How do BRAFV600E and TERT promoter mutations interact with the ATA and TNM staging systems in thyroid cancer?

Context: The American Thyroid Association risk stratification (ATA) and the American Joint Committee on Cancer Tumor Node Metastases (TNM) predict recurrence and mortality of differentiated thyroid cancer (DTC). BRAFV600E and TERT promoter mutations have been shown to correlate with the histopathological features and outcome of DTC. Our objectives were to study the correlation of these molecular markers with these clinicopathological-staging systems. Patients and methods: We studied 296 unselected patients, 214 females and 82 males with a median age of 36 years (IQR 23.3-49.0). BRAFV600E and TERT promoter mutations were tested by PCR-based Sanger sequencing. Data were extracted from medical records and analysed using Chi-Square and Fisher Exact tests and Kaplan Meier analysis. Results: Of 296 patients tested, 137 (46.3%) had BRAFV600E-positive tumors and 72 (24.3%) were positive for TERT promoter mutations. The BRAFV600E mutation did not correlate with the ATA and TNM staging, being non-significantly different in various stages of these systems and did not predict the development of persistent disease (PD) (P 0.12). Unlike BRAFV600E, TERT promoter mutations were more frequent in the ATA high-risk than in intermediate- or low-risk tumors (P 0.006) and in TNM stages III and IV than lower stages (P <0.0001). TERT promoter mutations also predicted the outcome, being present in 37.2% of patients with PD compared to only 15.4% in those without evidence of disease (P <0.0001). The same pattern was also seen when BRAFV600E and TERT promoter mutations were combined. Conclusion: TERT promoter mutations alone or in combination with BRAFV600E mutation, but not BRAFV600E mutation alone, correlated well with the ATA and TNM staging and predicted development of PD, especially in higher stages of these systems.

Incomplete response to therapy in intermediate- and high-risk thyroid cancer.

CONTEXT: The American Thyroid Association (ATA) risk stratification system predicts risk of recurrence of differentiated thyroid cancer (DTC). Although the majority of patients achieve an excellent response, patients with intermediate- or high-risk DTC are at a significant risk of developing incomplete responses. We undertook this work to understand the factors associated with development of biochemically or structurally incomplete response in these two risk subgroups of DTC. PATIENTS AND METHODS: We retrospectively reviewed 287 consecutive patients with intermediate- (213 patients) or high-risk (74 patients) DTC. All patients underwent total thyroidectomy with (223 patients) or without (64 patients) lymph node dissection and 94% of them received at least one dose of I-131ablation/therapy. Univariate and multivariate analysis and Kaplan Meier analysis were used to compare patients who achieved an excellent response with those who continued to have biochemically or structurally incomplete responses. RESULTS: In univariate and multivariate analyses, age (P 0.002, Odds ratio 4.8, 95% CI: 1.8-12.9), tumor size (P 0.027, Odds ratio 1.30, 95% CI: 1.03-1.64) and distant metastases (P < 0.0001, Odds ratio 44.6, 95% CI: 10.7-184.5) were significantly associated with the risk of developing biochemically or structurally incomplete statuses. Patients ≥ 55 years, tumors > 2.5 cm and presence of distant metastasis were associated with higher risk of incomplete response and death from DTC. However, when this analysis was performed on intermediate and high-risk groups separately, only age was consistently associated with risk of biochemically or structurally incomplete response in either and both groups. CONCLUSION: Age is a strong predictor of biochemically and structurally incomplete responses in patients with intermediate and high-risk DTC.

COVID-19 infection and thyroid function.

Context: COVID-19 is a new viral infection affecting mainly the respiratory system with involvement of many other organs. Thyroid dysfunction has been described in COVID-19 but data are still unclear and conflicting on its frequency, severity and relationship with the outcome. Patients and methods: We assessed thyroid function tests (TFT) in 50 patients admitted to our institution with confirmed COVID-19 infection. We excluded patients known to have thyroid diseases or taking drugs that may affect thyroid function. Serum free thyroxine (FT4), thyrotropin (TSH) and triiodothyronine (T3) were measured once or more during the first 10 days after admission. In about 50 % of the cases, a follow up TFT was obtained during the first year after discharge (at a median follow up of 6 months). Results: We included 50 patients, 29 males (58 %) and 21 females (42 %). The median age was 47 years (range 25-89). Overall, TFTs were completely normal in all patients except for minor transient abnormalities in 5 patients (10 %) as follows: three patients had a mild transient elevated TSH, one had a mild transient suppressed TSH and one patient had a mildly low FT4 with normal TSH. There were no differences between the follow up TFTs obtained after discharge and TFTs obtained during admission in the acute phase. Conclusion: In this study, thyroid dysfunction during acute COVID-19 infection was rare, mild and transient. However, the study might not be powered enough to detect an association between thyroid dysfunction and the severity of illness and further studies are needed to assess this issue. Late-onset thyroid dysfunction does not seem to occur in COVID-19 infection during the next year after discharge.

Spinal epidural lipomatosis: a rare and frequently unrecognized complication of Cushing syndrome.

CONTEXT: Spinal Epidural Lipomatosis (SEL) is a rare and frequently unrecognized complication of Cushing syndrome (CS). Only nine previous cases of SEL have been described in CS. Here, we present a case of severe SEL and review the literature. CASE REPORT: A 29-year-old man who had severe CS secondary to an ACTH-secreting pituitary macroadenoma. He presented with progressive lower limb weakness over a 2-year period leading to complete paraplegia in the last 4 months. In addition, he had classic symptoms and signs of severe CS. His evaluation confirmed the diagnosis of CS with a 4-fold increase in his daily free urinary cortisol (1190 mg/day), a positive 1-mg dexamethasone suppression test (AM cortisol 729 nmol/l) and an elevated ACTH of 196 ng/dl (10-65). Magnetic resonance imaging (MRI) revealed a 20-mm pituitary adenoma and extensive fat accumulation in the spinal canal extending from C7 to S5 with significant spinal cord compression from T2-T10. The patient underwent an urgent spinal cord decompression surgery. He showed an immediate improvement and was able to walk with crutches 3 weeks later and independently 3 months later. About 13 days after the spinal surgery, he underwent a trans-sphenoidal surgery resulting in eucortisolemia. CONCLUSION: SEL is a rare and serious complication of CS. It should be considered in any patient with CS, especially when there is neurological symptoms or disproportionate weakness of the lower limbs. Its management should be individualized but prompt surgical decompression should be considered even in patients with relatively long history of paraparesis.

Natural Course of the American Thyroid Association Response to Therapy Statuses (Dynamic Risk Stratification) in Differentiated Thyroid Cancer.

The concept of response to therapy in differentiated thyroid cancer (DTC) was introduced as a dynamic risk stratification used to assess the status of the disease at the time of the evaluation during the follow-up and the risk of recurrence in the future. Our aim in this study was to evaluate the natural course over time of different response to therapy statuses. METHODS: We studied 501 nonselected DTC patients (102 males and 399 females) with a median age of 37 years (interquartile range [IQR] 29-48). All patients underwent near-total or total thyroidectomy followed by I-131 ablation (initial management). RESULTS: Of the 501 patients, 387 patients (77.2%) did not have any additional therapuetic interventions after the initial management. In this group, the response to therapy status at the time of the first evaluation after I-131 (median 17 months, IQR 14-22) was an excellent response in 258 (66.7%), an indeterminate response in 101 (26.1%), biochemically incomplete in 17 (4.4%), and structurally incomplete in 11 patients (2.8%). The status changed spontaneously without any intervention in many of them. At the last follow-up visit (median duration 101 months, IQR 71-126), 357 patients (92.2%) achieved an excellent response, 4 (1%) an indeterminate response, 8 (2.1%) a biochemically incomplete status, 16 (4.1%) a structurally incomplete status, and 2 (0.5%) died secondary to DTC with a structurally incomplete status. The response to therapy in the other 114 patients who underwent additional interventions changed from before intervention to the last evaluation as follows: excellent response, 0 to 60 patients (52.6%), indeterminate response, 20 (17.5%) to 1 patient (0.9%), biochemically incomplete 25 (21.9%) to 10 patients (9%), and structurally incomplete 69 (60.5%) to 43 patients (37.7%). Overall, at the last evaluation, 417 (83.2%) were in an excellent response, 5 (1%) in an indeterminate response, 18 (3.6%) in a biochemically incomplete status, 50 (10.2%) in a structurally incomplete status, and 11 (2.2%) died secondary to DTC with a structurally incomplete status. CONCLUSIONS: The response to therapy at the initial evaluation is predictive of the long-term outcome. Most patients with the indeterminate response and some in the biochemically incomplete statuses spontaneously regress to an excellent status. Mortality and progression of DTC occur mostly in the structurally incomplete status.

How Does The AJCC/TNM Staging System Eighth Edition Perform in Thyroid Cancer at A Major Middle Eastern Medical Center?

OBJECTIVE: The American Joint Committee on Cancer tumor node metastasis (TNM) staging system eighth edition (TNM-8) for differentiated thyroid cancer (DTC) has been introduced as a replacement for tumor node metastasis staging system seventh edition (TNM-7). We present the first study from a Middle Eastern population comparing these 2 versions of the TNM staging system. METHODS: We compared TNM-8 with TNM-7 in 701 patients with DTC seen during a 3-year period with a median age of 37 years (6-83) and a female-to-male ratio of 558 (79.6%) to 143 (20.4%). RESULTS: The number (%) of patients within each stage in TNM-7 and TNM-8, respectively, are as follows: stage I = 503 (71.6%) and 583 (83.2%), stage II = 52 (7.4%) and 81 (11.4%), stage III = 53 (7.6%) and 6 (0.9%), and stage IV = 93 (13.2%) and 31 (4.6%). Overall, 172 patients (24.5%) were downstaged in TNM-8 compared to that in TNM-7, as follows: 26, 30, and 24 patients from stages II, III, and IV in TNM-7 to stage I in TNM-8; 23 and 32 patients from TNM-7 stages III and IV to TNM-8 stage II; 6 patients from stage IVa in TNM-7 to stage III in TNM-8; and 31 patients from stage IVc in TNM-7 to stage IVb in TNM-8. TNM-7 and TNM-8 predicted the long-term outcome well (median follow-up, 7.9 years), but Kaplan-Meier analysis showed better separation of cancer-specific survival in TNM-8 compared to TNM-7. CONCLUSIONS: Compared with TNM-7, TNM-8 approximately downstaged a quarter of DTC patients and was more robust in separating the outcome of different stages over time.

The Impact of COVID-19 Viral Infection on the Hypothalamic-Pituitary-Adrenal Axis.

OBJECTIVE: To study the adrenocortical response to an acute coronavirus disease-2019 (COVID-19) infection. METHODS: Morning plasma cortisol, adrenocorticotropic hormone (ACTH), and dehydroepiandrosterone sulfate levels were measured in 28 consecutive patients with COVID-19 (16 men, 12 women, median age 45.5 years, range 25-69 years) on day 1 to 2 of hospital admission. These tests were repeated twice in 20 patients and thrice in 15 patients on different days. The hormone levels were correlated with severity of the disease. RESULTS: The median morning cortisol level was 196 (31-587) nmol/L. It was <100 nmol/L in 8 patients (28.6%), <200 nmol/L in 14 patients (50%), and <300 nmol/L in 18 patients (64.3%). The corresponding ACTH values had a median of 18.5 ng/L (range 4-38 ng/L), and the ACTH level was <10 ng/L in 7 patients (26.9%), <20 ng/L in 17 patients (60.7%), and <30 ng/L in 23 patients (82.1%). The repeated testing on different days showed a similar pattern. Overall, if a cutoff level of <300 nmol/L is considered abnormal in the setting of acute disease, 9 patients (32%) had cortisol levels below this limit, regardless of whether the test was done only once (3 patients) or 3 times (6 patients). When the disease was more severe, the patients had lower cortisol and ACTH levels, suggesting a direct link between the COVID-19 infection and impaired glucocorticoid response. CONCLUSION: Unexpectedly, the adrenocortical response in patients with COVID-19 infection was impaired, and a significant percentage of the patients had plasma cortisol and ACTH levels consistent with central adrenal insufficiency.

Misleading localization by 18F-fluorocholine PET/CT in familial hypocalciuric hypercalcemia type-3: a case report.

BACKGROUND: Familial hypocalciuric hypercalcemia (FHH) is a heterogeneous autosomal-dominant disorder of calcium hemostasis that may be difficult to distinguish clinically from mild primary hyperparathyroidism. Loss-of-function mutations mainly involving Arg15 residue of the adaptor-related protein complex 2, sigma subunit 1 (AP2S1) cause a rarer, more recently recognized form of FHH, FFH type-3. Recently, 18F-fluorocholine positron emission tomography/computed tomography (FCH-PET/CT) showed superior sensitivity to conventional imaging in localizing parathyroid adenomas. We report a new FFH type-3 patient who underwent unnecessary parathyroidectomy in association with misleading FCH-PET/CT imaging. CASE PRESENTATION: A 29-year old woman was initially evaluated for parathyroid hormone (PTH)-dependent hypercalcemia in 2013. Medical history was positive only for chronic constipation and malaise with no personal or family history of hypercalcemia, kidney stones, or neck surgery. Over seven years, serum calcium level was 2.51-2.89 mmol/L with concomitant PTH level of 58.7-94.8 mmol/L. Serum phosphate levels were in the low/low normal range. Serum creatinine and magnesium levels were normal. 25-hydroxy vitamin D level was 13 nmol/L. 24-hour urine calcium level was 1.92 mmol/day but increased to 6.99 mmol/day after treatment with cholecalciferol 1000 IU daily. Bone mineral density and renal ultrasound were normal. Parathyroid ultrasound showed two hypoechoic nodules inferior to the left and right thyroid lobes; however, 99mtechnitium-sestamibi scans (2013, 2016, 2018) were negative. FCH-PET/CT (2019) showed focal uptake co-localizing with the nodule inferior to the left thyroid lobe. The patient underwent left inferior parathyroidectomy and pathology was consistent with parathyroid hyperplasia. However, postoperatively, serum calcium and PTH levels remained elevated and FCH-PET/CT and ultrasound showed persistence of the uptake/nodule. Whole exome sequencing showed Arg15Cys mutation in the AP2S1 gene characteristic of FHH type-3. CONCLUSIONS: In this new case of FHH type-3, FCH-PET/CT failed to localize to the hyperplastic parathyroid glands and localized instead to apparently a lymph node. This, together with increased urinary calcium after vitamin D supplementation, led to unnecessary parathyroidectomy. Given the increasingly lower cost of genetic testing and the cost of follow up and unnecessary surgery, it may prudent to include genetic testing for FHH early on in patients with mild PTH-dependent hypercalcemia.

Course and Predictive Factors of Incomplete Response to Therapy in Low- and Intermediate-Risk Thyroid Cancer.

CONTEXT: Controversy surrounds the extent and intensity of the management of American Thyroid Association (ATA) intermediate- and low-risk patients with differentiated thyroid cancer (DTC). Understanding the natural history and factors that predict outcome is important for properly tailoring the management of these patients. OBJECTIVE: This work aims to study the natural course and predictive factors of incomplete response to therapy in low- and intermediate-risk DTC. PATIENTS AND METHODS: We studied a cohort of 506 consecutive patients [418 women (82.6%) and 88 men (17.4%)] with low and intermediate risk with a median age of 35 years (interquartile range [IQR], 27-46 years). We analyzed the natural course and the predictive factors of biochemically or structurally incomplete response. RESULTS: Of 506 patients studied, 297 (58.7%) patients were in the low-risk group and 209 (41.3%) were in the intermediate-risk group. Over a median follow-up of 102 months (IQR, 66-130 months), 458 (90.5%) patients achieved an excellent response, 17 (3.4%) had a biochemically incomplete status, and 31 (6.1%) had a structurally incomplete status. In univariable and multivariable analyses, age (≥ 33 years) (P < .0001, odds ratio 1.06 [1.04-1.08]) and lateral lymph node metastasis (LNM; P < .0001, odds ratio 3.2 [1.7-5.9]) were strong predictive factors for biochemically and structurally incomplete response to therapy. Sex, tumor size, multifocality, extrathyroidal extension, and lymphovascular invasion did not predict incomplete response to therapy. CONCLUSIONS: Patients with low- and intermediate-risk DTC have favorable outcomes. Age and lateral LNM are strong predictors of an incomplete response to therapy. This suggests that older patients and those with LNM should be managed and followed up more actively than younger patients and those without LNM.

Q-fever prosthetic valve endocarditis in a patient with SLE and antiphospholipid antibody syndrome.

Q fever prosthetic valve endocarditis in association with antiphospholipid antibody syndrome (APS) in systemic lupus erythematosus (SLE) has not been previously reported. Here, we report a 22-year-old Saudi female diagnosed with SLE and APS. She had mitral valve replacement with bio-prosthesis five years earlier for Libman-Sack endocarditis. She presented with two months' history of fever, cough, palpitations, and progressive shortness of breath. A transthoracic echocardiogram showed a degenerative mitral valve prosthesis with a large mass causing severe obstruction. Open heart surgery revealed multiple masses on the mitral valve. PCR from the resected tissues was positive for Coxiella burnetii DNA. Q fever serology showed phase two IgG 1:2048, phase one IgG 1:512, and IgM 1:1024. The valve was replaced with a bio-prosthesis. She was well at 12 months of follow-up.

A Life-Changing Moment in a Patient with Type 1 Diabetes: Insulin Holiday.

BACKGROUND: The diagnosis of type 1 diabetes can be a life-changing moment for our patients particularly having to live with the idea of taking insulin all their life and the barriers it can bring about. CASE REPORT: We report a patient with ten years of autoimmune type 1 diabetes treated with insulin. He was able to stop insulin in favour of oral diabetes agents after dynamic endocrine tests confirmed micro insulin secretion despite autoimmunity. Our case demonstrates that a detailed history and thorough investigations adopting a holistic approach can sometimes change the course of disease management and can leave a positive impact on the life of our patients. CONCLUSION: Patients with partial retention of beta-cell function in type 1 diabetes can temporarily stop insulin safely with ongoing surveillance.