Familial Nonautoimmune Hyperthyroidism Due to a TSH Receptor Gene Pathogenic Variant.

Familial nonautoimmune hyperthyroidism (NAH) is a rare type of autosomal dominant hyperthyroidism caused by constitutively active pathogenic variants of the thyrotropin receptor (TSHR) gene. Although affected family members present with varied levels of hyperthyroid features, even when the same pathogenic variant is present, total thyroidectomy followed by radioiodine therapy is recommended for long-term management. Herein, we present the case of an 18-year-old proband and her family members with NAH (TSHR-I640V), who presented with diverse thyroid dysfunctions: fluctuations between euthyroid and subclinical hyperthyroidism, mild hyperthyroidism, and overt hyperthyroidism. Almost all affected adult family members, except the proband, showed no progression of hyperthyroidism or thyroid enlargement. A family history of thyrotropin receptor antibodies (TRAb)-negative hyperthyroidism is important for the identification of NAH in adults before TSHR genetic testing can be performed. Ablative therapy is not necessary when familial NAH presents with late-onset mild hyperthyroidism without coexisting diseases.

A high Ki-67 labeling index and high thyroglobulin doubling rate are significant predictors of excision-site recurrence of papillary thyroid carcinoma following airway resection for locally curative surgery.

BACKGROUND: Papillary thyroid carcinoma (PTC) occasionally invades the trachea and requires airway resection. Tracheal excision site recurrence (ESR) is a serious problem. We investigated predictors of ESR in patients with PTC who underwent airway resection for locally curative surgery. METHODS: We enrolled 149 patients with PTC who underwent airway resection (median age at the initial surgery: 67 years), including partial-thickness resection (n = 73) or full-thickness resection (n = 76), for grossly curative surgery. The median postoperative follow-up period was 93 months. RESULTS: To date, 11 patients (6.7%) underwent ESR: 6 underwent full-thickness resection and 5 underwent partial-thickness resection. The time to ESR ranged from 14 to 113 months (median: 57 months) after the initial surgery. None of the 11 ESR patients underwent adjuvant external beam radiotherapy (EBRT) and none of the 4 airway resection patients who underwent EBRT developed ESR. The 5- and 10-year ESR rates were 4.3% and 11.3%, respectively. In the multivariate analysis (forward-backward stepwise selection method), a Ki-67 labeling index (LI) ≥5% (p = 0.048) and the thyroglobulin doubling rate (Tg-DR) >0.33/year (p = 0.009) (for Tg-antibody negative cases) were independent predictors of ESR. Nine of the 11 patients underwent ESR resection and only one developed a second recurrence. CONCLUSIONS: A high Ki-67 LI was a static predictor, and high Tg-DR was a dynamic predictor, of ESR in patients with PTC following airway resection. In such patients, careful postoperative monitoring for ESR is necessary and adjuvant therapies, such as EBRT, may be considered.

Predictors of distant metastatic recurrence in intermediate-risk papillary thyroid carcinoma.

BACKGROUND: Patients with intermediate-risk papillary thyroid carcinoma (PTC) have a favorable prognosis with standard treatment of total thyroidectomy (TT) and adjuvant radioactive iodine therapy (RAIT). However, the benefits of TT or adjuvant RAIT remain undetermined, and they are often omitted in Japan. We investigated risk factors for life-threatening distant recurrence in patients with intermediate-risk PTC who are optimal candidates for adjuvant RAIT. PATIENTS AND METHODS: Outcomes without RAIT were retrospectively examined in 4030 intermediate-risk conventional PTC cases underwent initial surgery from 2005 to 22 (IRB approval 20200709-1). RESULTS: Lobectomy (LT) and TT was performed in 11.5% and 88.5%, respectively. Recurrent laryngeal nerve paralysis and hypoparathyroidism was less commonly observed in LT (1.3% and 0%) than TT (2.4% and 3.5 %). Fifty-six cases (1.4%) had distant recurrence. Recurrence-free survival rates at 10 years was 93.5%. There was no significant difference in recurrence rate between LT and TT. Age ≥55, cN1b, and tumor diameter >30 mm significantly associated with distant recurrence. There was a strong relationship between the number of positive risk factors and recurrence; the distant recurrence rate in cases of 0, 1, 2, and 3 positive factors was 0.3% (4/1203), 1.3% (25/1889), 2.7% (23/830) and 7.1% (4/52) (HR 6.46 (2.34-17.86), Log-rank <0.001). CONCLUSION: For intermediate-risk conventional PTC, there is no difference in prognosis even if LT was selectively conducted. However, in patients with risk factors for distant metastatic recurrence, such as age ≥55 years, cN1b, and tumor size >30 mm, adjuvant RAIT was considered eligible.

Prognostic factors of papillary and follicular carcinomas based on pre-, intra-, and postoperative findings.

Papillary and follicular thyroid carcinomas (PTC and FTC) are prominent malignancies that originate from thyroid follicular cells. PTC is usually diagnosed via preoperative cytology, and large tumor size, clinical node metastasis, and distant metastasis constitute preoperative prognostic factors. Gross extrathyroidal and extranodal tumor extensions have a significant prognostic impact, are evaluated intraoperatively, and are useful for determining the extent of surgery. Aggressive variants, such as tall cell and hobnail variants, a high Ki-67 labeling index (LI), and somatic gene mutations are prognostic factors in postoperative pathological and molecular examinations. In contrast, FTC is generally diagnosed based on the postoperative pathology. Large tumor size and M factors have prognostic value; however, the findings of pathological examinations are very important. FTCs are classified as minimally invasive, encapsulated angioinvasive, and widely invasive FTCs. Widely invasive FTC with vascular invasion (VI) and encapsulated angioinvasive FTCs with extensive VI have a poor prognosis, whereas widely invasive FTC without VI has an excellent prognosis, which is similar to that of minimally invasive FTC. This indicates that VI is a considerably more important prognostic marker than capsular invasion. For postoperative follow-up, dynamic markers such as the thyroglobulin-doubling rate (DR), metastatic tumor volume-DR, and change in neutrophil-to-lymphocyte ratio are important and are useful for evaluating the effectiveness of treatments, such as radioactive iodine therapy and molecular targeted therapy, for recurrent lesions. For clinicians, it is important to accurately evaluate prognostic markers of PTC and FTC in the pre-, intraoperative, and postoperative phases.

Prognostic significance of T3b in papillary thyroid carcinoma: Appropriateness of classifying T3bN0M0 in patients aged 55 years or older into stage II.

BACKGROUND: Papillary thyroid carcinoma (PTC) often extends to adjacent organs. According to the 8th Tumor-Node-Metastasis Classification, extension to the strap muscles was graded as T3b. We investigated the prognostic impact of T3b and the appropriateness of T3b in patients aged ≥55 years who were classified as stage II. METHODS: We enrolled 7811 patients with M0 PTC who underwent initial surgery at the Kuma Hospital (Kobe, Japan) between January 2007 and December 2016. Tumor extension was divided into T3b, T4a1 (extension to the tracheal adventitia, tracheal cartilage, esophageal muscle layer, recurrent laryngeal nerve, cricothyroid, and inferior constrictor muscles), and sT4a2 (extension to the subcutaneous soft tissues, tracheal mucosa, esophageal mucosa, internal jugular vein, brachiocephalic vein, larynx, pharynx, and sternocleidomastoid muscle). RESULTS: In patients ≥55 years, the local recurrence-free survival (LR-FS), distant recurrence-free survival (DR-FS), and cause-specific survival (CSS) rates of T3bN0M0 were significantly poorer than those of T1/T2N0M0 but did not significantly differ from those of T3aN0M0. The LR-FS, DR-FS, and CSS rates of T3b stage II patients did not differ from those of T4a1 stage III patients but were significantly better than those of T4a2 stage III patients. T3b was an independent predictor of local recurrence and distant recurrence but not of death due to carcinoma in the multivariate analysis. In patients aged <55 years with M0 PTC, T3b had no prognostic value in both analyses. CONCLUSIONS: T3bM0 patients are appropriate to be classified as stage II in patients ≥55 years but be kept in stage I in patients <55 years.

Diagnostic significance of clay-like materials aspirated from thyroid nodules.

Objective: The simplest way to determine the adequacy of aspirated materials is the on-site gross visual assessment of aspirated materials. However, few studies have examined the gross findings of thyroid aspirates. This study aimed to clarify the diagnostic significance of clay-like material aspirated from thyroid nodules. Material and Methods: We reviewed 69,848 thyroid nodules that underwent aspiration cytology at Kuma Hospital between January 2007 and August 2021. Among them, 355 (0.5%) nodules with aspirated materials described as clay-like materials were retrospectively examined. Results: Among 355 nodules, 322 (90.7%) were categorized as cystic fluid or benign. The aspirated materials were mainly composed of non-epithelial components, including colloid or proteinaceous materials, foamy histiocytes, and degenerative red blood cells. In original ultrasound reports, the incidence of intermediate and high suspicion was 11.0%. Malignant cells were observed in 21 nodules (5.9%), one-third of which were papillary thyroid carcinomas. The materials aspirated from papillary and follicular thyroid carcinomas exhibited necrotic carcinoma cells derived from infarcted areas. The overall risk of malignancy was 3.9%. The risk of malignancy in nodules interpreted as highly suspicious on ultrasound examination was 37.5%. Conclusion: As clay-like materials aspirated from thyroid nodules were considered sufficient specimens, the recognition contributes to avoiding unnecessary second punctures. The presence of clay-like materials was indicative of the colloid and/or blood components of benign cystic lesions, or, more rarely, of infarcted carcinoma. The ultrasound examination results tended to overestimate nodules. We should reaffirm that on-site gross visual assessment of aspirated materials is a fast and reasonably accurate predictor of the on-site adequacy of the samples.

Clinicopathological characteristics of methotrexate-related lymphoproliferative disorder of the thyroid: A study of 11 patients.

Methotrexate (MTX) is a well-known agent that can potentially cause lymphoproliferative disorder (LPD), known as MTX-related LPD (MTX-LPD). Only two cases of thyroid MTX-LPD have been reported to date. This study aimed to report 11 cases of MTX-LPDs arising in the thyroid gland and discuss their clinicopathological characteristics. Of the 747 patients with cytologically suspected lymphoma, 11 had received MTX. The mean age of the patients with MTX-LPD was 70.2 years (range: 51-82 years), and all were female. The duration of MTX administration ranged from 5 to 31 years (mean: 19.5 years). Nine patients (81.8 %) tested positive for anti-thyroglobulin antibody and/or anti-thyroid peroxidase antibody. In three patients, the tumor decreased in size or disappeared without surgery or chemotherapy after withdrawal of MTX therapy. Histologically, all eight nodules examined were B-cell lymphomas, and seven were mucosa-associated lymphoid tissue (MALT) lymphomas. Epstein-Barr virus-encoded small RNA in situ hybridization showed negative results for all six nodules examined. All five patients who were followed-up at our hospital exhibited progression-free survival for >3 years without chemotherapy. Six patients were transferred to other hospitals, and their follow-up details are unknown. MTX-LPDs occurring in the thyroid are characterized by a high female predominance, positivity for anti-thyroid autoantibodies, high prevalence of MALT lymphomas, negativity for Epstein-Barr virus, and good outcomes without chemotherapy. We recommend that patients with thyroid lymphoma should be checked for a history of MTX.

Availability of Serum Levels of Carbohydrate Antigen 19-9 (CA19-9) as a Surrogate Tumor Marker for Papillary Thyroid Carcinoma.

Introduction: Thyroglobulin (Tg) is a very sensitive and specific marker in patients who have undergone total thyroidectomy for papillary thyroid carcinoma (PTC). However, the presence of a Tg antibody (TgAb) interferes with Tg immunometric assays, making Tg levels unreliable indicators. There are currently no other tumor markers to monitor in patients with PTC whose serum is TgAb-positive. Thus, we investigated whether carbohydrate antigen 19-9 (CA19-9) can be used as a tumor marker for PTC. Methods: We retrospectively analyzed 196 consecutive patients with PTC (maximum diameter ≥ 2 cm). The serum CA19-9 and Tg values of each patient were obtained before and 0.5-1 month postsurgery. Immunohistochemical staining for PTC was performed using an antibody against CA19-9. Results: High pre-surgery serum levels of CA19-9 were observed in 6.1% of the patients. Postsurgery, serum CA19-9 levels in all 196 patients decreased considerably and were within the normal range. CA19-9 expression was detected in 28 of 62 PTCs (45.2%) and was detected at various degrees and ranges in conventional PTC histology. Conclusions: Although further studies with longer follow-ups are necessary, serum CA19-9 levels may serve as a surrogate tumor marker for PTC in place of serum Tg levels sin some patients.

Calcium oxalate crystals as a cause of multiple punctate echogenic foci in benign thyroid lesions.

PURPOSE: Multiple punctate echogenic foci (MPEF) on thyroid ultrasonography reflects psammoma bodies in papillary thyroid carcinomas. However, MPEF is also observed in benign thyroid lesions. The aim of this study was to determine the origin of MPEF in patients with benign thyroid lesions. METHODS: We enrolled 26 patients with Graves' disease (GD) and 24 with follicular nodular disease (FND) who exhibited MPEF and underwent surgery. As controls, we enrolled 40 patients with GD and 32 with FND, but without MPEF, who underwent surgery. RESULTS: MPEF was observed in both lobes in 80.8% of GDs with MPEF, but was limited to a single lobe in the remaining cases. MPEF was diffusely distributed in 72.3% of the cases and focally distributed in the remaining cases. On ultrasonography, most (92.3%) FNDs with MPEF were solid lesions, and seven nodules (26.9%) were interpreted as intermediate suspicion and their frequencies were higher than in those without MPEF (p < 0.01). Microscopically, calcium oxalate (CaOx) crystals were observed more frequently in GDs and FNDs with MPEF (100% and 88.5%, respectively) than in those without MPEF (p < 0.001). These differences were particularly significant for CaOx crystals > 100 µm. In GD cases, large CaOx crystals were observed more frequently in the lobes with MPEF than in those without (p < 0.05). No psammoma bodies were present in any of the cases. CONCLUSION: Appearance of MPEF in GDs and FNDs is not because of psammoma bodies; it is attributable to CaOx crystals larger than 100 µm. Therefore, MPEF is not an indicator of malignancy.

Utility of solid area diameter in management of cystic papillary thyroid carcinoma.

Papillary thyroid carcinoma (PTC) with marked cystic formation (CPTC) is not a subtype of PTC, and its clinical characteristics have not been fully investigated. This study aimed to clarify the clinical and pathological characteristics of CPTC and propose important indicators for its clinical management. Thirty-three CPTC nodules with cystic areas occupying >50% of their volume were examined. Two matched controls (MCs) were prepared, one with tumor diameter matched for whole tumor diameter (WTD) of CPTCs and the other with tumor diameter matched for solid area diameter (SAD) of CPTCs. The mean age of patients with CPTC was 55.2 years significantly older than that in SAD-MCs. Of the CPTCs, 69.7% were classified as highly suspicious by ultrasonography, and the prevalence was lower than that in WTD-MCs (88.9%) and SAD-MCs (91.5%). Total thyroidectomy was performed in 69.7% of CPTC cases, which was significantly less frequent than that in WDT-MCs (91.7%) and similar to that in SAD-MCs (76.1%). Histologically, CPTCs exhibited two characteristic findings: invasion from the solid area into the surrounding normal thyroid tissue and granulation tissue around the cystic wall. The frequencies of the cases with pathological lateral node metastasis, extrathyroidal extension, and Ki-67 labeling index ≥5% in CPTCs were significantly lower than those in WTD-MCs and relatively similar to those in SAD-MCs. In the surgical strategy and prognosis of CPTC, the evaluation of tumor size should be based on SAD rather than on WTD. We advocate measuring not only WTD but also SAD in CPTC.

Ansa Cervicalis External Branch Anastomosis to Restore High Tone Voice in Thyroid Surgery.

OBJECTIVES: Injury to the external branch of the superior laryngeal nerve (EBSLN) causes low-pitch voice and voice fatigue, particularly in female subjects, and available treatments are limited. Here, we assess a novel surgical procedure to restore a high-tone voice: ansa cervicalis to EBSLN anastomosis (A-E anastomosis). METHODS: Between November 2012 and April 2022, 13 patients (12 female) underwent unilateral EBSLN resection and A-E anastomosis, while 20 (16 female) underwent EBSLN resection during thyroid surgery. Patients (4494 women and 1025 men) with normal laryngoscopy scheduled for thyroid surgery served as normal controls. Phonatory function was examined using a Phonation Analyzer PA-1000 preoperatively and intermittently postoperatively. RESULTS: In patients who underwent A-E anastomosis, high-tone voice pitch decreased significantly postoperatively (673.9-471.5 Hz, p = 0.047), with restoration achieved within 5 months. The mean voice pitch in female patients who underwent A-E anastomosis, EBSLN resection, and controls were 580.4, 522.8, and 682.0 Hz, respectively, indicating a significant decrease in EBSLN resection patients than controls (p = 0.002). The (mean - 1SD) of high-tone voice pitch in female controls was 497 Hz; exceeding this may indicate recovery to a high-tone voice. Overall, 73% (8/11) of A-E anastomosis patients exceeded this value, which was marginally larger than the 43% (6/14) who underwent EBSLN resection. Data on male subjects are limited. There were no cases of adverse functional or cosmetic events. CONCLUSIONS: A-E anastomosis, a novel simple procedure, restored high-tone voice to some extent without any adverse events and thus warrants further investigation. LEVEL OF EVIDENCE: 3 Laryngoscope, 134:3868-3873, 2024.

Impact of the quality of resected thyroid cancer tissue sample on next-generation sequencing testing.

Activating rearranged during transfection (RET) proto-oncogene alterations can be identified using next-generation sequencing (NGS) of tumor DNA/RNA. We assessed factors associated with NGS (Oncomine Dx Target Test [ODxTT]) success for resected thyroid cancer (TC) specimens, including sample age, processing conditions, and DNA/RNA quality. TC samples were from three Japanese hospitals, with sample age <1-<10 years, fixative 10%/15% neutralized buffered formalin (NBF), and fixation time ≤48 h/>48 h-≤72 h. NGS success rate was defined as the percentage of samples returning validated NGS results (RET fusion-positive/negative [RNA] or RET mutation-positive/negative [DNA], detected using ODxTT). DNA/RNA quality was assessed with indexes based on electrophoresis (DNA/RNA integrity number, DV200 ) and quantitative polymerase chain reaction (DNA/RNA integrity score [ddCq/ΔCq]). NGS success rate (N = 202) was 90%/93% (DNA/RNA) overall, 98%-100% (DNA and RNA) for samples <3 years old, and 91% (DNA and RNA) for samples ≥3-<5 years old fixed in 10% NBF for ≤48 h. Multivariate logistic regression analysis identified ddCq and ΔCq as significant predictors of DNA and RNA NGS success rates, respectively. Quality assessment of nucleic acid extracted from archival tissue samples is important for achieving high NGS success rates in clinical practice, especially for samples ≥3 years old.

Comparison of pathophysiology in subclinical hyperthyroidism with different etiologies.

Subclinical hyperthyroidism (SHyper) is defined as normal levels of free thyroxine (fT4) and free triiodothyronine (fT3) with suppressed levels of TSH. Previous studies have reported the individual pathophysiology of endogenous SHyper patients and athyreotic patients receiving TSH suppression therapy with levothyroxine; however, apparently no studies have compared the two conditions. Five-hundred-forty untreated endogenous SHyper patients and 1,024 patients receiving TSH suppression therapy who underwent total thyroidectomy for papillary thyroid carcinoma were sampled. Thyroid hormone profiles and peripheral indices related to thyrotoxicosis were investigated in endogenous SHyper patients, athyreotic patients receiving TSH suppression therapy, and healthy participants. Endogenous SHyper patients showed significantly higher thyroid hormone levels (fT4 [p < 0.001] and fT3 [p < 0.001]), and peripheral indices showed a significant tendency towards thyrotoxicosis (strong TSH suppression: alkaline phosphatase [ALP, p < 0.001], creatinine [Cre, p < 0.001], pulse rate [p < 0.05]; and mild TSH suppression: Cre [p < 0.05]) than healthy participants. In contrast, athyreotic patients receiving TSH suppression therapy showed a significant tendency towards thyrotoxicosis than healthy participants only when TSH was strongly suppressed (fT3 [p < 0.001] and Cre [p < 0.001]). Endogenous SHyper patients showed significantly higher fT3 levels (p < 0.001) than athyreotic patients receiving TSH suppression therapy; however, there was a significant tendency towards thyrotoxicosis only when TSH was strongly suppressed (ALP [p < 0.05] and pulse rate [p < 0.05]). The effects of endogenous SHyper and TSH suppression therapy on target organ function are different. Although the serum thyroid hormone profile is similar to that of the thyrotoxic state, athyreotic patients receiving TSH suppression therapy with mildly suppressed serum TSH levels are not thyrotoxic.

Active surveillance for adult low-risk papillary thyroid microcarcinoma-a review focused on the 30-year experience of Kuma Hospital.

Active surveillance (AS) for low-risk papillary thyroid microcarcinoma (PTMC), which was initiated at Kuma Hospital (Kobe, Japan) in 1993 and Cancer Institute Hospital (Tokyo) in 1995, is now gradually being adopted worldwide, and several prospective studies have described the favorable outcomes of PTMC patients who underwent AS. The most important factor predicting PTMC growth is young age, and PTMC enlargement in young patients may be affected by high serum levels of thyroid-stimulating hormone. This review notes that one patient showed lung metastasis after conversion surgery (CS) following AS, but there are no reports of patients dying of thyroid carcinoma during or after AS. Some PTMCs enlarge or show newly appeared metastatic nodes requiring CS, and findings on the postoperative prognosis and incidence of significant surgical complications (e.g., permanent vocal cord paralysis, hypoparathyroidism) do not differ significantly between patients who underwent CS after AS and those who underwent immediate surgery (IS). IS has been associated with significantly higher incidences of these complications compared to AS as the initial management. Several studies have examined the quality of life (QoL) of patients who underwent AS versus IS, and reported discrepant findings regarding various psychological conditions (including anxiety). Medical costs for AS and IS vary regionally, and in Japan, the 10-year total cost of IS was 4.1 times greater than that of AS in 2017. Taken together, the existing findings demonstrate that AS can be appropriate for the initial management of patients with PTMC.

Prevalence and diagnostic significance of non-invasive follicular thyroid neoplasm with papillary-like nuclear features in Japan-A multi-institutional study.

This multi-institutional study investigated non-invasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) frequency and its diagnostic significance in Japan. We reviewed 4008 thyroid nodules resected in six institutions before NIFTP was proposed. Overall, 26 cases diagnosed as non-invasive encapsulated follicular variant of papillary thyroid carcinoma (PTC) and 145 cases of follicular thyroid adenoma (FTA) were included. Of these nodules, 80.8% and 31.0%, respectively, were NIFTPs. In five institutions, NIFTPs were more commonly found in FTA than in PTC nodules. When NIFTP was included with PTC, the overall prevalence was 2.3%, with rates in five institutions below 5.0% (0.8%-4.4%). One NIFTP case with nuclear score 3 revealed nodal metastasis 2.5 years post-resection, and the carcinoma cells were immunohistochemically positive for BRAF. FTAs or NIFTPs with nuclear score 2 did not metastasize. NIFTP was more common among FTA than among PTC nodules, possibly due to underdiagnosis of PTC on nuclear findings. Considering the clinical findings, molecular pathogenesis, and therapeutic strategy in Japan, NIFTP with nuclear score 2 is not different from FTA, and use of this entity terminology is not meaningful. In contrast, NIFTP with nuclear score 3 has potential for metastasis and BRAFV600E mutation. Therefore, in NIFTP cases, nuclear scores 2 and 3 should be separately reported.

Interference against a newly labeled substance with ruthenium sulfonate complexes showing discrepant thyroid function test results.

We report here two patients exhibiting a combination of falsely elevated serum levels of free thyroxine (FT4), free triiodothyronine (FT3), and thyrotropin receptor antibodies (TRAb), measured using Elecsys assay kits (Roche Diagnostics GmbH). The first patient was a 74-year-old man misdiagnosed with Graves' disease and treated with methimazole. The second patient was a 48-year-old woman whose serum FT4 and FT3 concentrations were found to be high during a blood test. These patients denied taking biotin or any other supplements. Further detailed examination, including a heterophilic blocking tube test, revealed the presence of serum antibodies. The abnormal reactions were observed only using the improved assay kits using ruthenium (Ru) sulfonate instead of Ru as a chemiluminescent agent. Therefore, serum antibodies to the Ru sulfonate complex caused the pseudo-high levels of FT4, FT3, and TRAb. To our knowledge, this is the first report showing that antibodies to the Ru sulfonate complex in the electrochemiluminescence immunoassay can cause falsely elevated levels of the combination, leading to discrepant thyroid function test results. We emphasize that in cases of abnormal test results, alternative assay methods should be considered for further examination; unusual test results should not be impulsively interpreted, even when using revised assay kits.

The Minimal Important Difference of Acoustic Voice Quality Index in the Treatment of Voice Disorders.

OBJECTIVES: The acoustic voice quality index (AVQI) is a reliable tool that objectively assesses dysphonia levels using six acoustic parameters. Despite its high criterion-related concurrent validity, diagnostic accuracy, and minimal detectable change derived from test-retest reliability, the minimal important difference (MID) of the AVQI has not been tested before. This study aimed to estimate the MIDs of AVQI for improvement audibly perceived by clinicians and self-reported improvement by patients. METHODS: A retrospective study was conducted on 110 patients who received treatment for voice disorders. Patients completed AVQI and Voice Handicap Index-10 (VHI-10) questionnaires before and after the therapy. The MIDs of the AVQI were estimated using the anchor of either auditory-perceptual judgment of total dysphonia levels by clinicians or the VHI-10 questionnaire by patients. A distribution-based approach was also used to complement the results. RESULTS: First, using the auditory-perceptual anchor, a decrease of 0.95 in the AVQI was estimated as the MID for clinicians' perception, as a result of the receiver operating curve. Then, using the patient-reported anchor, an improvement of 1.36 in the AVQI was estimated as the MID for patients' voice-related disability. The distribution-based approach also ensured the anchor-based results of both the MIDs. CONCLUSIONS: The AVQI is a reliable and valid tool for evaluating voice quality, and a 0.95 decrease in the AVQI represents a meaningful improvement for clinicians' perception, whereas a 1.36 decrease in the AVQI influences patients' self-reported disability. This study contributes to understanding the minimal change necessary for clinicians to make informed decisions and ensure patient satisfaction. LEVEL OF EVIDENCE: 3 Laryngoscope, 134:2805-2811, 2024.

Tumor volume-doubling rate is negatively associated with patient age in papillary thyroid microcarcinomas under active surveillance.

BACKGROUND: Active surveillance of low-risk papillary thyroid microcarcinomas has gained popularity worldwide as a management strategy. We previously reported that young age was associated with tumor enlargement by ≥3 mm. Here, we used the tumor volume-doubling rate to study the age-related tumor volume dynamics of papillary thyroid microcarcinomas under active surveillance. METHODS: Between 2005 and 2019, 2,896 patients diagnosed with low-risk papillary thyroid microcarcinomas underwent active surveillance. We excluded patients who underwent ultrasound examination fewer than 4 times, had coexisting Graves' disease, or were treated with levothyroxine at the time of diagnosis, and we enrolled 2,129 patients for this study. We divided them into 3 subsets based on the age at diagnosis: young (<40 years), middle-aged (40-59 years), and elderly (≥60 years). The tumor volume-doubling rate was calculated based on ultrasound-derived tumor sizes and the respective examination date for each patient. RESULTS: Overall, 140 patients (6.6%) had moderate or rapid growth (tumor volume-doubling rate ≥0.3/year), and the incidence significantly decreased with advanced age (P < .01): 11.3%, 7.1%, and 5.0% in the young, middle-aged, and elderly groups, respectively. Tumor regression (tumor volume-doubling rate <0/year) was detected in 1,200 patients (56.4%), and the incidence significantly increased with age (P < .01): 44.6%, 55.3%, and 60.0% in the young, middle-aged, and elderly groups, respectively. On multivariate analysis, both the ≥60 years and 40 to 59 years age groups were independent negative predictors of papillary thyroid microcarcinoma enlargement and positive predictors of tumor regression. CONCLUSION: Tumor volume-doubling rate analysis demonstrated that the incidence of tumor enlargement decreased and that of tumor regression increased with advancing age in patients with papillary thyroid microcarcinomas.

Validation of Subharmonics Quantification Using Two-Stage Cepstral Analysis.

OBJECTIVES: Hoarseness is primarily perceived as breathiness or roughness. Despite the various tools that quantitatively assess hoarseness, roughness has been difficult to quantify because of its complex acoustic structure, such as subharmonics. The parameter obtained from the two-stage cepstral analysis is promising for evaluating roughness. Thus, this study aimed to improve the accuracy of the parameter using a customized pitch setting and investigate the relationship between roughness and subharmonics. STUDY DESIGN: The design is a retrospective study. METHODS: Two-stage cepstral analysis was used to analyze the voice recordings of 455 participants, speech impaired and normal controls, using the Analysis of Dysphonia in Speech and Voice and Praat software. For validation, the ground truth of subharmonics was visually quantified using a narrowband spectrogram. The reliability and validity of the two-stage cepstral analysis and subharmonics measures on spectrograms were evaluated. RESULTS: The two-stage cepstral analysis showed a very strong correlation (r = 0.963) between the two software programs. Intra- and inter-rater reliability of the subharmonics measures on spectrograms were also good. Two-stage cepstral analysis showed that even with customized pitch settings, the diagnostic systems and correlations for perceptual roughness and subharmonics were weak to moderate. The subharmonics measures on spectrograms showed a strong correlation with roughness and moderate diagnostic accuracy of subharmonics. CONCLUSIONS: The two-stage cepstral analysis showed some improvement in diagnostic accuracy and correlation with customized pitch settings, but it did not sufficiently detect subharmonics or roughness. The analysis using subharmonics measures on spectrograms proved the high correlation between subharmonics and roughness, indicating that developing acoustic analysis parameters that sufficiently detect subharmonics is necessary.