Dose-dependent incidence of agranulocytosis in patients treated with methimazole and propylthiouracil.

Agranulocytosis is a serious adverse effect of methimazole (MMI) and propylthiouracil (PTU), and although there have been reports suggesting a dose-dependent incidence in relation to both drugs, the evidence has not been conclusive. The objective of our study was to determine whether the incidences of agranulocytosis induced by MMI and PTU exhibit dose-dependency. The subjects were 27,784 patients with untreated Graves' disease, 22,993 of whom were on an antithyroid drug treatment regimen for more than 90 days. Within this subset, 18,259 patients had been treated with MMI, and 4,734 had been treated with PTU. The incidence of agranulocytosis according to dose in the MMI group was 0.13% at 10 mg/day, 0.20% at 15 mg/day, 0.32% at 20 mg/day, and 0.47% at 30 mg/day, revealing a significant dose-dependent increase. In the PTU group, there were 0 cases of agranulocytosis at doses of 125 mg/day and below, 0.33% at 150 mg/day, 0.31% at 200 mg/day, and 0.81% at 300 mg/day, also revealing a significant dose-dependent increase. The incidence of agranulocytosis at MMI 15 mg and PTU 300 mg, i.e., at the same potency in terms of hormone synthesis inhibition, was 0.20% and 0.81%, respectively, and significantly higher in the PTU group. Our findings confirm a dose-dependent increase in the incidence of agranulocytosis with both drugs, but that at comparable thyroid hormone synthesis inhibitory doses PTU has a considerably higher propensity to induce agranulocytosis than MMI does.

The importance of early-stage blood pressure control in thyroid cancer patients treated with lenvatinib from the perspective of dose intensity.

PURPOSE: Lenvatinib (LEN) is a multikinase inhibitor that strongly inhibits tyrosine kinase receptors, especially VEGFR-2, which can cause hypertension, as well as strong tumor shrinkage. Though control of any side effects (SEs) is important for maintaining dose intensity (DI), hypertension is particularly important, because blood pressure (BP) can change quickly and respond to LEN administration and withdrawal, and it can be controlled with antihypertensive medications. Focusing on the early phase of treatment, the effect of BP 8 weeks after LEN initiation (BP8w) on DI at 8 weeks (DI8w) was investigated. METHODS: The subjects were 85 thyroid cancer patients who started LEN at 24 mg/day and continued for ≥8 weeks. The BP at the start of LEN (BPbase), BP8w grade, and DI8w were examined. RESULTS: Median (range) systolic BP changed significantly from BPbase of 117 (84-167) mmHg to BP8w of 134 (103-168) mmHg (p<0.001). Antihypertensive treatment at baseline, systolic BPbase, and male sex were related to higher DI8w on multivariate analysis. The median DI8w of the 23 patients who required dose modification due to hypertension was 20.2 mg/day (n=6) in grade 1, 15.8 mg/day (n=13) in grade 2, and 14.5 mg/day (n=4) in grade 3, showing a trend toward lower DI8w as the grade level increased. CONCLUSION: LEN can increase BP by 20 mmHg at 8 weeks even with intensive antihypertensive management. Baseline antihypertensive treatment and BPbase can affect DI8w. A higher DI8w may be achieved by aiming for a low 8-week BP with more intensive antihypertensive therapy after LEN initiation.

New Insights on the Importance of the Extent of Vascular Invasion in Widely Invasive Follicular Thyroid Carcinoma.

BACKGROUND: This study aimed to investigate the association between the extent of vascular invasion (VI) and the outcome of widely invasive follicular thyroid carcinoma (WI-FTC). METHODS: The records of 107 patients with WI-FTC confirmed by surgical specimens from January 2005 to December 2016 were retrospectively reviewed. RESULTS: Among the 107 patients with WI-FTC, those with a VI of < 4 (n = 62) and ≥ 4 (n = 45) had a 10 year cause-specific survival (CSS) rate of 97.7% and 89.4% (p = 0.008), respectively. Univariate analysis identified M1 (p = 0.001), and the number of VI of ≥ 4 as significant negative prognostic factors for CSS. Multivariate analysis identified M1 (hazard ratio [HR] = 9.366) as independent negative prognostic factor for CSS. Among the 72 patients with M0 WI-FTC, those with a VI of < 2 (n = 33) and ≥ 2 (n = 39) had a 10-year distant metastasis-free survival (DMFS) rate of 96.8% and 56.8% (p = 0.001), respectively. Univariate analysis identified age ≥ 55 years (p = 0.011), presence of VI, the number of VI of ≥ 2, and resection margin status (p < 0.001) as significant negative prognostic factors for DMFS. Multivariate analysis identified the number of VI ≥ 2 (HR = 9.137), and resection margin status (HR = 5.853) as independent negative prognostic factors for DMFS. CONCLUSIONS: It may be unnecessary that WI-FTC with curative resection margin status and a VI of < 2, especially in capsular invasion only, routinely undergo completion thyroidectomy and postoperative ablation.

Impact of Age on Prognosis in Papillary Thyroid Carcinoma: How Should Age be Incorporated into the Treatment Strategy?

BACKGROUND: Age has been recognized as one of the strong prognostic indicators for thyroid cancer. However, treatment strategies for papillary thyroid cancer (PTC) are usually determined only by the extent of disease progression, without considering the patient's age. The aim of this study was to investigate how the surgical strategy for PTC should take into account patient age. METHODS: To exclude the effect of treatment strategy, 837 patients treated with uniform treatment strategies (hemithyroidectomy without radioiodine therapy) between 1986 and 1995 were the subjects of this study. Using a Cox proportional hazard model, clinical risk factors related to disease-specific survival (DSS), disease-free survival (DFS), and distant metastasis-free survival (DMFS) were analyzed. A receiver-operating characteristic (ROC) curve analysis was performed to identify the optimal cutoff points. RESULTS: Significant risk factors related to DSS and DMFS were age, extrathyroidal extension (ETE), and numbers of metastatic lymph nodes (NMLNs), but age was not significantly related to DFS. The 20-year DSS and DMFS rates were fair in patients without ETE regardless of age or NMLNs. However, in patients with ETE, DSS and DMFS rates were significantly worse in elderly patients than in young patients. ROC curve analysis showed that the optimal cutoff age was 48 years for discriminating DSS in patients with ETE. CONCLUSION: Regardless of age, PTC patients without ETE are candidates for a treatment strategy not using RAI, and more aggressive treatment may be recommended for elderly PTC patients with ETE.

Clinical features of moyamoya disease with Graves' disease: a retrospective study of 394,422 patients with thyroid disease.

Graves' disease has been reported to affect the clinical features of moyamoya disease (MMD), an occlusion of the circle of Willis. This study aimed to clarify the characteristics of MMD in patients with Graves' disease. This was a single-center, retrospective study. The prevalence and clinical features of MMD patients among all patients with thyroid disease who visited Ito Hospital from January 2005 to December 2019 were evaluated. The relationship between MMD and hyperthyroidism was analyzed in new-onset Graves' disease patients during the same period. Of all 394,422 patients with thyroid disease, 88,180 had Graves' disease, and 40 had MMD with Graves' disease, i.e., the prevalence was 45.36 per 100,000 patients with Graves' disease (0.0454%). The median age at onset of MMD was 39 years (interquartile range, 31-54 years), with a male to female ratio of 1:12. The most common time that MMD was diagnosed was within 1 year after the onset of Graves' disease, in 9 of 40 patients (22.5%), and 19 of 40 patients (47.5%) underwent bypass surgery for MMD. In MMD with Graves' disease, headache was the most frequent symptom, and ischemic types of stroke and bilateral lesions were common. Of 23,347 patients with new-onset Graves' disease, 7 were diagnosed with MMD and the incidence of MMD was 5.94 patients per 100,000 person-years. Most patients developed MMD symptoms during hyperthyroidism. Although MMD is a rare condition, it should be noted that it can occur with Graves' disease.

Radioiodine uptake after monotherapy with potassium iodide in patients with Graves' disease.

The effect of potassium iodide (KI) on radioiodine uptake (RAIU) before radioisotope therapy in Graves' disease (GD) patients was investigated. A total of 82 patients who had been treated with KI monotherapy before 24-hour RAIU (24 h RAIU) were evaluated and 354 of those who had been treated with thiamazole (MMI) monotherapy were extracted from the 1,130 GD patients who were identified as having had appropriate iodine restriction based on urinary iodine excretion. Urinary iodine excretion (UIE) <200 µg/day was confirmed in all subjects. Propensity score-matching was performed to identify the difference in 24 h RAIU between the KI group and the MMI group. In addition, multiple regression analysis was performed to evaluate related to 24 h RAIU. Propensity score-matching resulted in 57 matched patients in each group. After matching, 24 h RAIU was still significantly lower in the KI group than in the MMI group (median 53% (interquartile range 47-61%) vs. 63% (56-66%); p = 0.001). In addition, KI monotherapy was weakly negatively correlated with 24 h RAIU, whereas the female sex and FT3 were very weakly positively correlated on multiple regression analysis. The results suggest that KI monotherapy likely suppressed 24 h RAIU more than MMI monotherapy in GD patients with appropriate iodine restriction, given the difference in the mechanism of hormone suppression.

Establishment of reference intervals for fT3, fT4, and TSH levels in Japanese children and adolescents.

The present study aimed to establish new reference intervals (RIs) for serum free triiodothyronine (fT3), free thyroxine (fT4), and thyroid stimulating hormone (TSH) levels in Japanese children and adolescents aged 4 to 19 years. A total of 2,036 (1,611 girls, 425 boys) participants were included over a 17-year period; they all tested negative for antithyroid antibodies (TgAb, TPOAb) and were found to have no abnormalities on ultrasonography. RIs were determined by nonparametric methods. The results showed that serum fT3 was significantly higher in the 4-15-year-olds than in the 19-year-olds. The serum fT4 was significantly higher in the 4-10-year-olds than in the 19-year-olds. The serum TSH was significantly higher in the 4-12-year-olds than in the 19-year-olds. All of them gradually decreased with age to approximate the adult levels. The upper limit of TSH was lower in those aged 13 to 19 years than in adults. The differences were examined by sex. The serum fT3 was significantly higher in boys than in girls between the ages of 11 and 19 years. The serum fT4 was significantly higher in boys than in girls between the ages of 16 and 19 years. There did not seem to be any sex difference in those under 10 years of age. In conclusion, serum fT3, fT4, and TSH levels in children and adolescents differ from those in adults. It is important to evaluate thyroid function using the new RIs that are appropriate for chronological age.

Incidence and risk factors for Graves' orbitopathy in patients who underwent anti-inflammatory and immunosuppressive treatment during medical treatment for Graves' disease: investigation of 1,553 cases with newly diagnosed Graves' disease and proposal of a predictive score.

Appropriate administration of anti-inflammatory and immunosuppressive treatment (AIIST) is important for patients with Graves' orbitopathy (GO). This study aimed to clarify the incidence and risk factors for GO treated with AIIST and propose a predictive score, among newly diagnosed Graves' disease (GD) patients in Japan. A total of 1,553 GD patients who were newly diagnosed during the year 2011 were investigated. AIIST included local and/or systemic glucocorticoid administration and retrobulbar irradiation. A multivariable Cox proportional hazards model was used to investigate the risk factors for GO underwent AIIST during medical treatment, including at diagnosis, of GD. Then, a GO score was created by summing each point assigned to risk factors based on their coefficient obtained in the Cox model. AIIST was administered to 107 patients (6.9%). The risk factors and hazard ratios for GO underwent AIIST were: age (per 10 years), 1.32 (95% confidence interval: 1.16-1.50), p < 0.0001; TSH binding inhibitory immunoglobulin (TBII) (per 10 IU/L), 1.33 (1.15-1.54), p = 0.0001; and thyroglobulin antibody (TgAb) negativity, 2.98 (1.96-4.59), p < 0.0001. The GO score, ranging from 0 to 8 points, showed moderate performance (area under the curve: 0.71, cut-off value: 5 points, sensitivity: 0.76, specificity: 0.59, positive predictive value: 0.12, negative predictive value: 0.97). AIIST was performed for patients with active manifestations of GO in 6.9% of newly diagnosed GD patients. The risk factors for GO underwent AIIST were higher age, higher TBII, and TgAb negativity. The GO score based on these factors may be useful in managing GO.

Evaluation of factors predicting postoperative recurrence and metastasis of parathyroid cancer: a single-center study.

PURPOSE: The purpose of this study was to examine the postoperative clinical course of parathyroid carcinoma to determine factors that predict postoperative recurrence and distant metastasis. METHODS: In this retrospective study, we included 38 patients with parathyroid carcinoma who received surgical intervention at Itoh Hospital between 1979 and 2020. Clinicopathologic characteristics (age, sex, intact PTH, serum Ca level, operation type, parathyroid weight, parathyroid size, histopathologic findings: vascular invasion, capsular invasion, necrosis, histological type, and Ki-67 staining) were used. The median follow-up observation period was 63.7 months. RESULTS: Postoperatively, 5 patients (13.2%) developed distant metastasis or had localized recurrence, and 3 patients died (7.9%). The results of the univariate analysis revealed three factors affecting distant metastasis and recurrence, which were Ki-67 (p = 0.0041), the presence or absence of necrosis (p = 0.0163), and tumor weight (p = 00,189). Using the cutoff values obtained by ROC analysis, which were 4.1 for Ki-67 (sensitivity of 80% and specificity of 96.9%) and 4890 mg for tumor weight (sensitivity of 100% and specificity of 60.9%), we calculated the cumulative incidence of recurrence and distant metastasis by the three factors retained. We found that the presence of the three factors was associated with a high possibility of distant metastasis or recurrence during the 5-year follow-up period. CONCLUSIONS: Three factors, Ki-67, necrosis, and tumor weight in parathyroid carcinoma, may predict outcomes of postoperative recurrence and distant metastasis.

Spatially resolved immune microenvironmental profiling for follicular thyroid carcinoma with minimal capsular invasion.

Spatial profiles of the tumor-immune microenvironment are associated with disease progression and clinicopathological factors in various cancers. Follicular thyroid carcinoma (FTC) is the second most common thyroid cancer, where the presence of capsular invasion or angioinvasion determines the pathological diagnosis; however, little is known about the immune microenvironment profiles associated with the acquisition of invasive potential of FTC. In this study, we focused on FTC with minimal capsular invasion, and the spatially resolved immune microenvironment of FTC was studied in the discovery (n = 13) and validation cohorts (n = 40). CD8+ T cells, helper T cells, regulatory T cells, B cells, natural killer cells, tumor-associated macrophages, CD66+ granulocytes, mature dendritic cells, and mast cells were quantitatively evaluated in single tissue sections, via a 12-marker multiplex immunohistochemistry and image cytometry. Cell densities and compositions of immune cells were spatially stratified by six tissue regions including tumor center, subcapsular region, capsular invasion, adjacent stroma of capsular invasion, peritumoral stroma, and adjacent normal. Lymphoid cell lineages in the tumor center and subcapsular regions were significantly lower than those in adjacent normal and peritumoral stroma, potentially related to the lymphoid lineage exclusion from the intratumoral regions of FTC. Interestingly, immune cell composition profiles in the capsular invasive front were distinct from those of intratumoral region. The ratios of T cells to CD66b+ granulocytes with capsular invasion were significantly higher than those without capsular invasion, suggesting the presence of a unique immune microenvironment at the invasive front between tumor foci and stroma. In addition, tumor cells at the capsular invasive front showed significantly higher expression of tumor programmed cell death ligand 1 (PD-L1) than those at the tumor center. This study revealed spatial immune profiles associated with capsular invasion of FTC, providing new insights into the mechanisms underlying its development and initial invasion.

Encapsulated Angioinvasive Follicular Thyroid Carcinoma: Prognostic Impact of the Extent of Vascular Invasion.

BACKGROUND: Previous studies have reported an association between four or more foci of vascular invasion (VI) and thyroid cancer prognosis, while the current study aimed to investigate the association between extent of VI and outcome of encapsulated angioinvasive follicular thyroid carcinoma (FTC). METHODS: The records of 303 patients with encapsulated angioinvasive FTC confirmed by surgical specimens at Ito Hospital from January 2005 to December 2014 were retrospectively reviewed. Thirteen patients had distant metastasis at diagnosis and were classified as M1. RESULTS: Among the 290 patients with M0 encapsulated angioinvasive FTC, the 10-year disease-free survival (DFS) rate was 85.6%. Those with a VI of 1 (n = 131) or ≥ 2 (n = 159) had a 10-year DFS rate of 94.9% and 77.9% (p < 0.001), respectively, and those with a VI of 1-3 (n = 211) or ≥ 4 (n = 79) had a 10-year DFS rate of 86.3% and 83.3% (p = 0.311), respectively. Multivariate analysis identified age ≥ 55 years (p = 0.031) and VI ≥ 2 (p = 0.002) as independent negative prognostic factors for DFS. Patients with M0 encapsulated angioinvasive FTC aged ≥ 55 years and VI ≥ 2 had significantly poorer prognosis and a 10-year DFS rate of 66.4% (p < 0.001). CONCLUSIONS: Patients with encapsulated angioinvasive FTC who had two or more foci of VI, especially patients aged ≥ 55 years, should be carefully followed-up.

Impact of Local Control on Clinical Course in Stage IVC Anaplastic Thyroid Carcinoma.

BACKGROUND: The present study investigated the association between local resection and cause of death in anaplastic thyroid carcinoma (ATC) patients with stage IVC disease. METHODS: A total of 54 ATC patients with stage IVC disease were included in the study. Information including patient characteristics, laboratory data including complete blood count, treatment, and death were collected for analysis. RESULTS: The median overall survival (OS) for patients with or without resection was 8.4 [95% confidence interval (CI) 5.9-14.4)] and 4.2 (95% CI 2.5-6.2) months, respectively (p < 0.001). No patients survived without resection at 1 year. Univariate analysis revealed that resection (p < 0.001) and radiotherapy (p = 0.018) were significantly associated with OS. Multivariate analysis revealed that resection (hazard ratio 0.257; 95% CI 0.115-0.575; p < 0.001) was the only independent prognostic factor of OS. In ATC patients with known resection status, the median OS for the patients with a resection status of R0/1 (n = 28) and R2 (n = 7) were 13.0 (95% CI 7.5-18.7) and 1.7 (95% CI 0.1-6.2) months, respectively (p < 0.001). The most common specific cause of death was respiratory insufficiency (35%), followed by airway obstruction (25%) and cerebral cardiovascular-related death (5%). The frequency of airway obstruction was significantly lower in patients with resection (p = 0.018). CONCLUSIONS: Resection probably impacts on clinical course in ATC patients despite the presence of distant metastasis. However, R2 resection is likely to be harmful and surgeons should carefully consider the resectability of thyroid tumors.

Prediction model of Graves' disease in general clinical practice based on complete blood count and biochemistry profile.

Although untreated Graves' disease (GD) is associated with a higher risk of cardiac complications and mortality, there is no well-established way to predict the onset of thyrotoxicosis in clinical practice. The aim of this study was to identify important variables that will make it possible to predict GD and thyrotoxicosis (GD + painless thyroiditis (PT)) by using a machine-learning-based model based on complete blood count and standard biochemistry profile data. We identified 19,335 newly diagnosed GD patients, 3,267 PT patients, and 4,159 subjects without any thyroid disease. We built a GD prediction model based on information obtained from subjects regarding sex, age, a complete blood count, and a standard biochemistry profile. We built the model in the training set and evaluated the performance of the model in the test set by using the artificial intelligence software Prediction One. Our machine learning-based model showed high discriminative ability to predict GD in the test set (area under the curve [AUC] 0.99). The main contributing factors to predict GD included age and serum creatinine, total cholesterol, alkaline phosphatase, and total protein levels. We still found high discriminative ability even when we restricted the variables to these five most contributory factors in our prediction model (AUC 0.97) built by using artificial intelligence software showed high GD prediction ability based on information regarding only five factors.

Predictors of maximum efficacy of lenvatinib for real-world patients with differentiated thyroid carcinoma.

BACKGROUND AND OBJECTIVES: Tyrosine kinase inhibitors (TKIs) have provided excellent clinical benefits to patients with advanced differentiated thyroid cancer (DTC): however, the tumor status for which maximum efficacy can be obtained remains controversial. We conducted this study to identify effective clinical predictors, focusing on disease progression. METHODS: Using the data of 42 DTC patients treated with lenvatinib, we investigated the clinical factors related to overall survival (OS) and progression-free survival (PFS), and conducted analyses by the scoring of the factors. RESULTS: The 3 year OS and median PFS were 51% and 13.8 months, respectively. Univariate analysis identified performance status (PS), tumor-related symptoms, and tumor diameter as the only factors affecting both these outcomes. Giving 1-point for each of these three factors, a higher score was significantly related to shorter OS and PFS. Patients with two or fewer points (n = 34) had better median OS (NR vs 3.9 months, p < 0.001) and PFS (15.7 vs 2.1 months, p < 0.001) than patients with three points (n = 8). Patients with all three factors had a significantly worse prognosis than patients with two or fewer factors. CONCLUSION: DTC patients with all three indicators are unlikely to have longer survival. Therefore, it is important to commence TKIs before disease progression.

Outcomes for Minimally Invasive Follicular Thyroid Carcinoma in Relation to the Change in Age Stratification in the AJCC 8th Edition.

BACKGROUND: Completion total thyroidectomy with radioactive iodine (RAI) therapy is not uniformly recommended for minimally invasive follicular thyroid carcinomas (MI-FTCs) without distant metastasis, but may be considered for cases with a risk factor of recurrence, such as age ≥ 45 years. OBJECTIVE: The present study aimed to investigate the outcomes for patients with MI-FTC using a stratification age of 55 years. METHODS: The records of 478 patients with MI-FTC confirmed by surgical specimens at Ito Hospital from January 2005 to December 2014 were retrospectively reviewed. Twenty patients had distant metastasis at diagnosis and were subsequently classified as M1. RESULTS: Among the 478 patients with MI-FTC, univariate analysis identified that age ≥ 55 years (p = 0.002) and M1 (p < 0.001) were related to cause-specific survival. In 458 patients with M0 MI-FTC, male sex (p = 0.041), age ≥ 55 years (p = 0.001), and tumor size > 40 mm (p < 0.001) were related to poor disease-free survival (DFS) in univariate analysis. Multivariate analysis showed that age ≥ 55 years (p = 0.005) and tumor size > 40 mm (p = 0.005) were independent prognostic factors for DFS. The 10-year DFS rates of patients aged < 45 years, 45 years ≤ age < 55 years, and ≥ 55 years were 97.0%, 95.5%, and 86.4%, respectively. CONCLUSIONS: The change in the recommended age for completion total thyroidectomy with RAI, from 45 to 55 years, seemed reasonable.

Impact of lenvatinib on renal function: long-term analysis of differentiated thyroid cancer patients.

BACKGROUND: Because lenvatinib is well known to induce proteinuria by blocking the vascular endothelial growth factor (VEGF) pathway, renal function is a concern with long-term administration of lenvatinib. The long-term effects of lenvatinib on renal function in patients with advanced differentiated thyroid carcinoma (DTC) were analyzed. METHOD: This study involved 40 DTC patients who continued lenvatinib therapy for ≥6 months. Estimated glomerular filtration rate (eGFR) was calculated as an indicator of renal function. The temporal course of eGFR, effects of baseline eGFR on eGFR changes, and factors affecting renal impairment were investigated. RESULTS: The overall cohort showed sustainable decreases in eGFR, with decreased values of 11.4, 18.3, and 21.0 mL/min/1.73 m2 at 24, 36, and 48 months after starting treatment, respectively. No differences in eGFR decrease every 6 months were seen for three groups classified by baseline eGFR ≥90 mL/min/1.73 m2 (n = 6), < 90 but ≥60 mL/min/1.73 m2 (n = 26), or < 60 but ≥45 mL/min/1.73 m2 (n = 8). Grade 3 proteinuria was associated with declines in eGFR (p = 0.0283). Long observation period was also associated with decreases in eGFR (p = 0.0115), indicating that eGFR may decrease in a time-dependent manner. CONCLUSION: Lenvatinib can induce declines in eGFR, particularly with treatment duration > 2 years, regardless of baseline eGFR. Proteinuria is a risk factor for declines in eGFR. Patients who start lenvatinib with better renal function show a renal reserve capacity, prolonging clinical outcomes. Decision-making protocols must balance the benefits of lenvatinib continuation with acceptable risks of harm.

A case of macro-TSH consisting of IgA-bound TSH.

An asymptomatic, 68-year-old Japanese man visited our hospital for further examination of subclinical hypothyroidism. At the first visit, the serum TSH level was markedly elevated (36.6 µIU/mL), but the serum level of free T4 was within the reference interval. Thyroid dysfunction due to dietary iodine excess was initially suspected. However, even after iodine restriction, his thyroid function tests were the same as at the first visit, which suggested false elevation of the TSH level. The TSH levels were compared among three different measurement systems, which showed a similar tendency of TSH elevation above the reference interval, but the different TSH elevation levels among the measurement methods suggested the existence of some interfering substance. Neither serial dilution of the patient's serum nor polyethylene glycol and protein G precipitation tests showed any significant changes in the recovery rate. IgG-bound macro-TSH was ruled out. The TSH peak on gel filtration chromatography was located at a molecular size greater than IgA, which suggested the presence of IgA-bound TSH. After precipitation with Jacalin, which binds specifically to IgA, the TSH level decreased from 30.7 µIU/mL to 2.01 µIU/mL, within the reference interval. Thus, IgA-bound macro-TSH was identified. Macro-TSH is a rare condition in which an immunoglobulin-bound, high-molecular-weight form of TSH results in a false elevation of the serum TSH level. When there is a discrepancy between the results of thyroid function tests and clinical symptoms, and macro-TSH is suspected, it is necessary to know that not only IgG-bound TSH but also IgA-bound TSH could be the cause.

Propylthiouracil-induced otitis media with anti-neutrophil cytoplasmic antibody-associated vasculitis: a case report and review of the literature.

Propylthiouracil (PTU)-induced otitis media with anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (OMAAV) is an extremely rare adverse event associated with anti-thyroid drugs and is not well recognized. A 42-year-old woman with Graves' disease undergoing PTU therapy for 8 years visited our hospital because of earache and congested feeling in her left ear. Blood tests, a computed tomography scan and pure tone audiometry revealed otitis media and moderate mixed hearing impairment. Antibiotics, ear drops with antibiotics and painkillers were administered. However, her earache and hearing loss gradually got worse and symptoms of facial nerve palsy appeared. At several weeks after initiation of the treatment, a high serum level of myeloperoxidase (MPO)-ANCA, 75.6 U/mL, was revealed. After excluding other causes, she was diagnosed with OMAAV. PTU was suspected as the cause of her OMAAV and was immediately discontinued, and prednisolone was started. Hearing impairment in her left ear gradually got better and showed substantial improvement. Facial nerve palsy disappeared. Although PTU-induced OMAAV is an extremely rare disease, it is important to recognize the disease, as delayed treatment can lead to irreversible hearing loss, hypertrophic pachymeningitis, and subarachnoid hemorrhage. When patients taking anti-thyroid drugs, especially PTU, are diagnosed with refractory otitis media or hearing loss, it is possible that OMAAV might be the cause and thus serum ANCA levels should be evaluated.

The Time Series Behavior of Neutrophil-to-Lymphocyte Ratio in Thyroid Cancer Patients on Tyrosine Kinase Inhibitor Therapy.

INTRODUCTION: The neutrophil-to-lymphocyte ratio (NLR) reveals the balance of immune system is and associated with survival in various type of cancers. Tyrosine kinase inhibitors (TKI) improve patient survival with progressing thyroid cancer and are said to have less side effects, and are considered good palliation. OBJECTIVE: This study evaluated the time series behavior of NLR in advanced thyroid carcinoma patients on TKI therapy and examined what percentage of patients received TKIs in the last month of life. METHODS: We retrospectively reviewed medical records on 72 patients with advanced thyroid carcinoma treated with TKIs between May 2015 and October 2018. All patients had progressive disease and/or uncontrolled distant metastasis. Fifty-two patients had differentiated thyroid carcinoma (DTC), 19 patients had anaplastic carcinoma (ATC), and 1 had squamous cell carcinoma. NLR was calculated as the absolute neutrophil count divided by the absolute lymphocyte count. Median follow-up time in DTC and ATC patients was 12.3 months (range 0.9-40.4) and 2.7 months (range 0.6-14.3), respectively. RESULTS: In DTC patients, median NLR at initial treatment, at initiation of TKI, and for 20 patients who died at the time of death was 2.25 (range, 0.89-9.78), 3.55 (range, 0.86-28.3), and 11.78 (range, 0.98-98.0), respectively. In ATC patients, median NLR at initial treatment, at initiation of TKI, and for 16 patients who died at the time of death was 2.96 (range, 1.12-9.0), 11.43 (range, 2.32-95.0), and 16.9 (range, 3.45-95.0), respectively. NLR >10 at TKI initiation was significantly associated with shorter overall survival compared with NLR <4 and NLR 4-10 (p < 0.0001) in DTC patients. Among 46 dead patients, 32 patients (68.1%) received TKIs treatment in the last month of life (85% DTC patients and 61.5% ATC patients). In receiver operating characteristic curve analysis, cutoffs for DTC and ATC were 11.43 (p = 0.0488, area under the ROC curve 0.941) and 31.67 (p = 0.0034, area under the ROC curve 0.831) in patients who survived ≤6 weeks and >6 weeks, respectively. CONCLUSION: A substantial percentage of patients received TKIs in the last month of life. The NLR increased according to tumor progression and predicted survival after TKI initiation. We might refer the patients with NLR >11.43 in DTC and those with NLR >31.67 in ATC to a hospice/palliative care program.

Urinalysis by combination of the dipstick test and urine protein-creatinine ratio (UPCR) assessment can prevent unnecessary lenvatinib interruption in patients with thyroid cancer.

BACKGROUND: Proteinuria induced by lenvatinib is a class effect that occurs secondary to VEGFR suppression. Withholding of lenvatinib is required in cases with severe proteinuria. Urine protein-creatinine ratio (UPCR, g/gCre) has recently attracted attention as an alternative to 24-h urine collection for assessing proteinuria. The aim of this study was to examine the correlation between the results of proteinuria assessed by the dipstick test and UPCR, and to investigate the influence of proteinuria grading with UPCR on lenvatinib dose adjustment compared to that with only the dipstick test. METHOD: Three hundred and ten urine samples from 63 patients with advanced thyroid cancer under treatment with lenvatinib, which were tested by both the dipstick test and UPCR were analyzed. Lenvatinib was withheld when there was evidence of CTCAE grade 3 proteinuria, and restarted when it resolved. The frequency of proteinuria, correlation between the results of the dipstick test and UPCR test, and the effect of dose withholding in cases with results of 3 + in the dipstick test were calculated. RESULTS: Proteinuria was seen in 56 (88.9%) patients. Of the 154 dipstick 3 + samples, only 56 (36.4%) were judged as more than 3.5 g/gCre by UPCR (grade 3 proteinuria), although none of the 1 + and only 3.7% of 2 + samples were judged as grade 3 proteinuria. We were able to prevent unnecessary lenvatinib interruption due to proteinuria in 63.6% of dipstick 3 + samples by assessment of UPCR. CONCLUSIONS: Urinalysis by combination of the dipstick test and UPCR assessment might be a better strategy for preventing unnecessary interruption of lenvatinib.