14.5 years), including 80 microadenomas (mean size, 5.2 ± 2.2 mm) and 25 macroadenomas (mean size, 18.0 ± 7.7 mm). Other baseline characteristics were similar between groups. Most common presentation suggestive for hypercortisolemia among patients with both micro- and macroadenomas were weight gain (46.3% vs. 48.0%, p = NS) and Cushingoid features (27.5% vs. 20.0%, p = NS). Mean 24 h urinary free cortisol (5.2 ± 5.4 × ULN vs. 7.8 ± 8.7 × ULN) and serum cortisol following low-dose dexamethasone (372.0 ± 324.5 vs. 487.6 ± 329.8 nmol/L), though higher for macroadenomas, were not significant. Levels of ACTH were greater for macroadenomas (1.9 ± 1.2 × ULN vs. 1.3 ± 0.8 × ULN, respectively, p = 0.01). Rates of recurrent/persistent disease were similar, as were rates of post-operative adrenal insufficiency and duration of post-operative glucocorticoid replacement. Macroadenomas with sphenoid or cavernous sinus invasion were associated with higher ACTH, 24 h free urinary cortisol, and serum cortisol following low-dose dexamethasone, compared with suprasellar or intrasellar macroadenomas. Conclusions: While ACTH-secreting macroadenomas exhibit higher plasma ACTH than microadenomas, there was no association between tumor size with cortisol hypersecretion or clinical features of hypercortisolemia. Though overall rare, increased awareness is needed for patients with CD with tumor extension in the cavernous or sphenoid sinus, which displays increased biochemical burden, highlighting that extent/location of the adenoma may be more important than size per se. Our systematic review, the first on this topic, highlights differences and similarities with our study.

Adherence to Active Surveillance and Clinical Outcomes in Patients with Indeterminate Thyroid Nodules Not Referred for Thyroidectomy.

OBJECTIVE: Outcomes of patients with cytologically indeterminate thyroid nodules not referred for thyroidectomy have hardly been investigated. We previously reported outcomes of 322 patients with thyroid nodules classified according to the Bethesda System of Reporting Thyroid Cytology (BSRTC) as indeterminate (B3/B4), of whom 123 (38.2%) underwent thyroidectomy. In the present extension study, we investigated adherence and outcomes in the remaining unoperated 199 patients. METHODS: We conducted a file review of 189/199 patients with thyroid nodules cytologically diagnosed as B3 (n = 174) or B4 (n = 15) in 2011-2012 who were conservatively followed at our institution until 2019. RESULTS: Among 174 patients with B3 nodules, 140 (80.4%) underwent repeated ultrasound. Nodular growth was detected in 23 (16.4%), and findings remained stable in 105 (75%). Fine-needle aspiration was repeated in 88/174 patients (50.6%), with B2 results in 62 (70.4%) and B3/B4/B5 in 20 (22.7%). Thyroidectomy was performed in 14/174 patients (8%) in the B3 and 5/15 patients (33%) in the B4 group at a median of 5 years' follow-up; thyroid cancer was diagnosed in 4/14 patients (28.5%) and 3/5 patients (60%), respectively. For B3 patients who remained unoperated, none had evidence of thyroid cancer at last follow-up. A reason for avoiding surgery was documented in 6/10 unoperated B4 patients (1 thyroid lymphoma, 3 died of unrelated causes, 2 were considered inoperable due to advanced age). CONCLUSIONS: Most patients with initially unoperated B3/B4 nodules adhere, at least partially, to active surveillance. For B3 nodules, subsequent thyroidectomy and thyroid cancer detection are rare events, and patients may be safely managed without using molecular markers. Thyroid cancer is diagnosed in most B4 patients who undergo thyroidectomy in our institution.

Prophylactic central neck dissection has no advantage in patients with metastatic papillary thyroid cancer to the lateral neck.

BACKGROUND: Papillary thyroid cancer (PTC) usually metastasizes via lymphatic channels in a sequential fashion, first to the central compartment, followed by the lateral neck. PTC patients diagnosed with lateral neck disease (N1b) without proof for central involvement traditionally undergo prophylactic central neck dissection (pCND). However, substantial evidence on outcomes to support this approach is lacking. MATERIALS AND METHODS: We conducted a dual center retrospective study to compare the rate of central neck recurrence between N1b PTC patients undergoing pCND and those spared pCND. All patients diagnosed with N1b PTC who underwent total thyroidectomy and lateral neck dissections with or without pCND between January 1998 and December 2015 were included in this study. The rates of central neck recurrences were compared between the groups. RESULTS: The 111 patients who met the inclusion criteria were 44 females (39.6%) and 67 males (60.4%), with a mean age of 50.2 ± 17.7 years, and a mean follow-up of 10.2 ± 5.3 years. Sixty patients (54.1%) underwent a pCND and 51 patients (45.9%) did not (non-pCND). During follow-up, 18 patients (16.2%) had level VI recurrences, 13 in the pCND group and 5 in the non-pCND group. Cox-regression models with propensity scoring did not reveal any inclination or an advantage for performing pCND. CONCLUSION: The present study demonstrated no advantage in performing pCND to prevent central neck recurrence among PTC patients with lateral neck involvement only. These findings question the need for pCND in patients without clinical evidence of central neck disease.

The prognostic value of lymph node ratio in Medullary thyroid carcinoma: A multi-center study.

INTRODUCTION: The lymph node ratio (LNR), which represents the proportion of metastatic lymph nodes resected, has been found to be a prognostic variable in several cancers, but data for Medullary thyroid carcinoma (MTC) are sparse. The aim of this study was to determine the value of the LNR in predicting outcome in patients with MTC. MATERIALS AND METHODS: A retrospective multicenter study design of 107 patients with MTC who underwent total thyroidectomy with neck dissection between 1984 and 2016. The association of LNR with patient and tumor characteristics and prognostic factors was evaluated. RESULTS: Study population consisted of 53.3% female, mean age at diagnosis was 50.3 ± 18.4 years; 16.8% had inherited MTC. LNR was positively correlated with tumor size (p = 0.018) and inversely correlated with age at diagnosis (p = 0.024). A higher LNR was associated with extrathyroidal extension (p < 0.001), multifocality (p = 0.001), bilateral tumor (p = 0.002), distant metastases (p < 0.001), and tumor recurrence (OR = 14.7, p < 0.001). LNR was also correlated to postoperative calcitonin levels (p < 0.001) and carcinoembryonic antigen (p = 0.011). LNR >0.1 was associated with shorter disease-specific survival in patients at risk: tumor larger than 20 mm at diagnosis (p = 0.013), sporadic MTC (p = 0.01), and age above 40 years at diagnosis (p = 0.004). Cox multivariate survival analysis revealed LNR as the only significant independent factor for disease free survival (p = 0.005). CONCLUSIONS: This study showed that LNR correlates well with patient and tumor characteristics and prognostic variables. We suggest that LNR should be considered an important parameter for predicting outcome in MTC.

Hyperparathyroidism in patients over 75: Clinical characteristics and outcome. Is conservative treatment a safe alternative?

OBJECTIVE: With the current aging of the world's population, primary hyperparathyroidism (PHPT) is increasingly detected in the elderly. Yet data on the presentation and outcome of PHPT in this group are scarce. The objective was to describe a cohort of patients aged 75 years or more with PHPT observed in our endocrine clinic. STUDY DESIGN: A retrospective analysis of medical records in an endocrine clinic at a tertiary hospital. We evaluated 182 patients with PHPT, aged 75 years or more at their last follow-up, all diagnosed at age 65 or more. Laboratory data were compared at diagnosis and last follow-up. RESULTS: Mean age at diagnosis was 73 ± 4 years, last follow-up was at 83 ± 4 years, and mean follow-up was 11.3 ± 5.5 years. Osteoporosis, fractures, and nephrolithiasis were diagnosed in 114(63 %), 84(46 %), and 43(24 %) patients, respectively. Overall, 150 patients had an indication for surgery; of them, the 29 who underwent parathyroidectomy were younger than the non-operated patients and had higher rates of hypercalciuria. During the follow-up of the 141 patients who did not undergo operation, serum and urinary calcium levels significantly had decreased, and vitamin D level had increased at last visit (10.4 ± 0.5 mg/dl, 161 ± 70 mg/24 h, 69 ± 17 nmol/l, p < 0.01 respectively) compared with levels at diagnosis (10.6 ± 0.2 mg/dl, 223 ± 95 mg/24 h, 53 ± 15 nmol/l, respectively, p = 0.001). Overall, 38 of the 182 patients (20 %) died during follow-up; these patients were significantly older at diagnosis (76 ± 5 vs. 72 ± 4 years) but there were no differences in laboratory variables. CONCLUSIONS: While most patients had a formal indication for surgery, few underwent parathyroidectomy. Serum and urinary calcium significantly decreased during follow-up in patients who did not undergo surgery. Our data are reassuring and support at least the consideration of conservative treatment for these patients.

Detecting Recurrence Following Lobectomy for Thyroid Cancer: Role of Thyroglobulin and Thyroglobulin Antibodies.

BACKGROUND: The use of thyroglobulin (Tg) and thyroglobulin antibodies (TgAb) for detecting disease recurrence is well validated following total thyroidectomy and radioiodine ablation. However, limited data are available for patients treated with thyroid lobectomy. METHODS: Patients who had lobectomy for papillary thyroid cancer followed for >1 year, with sufficient data on Tg and TgAb, including subgroup analysis for Hashimoto's thyroiditis and contralateral nodules. RESULTS: One-hundred sixty-seven patients met the inclusion criteria. Average tumor size was 9.5 ±â€…6 mm. Following lobectomy, Tg was 12.1 ±â€…14.8 ng/mL. Of 52 patients with Hashimoto's thyroiditis, 38% had positive TgAb with titers of 438 ±â€…528 IU/mL, and in patients without TgAb the mean Tg level was 14.7 ±â€…19.0 ng/mL. In 34 patients with contralateral nodules ≥1 cm, Tg was 15.3 ±â€…17 ng/mL. During the first 2 years of follow-up, Tg declined ≥1 ng/mL in 42% of patients (by 5.1 ±â€…3.7 ng/mL), remained stable in 22%, and increased in 36% (by 4.9 ±â€…5.7 ng/mL). During a mean follow-up of 6.5 years (78 ±â€…43.5 months), 18 patients had completion thyroidectomy and 12 were diagnosed with contralateral cancer (n = 8) or lymph node metastases (n = 4). In patients with recurrence followed for >2 years, there was a rise in Tg in 3 cases, Tg was stable in 2 cases, and in 1 TgAb decreased from 1534 to 276 IU/mL despite metastatic lymph nodes. Basal Tg and Tg dynamics did not predict disease recurrence. CONCLUSIONS: Serum thyroglobulin used independently is of limited value for predicting or detecting disease recurrence following thyroid lobectomy. Other potential roles of Tg, such as detecting distant metastases following lobectomy, should be further studied.

Response to Therapy Assessment in Intermediate-Risk Thyroid Cancer Patients: Is Thyroglobulin Stimulation Required?

Introduction: The 2015 American Thyroid Association (ATA) guidelines recommend response to therapy (RTT) assessment 1-2 years after initial treatment in differentiated thyroid cancer (DTC) patients to guide thyrotropin (TSH) goals and long-term follow-up. We hypothesized that data collected during the first 2 years of follow-up may be sufficient to determine RTT without thyroglobulin (Tg) stimulation. Materials and Methods: Patients treated with total thyroidectomy and radioiodine for intermediate-risk DTC, followed for >2 years, and had sufficient follow-up data were included. Data on Tg, ultrasound, scans, and long-term outcomes were collected. Results: One-hundred twenty patients met inclusion criteria, with 68% women and mean age 55 ± 15 years. Intermediate risk was due to lymph-node involvement (72%), extrathyroidal extension (51%), vascular invasion (12%), and high-risk histology (9%). At the end of follow-up of 7 ± 4 years, 26% had persistent disease (14% biochemical, 12% structural). According to the ATA RTT system (using stimulated-Tg), 56% had excellent RTT, of whom only 2% had disease at the end of follow-up. In the "nonstimulated" system (which includes basal Tg, post-131I therapy whole-body scan (TxWBS) for assessment of residual lymph-node metastases after surgery, and structural imaging studies), 57% had excellent response, of whom none had disease at the end of follow-up. Only eight patients (7%) were classified differently due to recombinant human thyrotropin stimulation (as either excellent or indeterminate response), with no difference in predictive value, with a receiver-operator characteristic area under the curve of 0.903 with Tg-stimulation and of 0.918 without. Conclusions: In patients with no evidence of disease during the first 2 years of follow-up, the addition of stimulated-Tg adds little prognostic information. We suggest the use of excellent RTT based on basal Tg together with TxWBS and structural imaging studies.

Pheochromocytoma: Positive predictive values of mildly elevated urinary fractionated metanephrines in a large cohort of community-dwelling patients.

The diagnostic utility of different thresholds of elevated urinary fractionated metanephrine (UFM) for pheochromocytoma-paraganglioma (PPGL) was evaluated in 10 164 community-dwelling subjects (2012-2017). Levels were ≥1.5× the upper normal limit (UNL) in 276 subjects (2.7%) and ≥2×UNL in 138 (1.4%). PPGL was subsequently diagnosed in 59 (mean age 51.9 ± 14.3, 64% female); 58 (98.3%) with UFM ≥ 2×UNL. Positive predictive values (PPV) were 42% for UFM ≥ 2×UNL, 55% for UFM ≥ 2.5×UNL, and 69% for UFM ≥ 3×UNL. The main reason for PPGL screening (52.5%) was adrenal incidentaloma. Mean (median) metanephrine/normetanephrine levels were 6.7 ± 9×UNL (3 × UNL) and 6.1 ± 8.9×UNL (2.5 × UNL). Six patients (10.2%) had an extra-adrenal tumor (one malignant paraganglioma); one had bilateral pheochromocytoma. Only one patient presented with the "classic triad" (headache, palpitations, sweating). In conclusion, after excluding obvious reasons for false-positive results, thorough diagnostic assessment for PPGL is justified in all subjects with UFM ≥ ×2UNL. The PPV of milder UFM elevations is very low.

Hyperprolactinemia diagnosis in elderly men: a cohort of 28 patients over 65 years.

PURPOSE: To characterize a cohort of elderly men with prolactinomas and their response to treatment. METHODS: We have identified 28 elderly men diagnosed after the age of 65 with prolactinomas at seven different endocrine clinics in Israel. A retrospective electronic chart review identified a control group of 76 younger men with macroprolactinomas treated in one of the centers. RESULTS: Mean age at diagnosis was 71.3 ± 5.6 (range 65-86) years, and current age 76.6 ± 7.5 years. Initial complaints leading to diagnosis included sexual dysfunction in 17 males (61%), headaches in two patients (7%), and visual abnormalities in two (7%). Three men presented with osteoporosis. Ten patients (36%) were diagnosed incidentally following brain imaging for unrelated reasons. Seventeen patients (61%) had macroadenoma, while eleven (39%) presented with a microadenoma or no visible adenoma. Mean prolactin (PRL) at presentation was 1594 (median 382; range 50-18,329) ng/ml. Testosterone was low in 21 men. Patients were treated with cabergoline (max dose, 1.1 ± 0.5 mg/week), except for one given bromocriptine; none required pituitary surgery or radiotherapy. Treatment normalized PRL in 24 patients, and in three men PRL suppressed to <2 ULN. Fifteen men normalized testosterone, three improved without normalization, and in three the normal baseline level increased. After a mean follow-up of 5.3 years, 14/15 patients harboring a macroadenoma showed significant adenoma shrinkage. Most patients reported improvement of low libido/erectile dysfunction. In the control group 60 men (79%) achieved PRL normalization. CONCLUSIONS: Elderly men with prolactinomas are diagnosed incidentally in 36% of cases. Long-term medical therapy is successful, achieving biochemical remission, adenoma shrinkage, and clinical improvement in almost all patients.

Bone-Marrow Suppression in Elderly Patients Following Empiric Radioiodine Therapy: Real-Life Data.

Background: Elderly patients with differentiated thyroid cancer (DTC) tend to have more advanced disease at presentation, for which high activities of radioiodine (RAI) are often recommended. However, the 2015 American Thyroid Association guidelines recommend that empirically administered activities of RAI >150 mCi should be avoided in patients >70 years of age, based on calculated bone-marrow exposure according to two dosimetry-based studies. This study aimed to evaluate the effect of RAI treatment on bone-marrow function in elderly DTC patients. Methods: DTC patients ≥70 years of age who received RAI treatment and on whom a complete blood count was performed before and after treatment were included. Blood counts within one year before RAI and one year following treatment were compared in order to assess for marrow suppression. The impact of demographic, clinical, and laboratory variables on complete blood count were assessed. Results: One hundred fifty-three treatments in 122 patients met inclusion criteria, with a mean patient age of 76 ± 4.3 years, and 75% were women. High-risk features at presentation included T4 disease in 17%, lymph node metastases in 34%, and distant metastases in 14%. Mean RAI activity was 136.8 ± 48 mCi (82% ≥ 100 mCi, 66% ≥ 150 mCi). Of 153 RAI treatments analyzed, 114 (74%) were first treatments, 28 (18%) second treatments, seven (5%) third treatments, and four (3%) fourth treatments. At 0-3 months after RAI treatment, there was a statistically significant decrease in platelets (238 ± 66 vs. 216 ± 69 × 109/L, 10% decrease; p < 0.001), white blood cells (WBC; 6.9 ± 2 vs. 6.1 ± 1.9 × 109/L, 13% decrease; p < 0.001), and hemoglobin (Hb) in women (12.8 ± 1.1 vs. 12.4 ± 1.1 g/dL, 3% decrease; p = 0.01). Mean platelets, WBC, Hb in women, and lymphocytes remained decreased (but within the reference range) one year after treatment. Subgroup analysis demonstrated platelet suppression only with activities ≥100 mCi, and WBC and Hb suppression only with activities ≥150 mCi, with mean values within the reference ranges. There were no clinically significant cytopenia events during follow-up. Conclusions: Empiric RAI treatment in elderly patients causes mild bone-marrow suppression, with little clinical significance. Activities of 150-200 mCi can be safely used when indicated.

Clinico-pathologic and dynamic prognostic factors in sporadic and familial medullary thyroid carcinoma: an Israeli multi-center study.

OBJECTIVE: Multiple clinical, pathological and biochemical variables, including the response to initial treatment, are associated with medullary thyroid carcinoma (MTC) prognosis. Studies that include separate analyses of familial and sporadic MTC patients followed for long period are scarce. This study evaluated the association between baseline clinico-pathologic variables and response to initial treatment and short- and long-term disease outcomes in sporadic and familial MTC. METHODS: Patients treated for MTC at four tertiary medical centers were retrospectively analyzed. Clinical and pathological data were collected. The outcomes measured included disease persistence 1 year after diagnosis, disease persistence at last follow-up, disease-related mortality (DRM) and all-cause mortality. RESULTS: The study enrolled 193 patients (mean age: 48.9 ± 18.7, 44.7% males), of whom 18.1% were familial cases. The mean follow-up period was 10.1 ± 9.4 years (8.5 ± 8.1 in sporadic and 16.9 ± 11.6 in familial MTC). Disease persistence 1-year after diagnosis and at last follow-up was detected in 56.1 and 60.4% patients, respectively. All-cause and DRM were 28.5 and 12.6%, respectively. Extra-thyroidal extension (ETE) and distant metastases (DM) were associated with disease persistence at last follow-up. ETE and DM were also significantly associated with DRM. Complete remission 1 year after diagnosis had high correlation with no evidence of disease at last follow-up (Cramer's V measure of association 0.884, P < 0.001) and with 100% disease-specific survival (Cramer's V measure of association 0.38, P < 0.001). CONCLUSIONS: Apart from clinico-pathologic parameters, close correlation was found between 1-year status and long-term prognosis. These results underscore the importance of combining classical and dynamic factors for both sporadic and familial MTC prognostication and treatment decision making.

Multifocality Is not an Independent Prognostic Factor in Papillary Thyroid Cancer: A Propensity Score-Matching Analysis.

BACKGROUND: Papillary thyroid carcinoma (PTC) is the most common endocrine malignancy. Despite its low mortality rate, the disease has a recurrence rate of up to 30%. The mainstay of treatment for PTC is surgery, followed by radioiodine ablation and thyroxine therapy in appropriately selected patients. PTC can appear as a unifocal solitary tumor, but also as two or more anatomically separate foci. A great deal of controversy surrounds the significance of multifocality as a prognostic factor, and it is considered a poor prognostic factor that prompts more aggressive treatment. The aim of this study was to investigate the prognostic value of tumor multifocality on disease recurrence and mortality in PTC patients. METHODS: Data of 1039 consecutive PTC patients from two tertiary medical centers were reviewed. The baseline characteristics and short- and long-term outcome were analyzed to evaluate the prognostic significance of multifocal disease. The application of two different propensity score models followed multivariate analysis. RESULTS: The median follow-up was 10.1 years, and 534 (51.4%) patients had multifocal disease and 505 (48.6%) unifocal disease. Patients with the multifocal disease were significantly older, were more frequently male, had more extrathyroidal extension, more lymph node metastases, more advanced disease (stage III/IV), and a higher American Thyroid Association recurrence risk. Multifocal PTC patients had more persistence at one year (26.6% vs. 16.4%; p < 0.001), more recurrence during follow-up (12.7% vs. 6.6%; p = 0.002), and a higher overall mortality rate (15.5% vs. 9.7%; p = 0.002). However, there were no significant differences in recurrence, last-visit persistency, and mortality rates when adjusting for confounding variables by using propensity score matching. CONCLUSION: This propensity score-matching study provides the best available data to support the assertion that multifocality in PTC patients is a marker of more extensive disease at presentation, but not an independent prognostic factor for long-term outcomes.

LONG-TERM OUTCOMES AND PROGNOSTIC FACTORS IN PATIENTS WITH DIFFERENTIATED THYROID CARCINOMA AND BONE METASTASES.

Objective: This institutional study sought to retrospectively evaluate disease progression and survival of patients with differentiated thyroid cancer (DTC) and bone metastases (BM) and to investigate variables predictive of better long-term outcomes. Methods: The Rabin Medical Center Thyroid Cancer Registry was searched for patients with bone-metastatic DTC. Variables including a patient's gender and age, pathology of the thyroid tumor, and characteristics of BM were retrieved and analyzed in association with disease progression and mortality. Results: The cohort included 64 patients (48.4% female). Mean age at diagnosis was 62.1 ± 14.3 years; mean primary tumor size was 41 ± 30 mm. Overall, 60.4% had stage T3/T4 disease; 46.3% had extrathyroidal extension; 40% had lymph-node metastases. Histopathology yielded papillary and follicular DTC in 40.6% and 32.8% of patients, respectively, and poorly/intermediately differentiated carcinoma in 26.6%. BM were synchronous in 50%. Mean follow-up was 11 ± 9.6 years from DTC detection. The common first sites of BM detection were spine (46.9% of patients), pelvis (37.5%) and ribs (21.9%). Nineteen patients (29.7%) presented with multiple-site BM, of whom 15 (78.9%) had spinal metastases. After initial treatment, 62/64 patients had structural persistence, and at last follow-up, 57.8% had progressive disease. Overall, 54.7% of patients died, 71.4% of DTC. Improved long-term outcomes were associated with younger age, lower tumor stage, no extrathyroidal extension, bone-only metastases, and non-spinal BM. Younger age and non-spinal BM were the only independent predictors for improved survival. Conclusions: Selected patients with bone-metastatic DTC may achieve fair long-term outcomes. Spinal metastases are associated with disseminated skeletal spread and increased mortality. Abbreviations: BM = bone metastases; COX = multivariate analyses; DM = distant metastases; DSM = disease-specific mortality; DSS = disease-specific survival; DTC = differentiated thyroid carcinoma; ETE = extrathyroidal extension; LNM = lymph node metastases; OM = overall mortality; OS = overall survival; PTCFV = papillary thyroid carcinoma; RAI = radioactive iodine; SM = spinal metastases; SRE = skeletal-related event; txWBS = whole-body scan after RAI therapy.