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Purpose: To evaluate the potential benefit of adding a low frequency vascular probe to the conventional pre-operative ultrasound examination of patients with primary hyperparathyroidism., Methods: A prospective cohort of 136 patients with primary hyperparathyroidism underwent a conventional ultrasound examination of the neck with a high frequency ( > 10 MHz) linear ultrasound probe, followed by an add-on examination with a low frequency vascular probe. For each ultrasound probe, and for every potential parathyroid lesion, the presence of a feeding vessel, a polar placement of the feeding vessel, and the presence of a vascular arch was recorded., Results: A total of 146 ultrasound lesions were evaluated for vascularity by each probe. For both ultrasound probes, the odds of a hyperfunctioning parathyroid gland being correctly identified increased with the number of visible vascular features. The vascular probe identified a significantly higher number of vascular features among ultrasound true positive glands compared with the conventional probe (p < 0.0001). Among histopathologically verified pathological parathyroid glands, the vascular probe identified 20% more feeding vessels, 27% more polar placements of the feeding vessel, and 65% more vascular arches than the high frequency probe. However, the diagnostic confidence score for true positive glands did not differ significantly between the probes (p = 0.11)., Conclusion: The addition of a low frequency vascular probe increases the number of visible vascular features in hyperfunctioning parathyroid glands, which facilitates their preoperative detection. Whether or not this can increase the diagnostic confidence of ultrasound examiners has yet to be substantiated., Competing Interests: Compliance with ethical standards Conflict of interest The authors declare no competing interests. Ethics approval The study was carried out in accordance with the ethical principles of the 1964 Declaration of Helsinki and its later amendments. The study is registered at ClinicalTrials.gov (NCT04305561) and has been approved by the Regional Committees on Health Research Ethics for Southern Denmark (project ID S-20190077). Consent to participate Written informed consent was obtained from all participants in this study., (© 2024. The Author(s).)

Importance: Scintigraphy and ultrasonography are common imaging modalities for the preoperative localization of enlarged parathyroid glands in primary hyperparathyroidism. When comparing the 2 modalities, the benefits of ultrasonography in terms of convenience, patient comfort, duration, cost, and lack of radiation should be taken into account., Objective: To investigate whether surgeon-performed ultrasonography, with or without contrast-enhanced ultrasonography (CEUS), is noninferior to scintigraphy for localizing pathological parathyroid glands in patients with primary hyperparathyroidism., Design, Setting, and Participants: Prospective, paired, noninferiority cohort study performed at a high-volume tertiary referral center for parathyroidectomy with blinded examiners and a 6-month follow-up. Participants were adults (age ≥18 years) referred for parathyroidectomy due to primary hyperparathyroidism. Of 207 eligible patients, 35 were excluded, leaving 172 enrolled in the study. Inclusion lasted from September 2019 until February 2021. Follow-up ended in December 2021., Exposures: 99mTechnetium-pertechnetate/99mtechnetium-sestamibi subtraction scintigraphy with 99mtechnetium-sestamibi single-photon emission computed tomography/computed tomography, followed by surgeon-performed ultrasonography and CEUS., Main Outcomes and Measures: The sensitivity of each imaging modality in localizing pathological parathyroid glands, calculated on a per-quadrant and a per-patient basis, respectively. The a priori noninferiority margin was a lower 95% confidence limit for the difference in sensitivity not falling below -10%., Results: Out of 172 participants, 139 (80.8%) were women, the median (range) age was 65 (24-87) years, and the median (IQR) follow-up was 200.5 (181-280.25) days. Quadrant sensitivity (95% CI) was 70.9% (63.2%-78.5%) for ultrasonography, 68.4% (60.4%-76.5%) for ultrasonography plus CEUS, and 67.0% (60.0%-74.0%) for scintigraphy. The sensitivity difference (95% CI) compared with scintigraphy was 3.9% (-4.1% to 11.8%) for ultrasonography and 1.5% (-6.4% to 9.3%) for ultrasonography plus CEUS, establishing noninferiority for both modalities. Per-patient sensitivity was 81.4% (74.8%-86.9%) for ultrasonography and 79.1% (72.2%-84.9%) for both scintigraphy and ultrasonography plus CEUS. The sensitivity difference compared with scintigraphy was 2.3% (-6.8% to 11.4%) for ultrasonography and 0.0% (-9.1% to 9.1%) for ultrasonography plus CEUS, establishing noninferiority for both modalities., Conclusions and Relevance: In this cohort study, conventional ultrasonography by an experienced parathyroid surgeon-sonographer was noninferior to scintigraphy and may constitute a valid first-line imaging modality in patients with primary hyperparathyroidism, even without the addition of CEUS. Further imaging should be reserved for cases that are equivocal or nonlocalizing on ultrasonography.

The BRAF V600E (BRAF) mutation is present in 40-50% of papillary thyroid carcinomas (PTC) and has been associated with more aggressive clinicopathological characteristics of PTC. The aim of this study was to evaluate different methods for preoperative identification of the BRAF mutation in PTC using cytological and histological specimens. Prospectively collected preoperative cytological clots from patients with suspected PTC were tested with BRAF immunocytochemistry (ICC) and the Cobas Test (PCR). In addition, histological specimens were tested with BRAF immunohistochemistry (IHC) and the Cobas Test. All nodules were histologically examined. Fifty-three patients were included in the study. Complete mutation testing was available in 32 patients. The main reason for exclusion was insufficient cell content in the cytological specimen. Twenty-seven nodules were histologically diagnosed as PTC, and 41% (n = 11) of PTCs were BRAF ICC positive. All non-PTC nodules were negative by BRAF ICC. In 26 nodules, all four BRAF tests were concordant, while discordant test results were found in six nodules. ICC was in accordance with the consensus BRAF status in five of these nodules, while BRAF status was undetermined in one nodule. BRAF ICC showed high concordance with the Cobas Test and a low rate of false negative stain. These results indicate that BRAF ICC may be a feasible method for preoperative detection of the BRAF V600E mutation in patients with PTC., (© 2022 The Authors. APMIS published by John Wiley & Sons Ltd on behalf of Scandinavian Societies for Pathology, Medical Microbiology and Immunology.)

Background: Artificial intelligence algorithms could be used to risk-stratify thyroid nodules and may reduce the subjectivity of ultrasonography. One such algorithm is AIBx which has shown good performance. However, external validation is crucial prior to clinical implementation., Materials and Methods: Patients harboring thyroid nodules 1-4 cm in size, undergoing thyroid surgery from 2014 to 2016 in a single institution, were included. A histological diagnosis was obtained in all cases. Medullary thyroid cancer, metastasis from other cancers, thyroid lymphomas, and purely cystic nodules were excluded. Retrospectively, transverse ultrasound images of the nodules were analyzed by AIBx, and the results were compared with histopathology and Thyroid Imaging Reporting and Data System (TIRADS), calculated by experienced physicians., Results: Out of 329 patients, 257 nodules from 209 individuals met the eligibility criteria. Fifty-one nodules (20%) were malignant. AIBx had a negative predictive value (NPV) of 89.2%. Sensitivity, specificity, and positive predictive values (PPV) were 78.4, 44.2, and 25.8%, respectively. Considering both TIRADS 4 and TIRADS 5 nodules as malignant lesions resulted in an NPV of 93.0%, while PPV and specificity were only 22.4 and 19.4%, respectively. By combining AIBx with TIRADS, no malignant nodules were overlooked., Conclusion: When applied to ultrasound images obtained in a different setting than used for training, AIBx had comparable NPVs to TIRADS. AIBx performed even better when combined with TIRADS, thus reducing false negative assessments. These data support the concept of AIBx for thyroid nodules, and this tool may help less experienced operators by reducing the subjectivity inherent to thyroid ultrasound interpretation.

Purpose: The risk of malignancy (ROM) in FDG-avid thyroid incidentalomas varies between studies, which may be contributed by discordance between the anatomical localization depicted on 18 FDG-PET/CT and by histopathological examination. The purpose was to ensure anatomical congruity between the index tumour identified by 18 FDG-PET/CT and the histopathological examination, in order to assess the risk of malignancy (ROM) in PET-positive and PET-negative thyroid nodules. Further, preoperative characteristics indicative of thyroid malignancy were identified., Methods: Thirty-two patients referred to thyroid surgery were prospectively included. 18 FDG-PET/CT, fine-needle aspiration biopsy and thyroid ultrasonography examination were performed in all participants. The exact anatomical localization of the index nodule was established by histopathological examination to ensure concordance with the 18 FDG-PET/CT finding., Results: Forty thyroid nodules were included. Malignancy was identified in 10 of 28 PET-positive nodules and in 1 of 12 PET-negative nodules, resulting in a ROM of 36% and 8%, respectively. A Hurtle cell neoplasm was found in 50% of patients with a benign nodule and a PET-positive scan. One PET-negative nodule represented a papillary microcarcinoma. In PET-positive nodules, hypoechogenicity, irregular margins, and pathological lymph nodes on thyroid ultrasonography were characteristics associated with malignancy., Conclusions: In this study-ensuring anatomical congruity between PET-findings and the histopathological examination-the risk of malignancy in PET-positive thyroid nodules was 36%. A low ROM was seen in thyroid nodules without suspicious ultrasonographic findings, independent of the 18 FDG-PET/CT result., Trial Registration Number: NCT02150772 registered 14th of April 2014., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Purpose: Shear wave elastography (SWE), as a tool for diagnosing thyroid malignancy, has gathered considerable attention during the past decade. Diverging results exist regarding the diagnostic performance of thyroid SWE., Methods: A comprehensive literature review of thyroid SWE was conducted using the terms "Thyroid" and "shear wave elastography" in PubMed., Results: The majority of studies found SWE promising for differentiating malignant and benign thyroid nodules on a group level, whereas results are less convincing on the individual level due to huge overlap in elasticity indices. Further, there is lack of consensus on the optimum outcome reflecting nodule elasticity and the cut-off point predicting thyroid malignancy. While heterogeneity between studies hinders a clinically meaningful meta-analysis, the results are discussed in a clinical perspective with regard to applicability in clinical practice as well as methodological advantages and pitfalls of this technology., Conclusion: Technological as well as biological hindrances seem to exist for SWE to be clinically reliable in assessing benign and malignant thyroid nodules. Structural heterogeneity of thyroid nodules in combination with operator-dependent factors such as pre-compression and selection of scanning plane are likely explanations for these findings. Standardization and consensus on the SWE acquisition process applied in future studies are needed for SWE to be considered a clinically reliable diagnostic tool for detection of thyroid cancer., (© 2021. Italian Society of Endocrinology (SIE).)

Background: Oropharyngeal squamous cell carcinomas (OPSCC) are rising rapidly in incidence due to Human Papillomavirus (HPV) and/or tobacco smoking. Prognosis is better for patients with HPV-positive disease, but may also be influenced by tobacco smoking and other factors. There is a need to individualize treatment to minimize morbidity and improve prognosis. Patient-derived xenografts (PDX) is an emerging pre-clinical research model that may more accurately reflect the human disease, and is an attractive platform to study disease biology and develop treatments and biomarkers. In this study we describe the establishment of PDX models, compare PDX tumors to the human original, and assess the suitability of this model for radiotherapy research and biomarker development. Material and methods: Tumor biopsies from 34 patients with previously untreated OPSCC were implanted in immunodeficient mice, giving rise to 12 squamous cell carcinoma PDX models (7 HPV+, 5 HPV-). Primary and PDX tumors were characterized extensively, examining histology, immunohistochemistry, cancer gene sequencing and gene expression analysis. Radiosensitivity was assessed in vivo in a growth delay assay. Results: Established PDX models maintained histological and immunohistochemical characteristics as well as HPV-status of the primary tumor. Important cancer driver gene mutations, e.g., in TP53 , PIK3CA and others, were preserved. Gene expression related to cancer stem cell markers and gene expression subtype were preserved, while gene expression related to hypoxia and immune response differed. Radiosensitivity studies showed high concordance with clinical observations. Conclusion: PDX from OPSCC preserves important molecular characteristics of the human primary tumor. Radiosensitivity were in accordance with clinically observed treatment response. The PDX model is a clinically relevant surrogate model of head and neck cancer. Perspectives include increased understanding of disease biology, which could lead to development of novel treatments and biomarkers.

Thyroid nodular disease is common, but predicting the risk of malignancy can be difficult. In this prospective study, we aimed to assess the diagnostic accuracy of shear wave elastography (SWE) in predicting thyroid malignancy. Patients with thyroid nodules were enrolled from a surgical tertiary unit. Elasticity index (EI) measured by SWE was registered for seven EI outcomes assessing nodular stiffness and heterogeneity. The diagnosis was determined histologically. In total, 329 patients (mean age: 55 ± 13 years) with 413 thyroid nodules (mean size: 32 ± 13 mm, 88 malignant) were enrolled. Values of SWE region of interest (ROI) for malignant and benign nodules were highly overlapping (ranges for SWE-ROImean: malignant 3-100 kPa; benign 4-182 kPa), and no difference between malignant and benign nodules was found for any other EI outcome investigated (P = 0.13-0.96). There was no association between EI and the histological diagnosis by receiver operating characteristics analysis (area under the curve: 0.51-0.56). Consequently, defining a cut-off point of EI for the prediction of malignancy was not clinically meaningful. Testing our data on previously proposed cut-off points revealed a low accuracy of SWE (56-80%). By regression analysis, factors affecting EI included nodule size >30 mm, heterogeneous echogenicity, micro- or macrocalcifications and solitary nodule. In conclusion, EI, measured by SWE, showed huge overlap between malignant and benign nodules, and low diagnostic accuracy in the prediction of thyroid malignancy. Our study supports that firmness of thyroid nodules, as assessed by SWE, should not be a key feature in the evaluation of such lesions.

Objectives: Childhood cancer is rare and often difficult to diagnose. In the head and neck region, benign diseases are much more common. The aim of this study was to estimate the proportion of childhood cancer cases with a primary head and neck presentation, to describe symptoms, physical findings, diagnostic interval and tentative diagnoses., Methods: Registry-based retrospective cohort study, with patients identified in the Danish Childhood Cancer Registry. Review of medical records, imaging reports and pathology reports. All childhood cancer patients less than 15 years of age with primary disease presentation in the head and neck region from the Central Danish Region in the years 2003-2013. Outcome measures were proportion of patients with a primary head and neck presentation; frequency of physical findings; diagnostic intervals; and frequency of tentative diagnoses., Results: 85 patients (15% of all childhood cancers) had primary disease presentation in the head & neck region (95% confidence interval [CI]: 12 - 18%). A total of 24% (CI: 21 - 28%) of patients had any symptoms or findings from the head and neck region at presentation. Most common symptoms and findings were a swelling or a tumor, and possibly general symptoms. Diagnostic interval was more than three weeks in three out of four of patients. Primary suspicion was most commonly an infectious disease., Conclusions: A substantial proportion of patients with childhood cancer have disease presentation in the head and neck. Worth noting is, that symptoms and findings are easily mistaken for an infectious disease, which probably explains the significant diagnostic interval., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Purpose: To investigate the association between the pre-operative serum TSH (s-TSH) level and differentiated thyroid carcinoma (DTC) in a mildly iodine-deficient area., Methods: Patients undergoing surgery for thyroid nodular disease (TND) were included from three tertiary surgical departments. Data were collected from a national thyroid surgery database (THYKIR) and from patient charts. Individuals with overtly coexisting thyroid disorders were excluded for subgroup analyses. Patients were compared with the Danish background population, employing previous data from DanThyr, a study initiated to monitor the iodine fortification program in Denmark., Results: Nine-hundred ninety-eight patients [cases/controls: 265/733; female/male: 794/204; age (mean ± SD): 51 ± 15 years] were included. S-TSH was significantly higher in the DTC group [median (IQR): 1.3 (0.9-1.9 mIU/L)] compared with the benign TND group [0.9 (0.6-1.5 mIU/L)] (p < 0.0001). The median s-TSH in the background population was similar to that found among DTC patients (p = 1.00), but markedly higher than the s-TSH level in the benign TND group (p < 0.0001). There was no association between s-TSH and DTC disease stage (p = 0.08-0.87)., Conclusions: s-TSH was significantly higher in patients with DTC than in those with benign TND. However, this difference can be explained by abnormally lower s-TSH level in the latter group, probably caused by subtle nodular functional autonomy. Due to the huge overlap and the small difference in median s-TSH between patients with benign and malignant TND, s-TSH is not suitable as a biomarker of DTC in a clinical setting.

Objective: To systematically assess the reproducibility of thyroid ultrasonographic shear wave elastography (SWE)., Context: SWE has been suggested as a potential tool for thyroid nodule evaluation, but assessment of its reproducibility has been insufficiently addressed., Design: SWE examinations were performed prospectively by two investigators., Patients: Seventy-two patients (male/female: 19/53; mean age: 53 ± 14 years; malignant/benign 17/55) undergoing thyroid surgery were enrolled in the study., Measurements: Repeated and blinded measurements of elasticity index (EI) in predefined regions of interest (ROI) were collected. The inter- and intrarater agreement, along with the day-to-day agreement, was evaluated in terms of the 95% limits of agreement (LOA). Results are presented as a ratio, by which 1·0 indicates perfect agreement., Results: The interrater, intrarater and day-to-day LOA showed ratios between repeated measurements of 1·7-3·6, 1·8-3·7 and 2·2-2·9, respectively. These values reflect a low to moderate degree of agreement for all EI outcomes. The interrater LOA was higher for malignant nodules compared with benign nodules for six of seven EI outcomes (P < 0·001-0·03). The proportion of agreement calculated from the optimum cutoff point for differentiating malignant from benign nodules was 63-88% for the investigated EI outcomes., Conclusions: In this methodological study, EI measured by thyroid SWE seems suboptimal for clinical use, due to a low inter- and intrarater agreement. That EI varies from day to day furthermore jeopardizes the validity of the method. Although the proportion of agreement was acceptable for some EI parameters, it is questionable whether EI assessments can reliably differentiate malignant from benign nodules in the individual patient., (© 2016 John Wiley & Sons Ltd.)

Introduction: Development of hypocalcaemia is a serious complication to total thyroidectomy (TT). The measurement of intact plasma parathyroid hormone (iPTH) has been internationally described as a good predictor of hypocalcaemia. Despite this, consensus in the field has yet to be reached among clinicians. We aimed to evaluate if measurement of iPTH 24 hours post-operatively (24-iPTH) can identify patients who do not subsequently develop clinically significant hypocalcaemia (CSH), thereby allowing for early discharge after TT., Methods: This was a historic cohort study of all patients who had a TT in the period from January 2013 to March 2014 at the Department of Oto-rhino-laryngology, Aarhus University Hospital, Denmark. Only patients with 24-iPTH measurements were included. Post-operative treatment with calcium or activated vitamin D analogue was defined as CSH. Data were collected from medical records., Results: A total of 69 patients were included, 80% were women, the median age was 47 and 83% had a malignant disease. A total of 35% developed CSH and the median hospitalisation period was four days. The sensitivity, specificity and positive predictive value of 24-iPTH ≥ 2.8 pmol/l to exclude CSH were 76%, 92% and 94%, respectively. In addition, we found that a body mass index > 25 kg/m(2) significantly increased the risk of developing CSH., Conclusions: The measurement of 24-iPTH ≥ 2.8 pmol/l can be used to predict patients who will not develop CSH after TT and allow for early discharge of more than 50% of the patients., Funding: none., Trial Registration: not relevant.

Background: Residual neck disease after radiotherapy in advanced oropharyngeal squamous cell carcinoma (OPSCC) is associated with increased mortality, and some patients may benefit from post-radiotherapy neck dissection (PRND). The aim of the present study was to assess the value of magnetic resonance imaging (MRI) and other clinical characteristics in selecting patients for PRND., Materials and Methods: Retrospective cohort study. Consecutive patients with N+ OPSCC were included. Medical records, pathology reports and imaging reports were reviewed. Pre- and post-therapeutic imaging was re-evaluated., Results: A total of 100 consecutive patients from a three-year period were included. Neck response was evaluated with MRI two months after treatment. Sixty patients were suspicious for residual neck disease, and were offered surgery; seven of these patients had histologic evidence of carcinoma. Cumulative neck failure after three years was 14% (8.4-24%), and did not differ significantly among patients with positive compared to negative MRI (radiologist's initial description; p = 0.47, log-rank test). Applying neck failure as gold standard, sensitivity and specificity of MRI was 69% and 41%, respectively; positive and negative predictive value was 15% and 90%. Patients with p16 + disease had significantly larger lymph nodes after treatment, and imaging based on lymph node size resulted in many false positives. Analysis of receiver operating characteristic curves in 191 individual lymph nodes showed that a short axis ≥ 10 mm should be classified as suspicious. Furthermore, T-stage and p16-status were associated with increased risk of neck recurrence. Salvage was successful in four patients with early detected nodal recurrence., Conclusion: These results suggest that lymph node size, T-stage and p16 status could be used in selecting patients for PRND in OPSCC. Yet, early anatomical imaging may be inappropriate for evaluating neck response in patients with p16 + disease as enlarged lymph nodes often do not indicate residual neck disease.

Introduction: (99m)Tc-pertechnetate scintigraphy is much used in the evaluation of patients with nodular goitre. We investigated the ability of experienced observers to estimate the thyroid 24-h (131)I uptake (RAIU) and the thyroid volume by visual evaluation of the scintigram., Material and Methods: Two endocrinologists and two nuclear medicine specialists visually evaluated thyroid scintigrams from 171 patients with nodular goitre. The variables were assessed in a blinded fashion according to predefined categories and then compared with the true values. The assessments were repeated after four weeks. Kappa (κ ω) statistics were used., Results: There was a low probability (range 6-22%) for the observers to assess the thyroid RAIU correctly. The probability of assessing the thyroid volume correctly was in the 14-22% range. Endocrinologists tended to underestimate the thyroid RAIU, mostly in patients with a RAIU > 30%. All observers significantly underestimated the thyroid volume if this was > 80 ml. There was a low interobserver agreement for the thyroid RAIU assessment (κ ω-values: 0.03-0.43) as well as for the thyroid volume assessment (κ ω-values: 0.19-0.48). The corresponding κ ω-values for the intraobserver agreement were 0.34-0.68 and 0.37-0.62, respectively. Nuclear medicine specialists achieved a significantly higher agreement than endocrinologists in their evaluation of both thyroid parameters., Conclusion: Thyroid (99m)Tc scintigraphy has poor interobserver agreement and is inaccurate for assessment of quantitative thyroid parameters, even when performed by experienced specialists., Funding: This study was supported by grants from the Danish Agency for Science, Technology and Innovation., Trial Registration: not relevant.

Objective: The objective of the study was to evaluate the long-term outcome of recombinant human TSH (rhTSH)-augmented radioiodine ((131)I) therapy for benign multinodular nontoxic goiter., Patients and Methods: Between 2002 and 2005, 86 patients with a multinodular nontoxic goiter were treated with (131)I in two randomized, double-blind, placebo-controlled trials. (131)I-therapy was preceded by 0.3 mg rhTSH (n = 42) or placebo (n = 44). In 2009, 80 patients completed a follow-up (FU) visit, including determination of thyroid volume, thyroid function, and patient satisfaction by a visual analog scale., Results: In both groups, thyroid volume was further reduced from 1 yr to final FU (71 months). The mean goiter volume reductions obtained at 1 yr and final FU [59.2 ± 2.4% (sem) and 69.7 ± 3.1%, respectively] in the rhTSH group were significantly greater than those obtained in the (131)I-alone group (43.2 ± 3.7 and 56.2 ± 3.6%, respectively, P = 0.001 and P = 0.006), corresponding to a gain of 24% at final FU. At last FU the mean reduction in compression visual analog scale score was significantly greater in patients receiving rhTSH (P = 0.049). Additional therapy (thyroid surgery or (131)I) was required more often in the placebo group (nine of 44) compared with the rhTSH group (two of 42) (P = 0.05). The prevalence of hypothyroidism at 1 yr [9 and 43% in the placebo and rhTSH groups, respectively (P < 0.0001)] increased to 16 and 52%, respectively, at final FU (P = 0.001)., Conclusion: Enhanced goiter volume reduction with rhTSH-augmented (131)I therapy improves the long-term reduction in goiter-related symptoms and reduces the need for additional therapy compared with plain (131)I therapy. Overall patient satisfaction is benefited, despite a higher rate of permanent hypothyroidism.

We describe a case of spontaneous sublingual haematoma secondary to warfarin toxicity, leading to impending airway obstruction. The case was handled with the administration of vitamin K and fresh frozen plasma, and without invasive airway handling. Furthermore, we discuss the presentation of the condition and the signs of impending airway obstruction. Preferred management includes a safe airway and reversion of coagulopathy. The prognosis is good when treatment is prompt and correct.

Background: Radioiodine (131I) therapy is widely used for treatment of non-toxic goiters. A limitation for this treatment is a low thyroid radioiodine uptake (RAIU), often encountered in these patients., Aim: To estimate the impact of various factors on the thyroid RAIU., Methods: We examined prospectively 170 patients (146 females; age range: 22-87 yrs) with nodular goiter (median 64 ml, range: 20-464 ml) selected for 131I therapy. Serum TSH was sub-normal in 42.4%. None were treated with anti-thyroid drugs. The thyroid RAIU was determined at 24h and 96 h. The goiter volume was measured by ultrasound (no.=127), or by magnetic resonance imaging (no.=43)., Results: The 24h and the 96 h RAIU were 34.2 ± 9.8(SD)% (range: 11.4-66.0%) and 34.0 ± 10.0% (range: 10.5-60.9%), respectively. Sixty-one patients had a 24h RAIU <30% and these individuals were older than patients with a 24h RAIU ≥ 30% (median 58 vs 51 yrs, p=0.02). These two subgroups did not differ significantly in other variables. Overall, the 24h RAIU was positively correlated to the serum (s) free T4-index (r=0.20, p=0.01), and negatively to age (r=-0.18, p=0.02), but not significantly related to serum TSH or thyroid volume. Age correlated positively with thyroid volume (r=0.31, p < 0.001). In a regression analysis, s-free T4-index and age remained as the only determinants of the 24h and the 96 h RAIU., Conclusions: In patients with a symptomatic nodular goiter, serum T4 and age are the major determinants of the thyroid RAIU. A sub-normal serum TSH is not a marker of a compromised thyroid RAIU but reflects that the iodine is confined to a few 'hot spots'.

Context and Objective: Stimulation with recombinant human TSH (rhTSH) before radioiodine (131I) therapy augments goiter volume reduction (GVR). Observations indicate that rhTSH has a preconditioning effect beyond increasing thyroid (131)I uptake. We test the hypothesis that an equivalent GVR might be obtained by an absorbed thyroid dose well below what has been used previously., Patients and Design: In a double-blinded setup, 90 patients (78 women; median age, 52 yr; range, 22-83) with a nontoxic nodular goiter (median size, 63 ml; range, 25-379 ml) were randomized to either 0.1 mg rhTSH (n=60) followed by a thyroid dose of 50 Gy or placebo followed by 100 Gy (n=30)., Results: At 12 months, the mean relative GVR in the placebo and the rhTSH group was identical (35+/-3%; P=0.81). The median administered 131I-activity was 170 MBq (45-1269) in the rhTSH group and 559 MBq (245-3530) in the placebo group (70% reduction, P<0.0001). According to the official radiation regulation, hospitalization was required in 14 patients in the placebo group vs. one patient in the rhTSH group (P<0.0001). In both groups, goiter-related symptoms were effectively relieved in the majority of patients. The prevalence of myxedema (10%) did not differ among groups., Conclusions: This is the first study to demonstrate that rhTSH not only increases the thyroid 131I uptake, but per se potentiates the effect of 131I-therapy, allowing a major reduction of the 131I-activity without compromising efficacy. This approach is attractive in terms of minimizing posttherapeutic restrictions and in reducing the potential risk of radiation-induced malignancy.

Introduction: Surgical treatment of tracheal stenoses (TS) using tracheal resection (TR) is a treatment modality that should be considered in every case. We report the results from TR in a consecutive series of 17 patients in Western Denmark during the past five years., Material and Methods: A total of 32 patients with TS were retrospectively evaluated, of whom 17 underwent TR with end-to-end anastomoses. Age, gender, aetiology, symptoms, findings, localisation and length of the stenoses were registered. In addition, other procedures than TR and patient satisfaction were registered., Results: Nine (53%) and three (18%) had post-tracheostomy and post-intubation stenoses, three (18%) had an intraluminal tumour, two (12%) had amyloidosis and sequelae after fracture of a tracheal ring, respectively. Prior to surgery, 29% underwent stent implantation, 41 and 47%, respectively, had had laser resection and/or dilation a number of times. The median stenosis length was 1.1 cm (0.4-2.0 cm), and they were primarily located 2-4 cm below the vocal cords. The length of resection ranged from 2.0 to 3.5 cm (median 2.3). Postoperatively, one (5.8%) patient died and one needed reoperation due to haematoma, none developed insufficient anastomosis and of those with preoperative permanent tracheal tube, all but one could do without the tube after surgery. The follow-up period was 3.0 years (0.0-5.5 yrs). 75% was - according to questionnaire answers - very satisfied with the result, 25% were moderately satisfied., Conclusion: The results from surgical treatment of TS in Denmark are in line with international studies and TR is the treatment of choice in selected patients with TS.

Introduction: Mild to moderate blunt laryngeal injuries are frequent. Under the present management regimens patients are hospitalized for 24h observation due to the potential risk of developing endolaryngeal oedema. This group of patients is poorly described in the literature, and the aim of this study was to estimate the incidence of acute and especially tardive endolaryngeal oedema as well as the association between type of injury, symptoms and findings to improve existing evaluation criteria and treatment regimens., Materials and Methods: A retrospective analysis of 130 cases exposed to mild to moderate laryngeal injury was performed. The mechanism of injury, symptoms, findings and treatment were registered., Results: Strangulation was the most common type of injury which was seen in 43% of cases, while stranglehold, fall and blow were observed in 29, 14 and 14%, respectively. Dysphagia was reported by 55%, while hoarseness was observed in 17% and stridor in 5%. Fibreoptically, 33% had endolaryngeal pathology. Twenty cases received treatment, 110 were observed. Immediate intubation was performed in 2.3% of the cases. In the observation-group, more patients were exposed to self-inflicted strangulation (p = 0.01). Fall and blow accidents were more frequent in the treatment than in the non-treatment group (p = 0.03). More patients in the treatment group had dyspnoea (p < 0.001), stridor (p = 0.001), hoarseness (p = 0.007) and endolaryngeal pathology (p < 0.001) than in the non-treatment group., Conclusions: In general, mild to moderate blunt external laryngeal injuries seem rather harmless and should need no further treatment. Nevertheless, any injury against the paediatric larynx and injuries related to fall-accidents or genuine hangings are associated with an increased risk of a respiratory threat. No patients in this study developed tardive laryngeal oedema.

Context: Recombinant human TSH (rhTSH) is used to augment the effect of radioiodine therapy for nontoxic multinodular goitre. Reports of acute thyroid swelling and hyperthyroidism warrant safety studies evaluating whether these side-effects are dose dependent., Objective: To determine the effects on thyroid size and function of various doses of rhTSH., Design: In nine healthy male volunteers, the effect of placebo, 0.1, 0.3 and 0.9 mg of rhTSH was examined in a paired design including four consecutive study rounds., Main Outcome Measures: Main outcome measures were evaluated at baseline, 24 h, 48 h, 96 h, 7 days and 28 days after rhTSH and included: Thyroid volume (TV) estimation by planimetric ultrasound, and thyroid function by serum TSH, free T3, free T4 and Tg levels., Results: Following placebo or 0.1 mg rhTSH, the TV did not change significantly from baseline at any time. At 24 and 48 h after administration of 0.3 mg rhTSH, the TV increased by 37.4 +/- 12.3% (SEM) (P = 0.03) and 45.3 +/- 16.1% (P = 0.05) respectively. After 0.9 mg rhTSH, the TV increased by 23.3 +/- 5.8% (P = 0.008) and 35.5 +/- 18.4% (P = 0.02) respectively. The increase in serum FT3, FT4 and thyroglobulin (Tg) was greater when administering 0.3 mg compared with 0.1 mg (P = 0.02) and when administering 0.9 mg compared with 0.3 mg (P = 0.02). After 0.1 mg rhTSH, the increase in FT3 and Tg was not significantly different from placebo whereas the FT4 increase was significantly higher (P = 0.02 compared with placebo)., Conclusions: In healthy individuals, rhTSH-induced thyroid swelling and hyperthyroidism is rapid and dose dependent. If valid for patients with goitre, our results suggest that these adverse effects are unlikely to be of clinical significance, following doses of rhTSH of 0.1 mg or less.

Unlabelled: Prestimulation with recombinant human thyroid-stimulating hormone (rhTSH) augments radioiodine (131)I therapy for benign nontoxic multinodular goiter. The purpose of this study was to determine the optimal time interval between rhTSH and (131)I administration to enhance thyroid radioactive iodine uptake (RAIU)., Methods: Patients were randomized, in a 2-factorial design, to receive either a 0.1-mg dose of rhTSH (n = 60) or placebo (n = 30) and to a time interval of 24, 48, or 72 h before (131)I administration. The rhTSH- or placebo-stimulated RAIU study was performed at 4 wk after a baseline RAIU assessment in a tertiary referral center at a university hospital. A total of 90 patients (78 women; median age, 52 y; range, 22-83 y) referred to (131)I therapy for symptomatic nontoxic goiter (median goiter volume, 63 mL; range, 25-464 mL) were included in the study. Change in thyroid RAIU was determined at 24 and 96 h after (131)I tracer administration., Results: In the placebo subgroups, RAIU did not change significantly from baseline. The mean (+/-SE) 24-h RAIU increased from 33.8% +/- 2.3% to 66.0% +/- 1.8% (111.2% increase) with a 24-h interval, from 36.8% +/- 2.1% to 64.6% +/- 2.7% (83.3% increase) with a 48-h interval, and from 33.0% +/- 2.7% to 49.6% +/- 2.5% (62.4% increase) with a 72-h interval. All within-group changes were highly significant (P < 0.001). The effect was negatively correlated with initial RAIU (r = -0.703, P < 0.001). The increase in 24- and 96-h RAIU was significantly higher in the rhTSH/24-h group than it was in the rhTSH/72-h group (P = 0.023 and 0.012, respectively) and insignificantly higher than in the rhTSH/48-h group (P = 0.37 and 0.26, respectively)., Conclusion: The effect of rhTSH on thyroid RAIU is most pronounced when administered 24 h before (131)I administration and declines with longer time intervals. Whether there is a similar time dependency for goiter reduction after rhTSH-stimulated (131)I-therapy remains to be clarified.

The treatment of benign multinodular goitre (MNG) is controversial, but surgery is recommended in large compressive goitres. While some patients decline surgery others may have contraindications due to comorbidity, since MNG is prevalent in the elderly. Therefore, non-surgical treatment alternatives are needed. Until recently, levothyroxine therapy was the preferred non-surgical alternative, but due to low efficacy and potential side-effects, it is not recommended for routine use in recent international guidelines. Conventional radioiodine ((131)I) therapy has been used for two decades as an effective and safe alternative to surgery in the treatment of symptomatic non-toxic MNG. Since much higher activities of (131)I are employed when treating non-toxic rather than toxic MNG, there has been reluctance in many countries to use this treatment modality. Frequently, the (131)I -uptake in a non-toxic MNG is low, which makes (131)I therapy less feasible. Another challenge is the negative correlation between the initial goitre size and goitre volume reduction (GVR). With its ability to more than double the thyroid (131)I-uptake, recombinant human TSH (rhTSH) increases the absorbed radiation dose and thus enhances the GVR by 35-56% at the expense of up to fivefold higher rate of permanent hypothyroidism. An alternative strategy is to reduce the administered (131)I-activity with a factor corresponding to the rhTSH induced increase in (131)I-uptake. Hereby, the extrathyroidal irradiation can be reduced without compromising efficacy. Thus, although in its infancy, and still experimental, rhTSH-augmented (131)I therapy may profoundly alter the non-surgical treatment of benign non-toxic MNG.

Introduction: The impact on tracheal anatomy and respiratory function of recombinant human (rh)TSH-stimulated (131)I therapy in patients with goiter is not clarified., Methods: In a double-blinded design, patients (age 37-87 yr) with a large multinodular goiter (range, 99-440 ml) were randomized to placebo (n = 15) or 0.3 mg rhTSH (n = 14) 24 h before (131)I therapy. The smallest cross-sectional area of the trachea (SCAT; assessed by magnetic resonance imaging) and the pulmonary function were determined before, 1 wk, and 12 months after therapy., Results: Data on goiter reduction have been reported previously. In the placebo group, no significant changes in the lung function or SCAT were found throughout the study. In the rhTSH group, a slight decrease was observed in the forced vital capacity 1 wk after therapy, whereas the mean individual change in SCAT was significantly increased by 10.5% (95% confidence interval = 0.9-20.0%). A further increase in SCAT to 117 +/- 36 mm(2) (P = 0.005 compared with 92 +/- 38 mm(2) at baseline) was seen at 12 months, corresponding to a mean of 31.4% (95% confidence interval = 16.0-46.8%). The expiratory parameters did not change significantly, whereas forced inspiratory flow at 50% of the vital capacity (FIF50%) increased from initially 3.34 +/- 1.33 liters/sec to ultimately 4.23 +/- 1.88 liters/sec (P = 0.015) in the rhTSH group, corresponding to a median increase of 24.6%. By 12 months, the relative improvements in FIF50% and in SCAT were inversely correlated to the respective baseline values (FIF50%: r = -0.47, P = 0.012; SCAT: r = -0.57, P = 0.001)., Conclusion: On average, neither compression of the trachea nor deterioration of the pulmonary function was observed in the acute phase after rhTSH-augmented (131)I therapy. In the long term, tracheal compression is diminished, and the inspiratory capacity improved, compared with (131)I therapy alone.

Introduction: The effect of (131)I therapy amplification by recombinant human (rh) TSH prestimulation in very large goiters has not been evaluated in a double-blinded, placebo-controlled study., Methods: Twenty-nine patients (22 females; age range 37-87 yr) with a large multinodular goiter (median 160 ml, range 99-440 ml) were randomized to receive placebo (n = 15) or 0.3 mg rhTSH (n = 14) 24 h before (131)I administration. Goiter volume was monitored by magnetic resonance imaging., Results: On average, the goiter volume was unchanged 1 wk after therapy in both groups, but the largest deviations from baseline were observed in the rhTSH group. After 12 months the median goiter volume was reduced from 170 to 121 ml in the placebo group and from 151 to 72 ml in the rhTSH group, respectively (within group: P = 0.001; between group: P = 0.019). This corresponds to reductions of 34.1 +/- 3.2 and 53.3 +/- 3.3%, respectively (between group: P < 0.001). In the placebo group, the goiter reduction correlated positively with the retained thyroid (131)I dose, whereas such a relationship was absent in the rhTSH group. Adverse effects, mainly related to thyroid pain and cervical compression, were more frequent in the rhTSH group. At 12 months, goiter-related complaints were significantly reduced in both groups without any between-group difference. One and three patients in the placebo and the rhTSH group, respectively, developed hypothyroidism., Conclusion: rhTSH-stimulated (131)I therapy improves the reduction of very large goiters by more than 50%, compared with (131)I therapy alone, but at the expense of more adverse effects after therapy. Our data suggest that rhTSH stimulation may work through mechanisms that go beyond the increase in thyroid (131)I uptake.

In a randomized, double-blind, placebo-controlled trial, 57 patients with nontoxic nodular goiter were stimulated with either 0.3 mg recombinant human thyrotropin (rhTSH) or placebo before radioactive iodine 131I therapy. After one year the goiter reduction had improved by 35% compared to conventional 131I therapy. The difference was most pronounced in patients with a large goiter. Adverse effects, including development of permanent hypothyroidism, were significantly more frequent in the rhTSH group. Patient satisfaction was high and uninfluenced by the use of rhTSH.

Background: Recombinant human (rh) TSH, in doses from 0.01 to 0.9 mg, has been used to augment the effect of radioiodine ((131)I) therapy in patients with a benign nontoxic nodular goiter. Transient thyroid enlargement and thyrotoxicosis may be seen following (131)I therapy., Aim: The aim of the study was to investigate whether rhTSH per se causes goiter enlargement, until now an issue evaluated only in healthy nongoitrous subjects., Methods: In random order, 10 patients with nontoxic nodular goiter [mean 39.8 +/- 20.5 (sd) ml] received either 0.3 mg rhTSH or isotonic saline in a double-blinded crossover design. Thyroid volume (by ultrasound) and function were closely monitored during the following 28 d., Results: Saline injection did not affect thyroid function or size. After rhTSH, median serum TSH increased from baseline 0.97 mU/liter (range 0.39-1.56) to 37.0 mU/liter (range 18.5-55.0) at 24 h (P < 0.01), with a subsequent decline to subnormal levels at d 7. Mean free T(4) and free T(3) increased significantly from baseline to a maximum at 48 h. Twenty-four hours after rhTSH, the mean goiter volume was significantly increased by 9.8 +/- 2.3% (sem) (P = 0.01) and after 48 h by 24.0 +/- 5.1% (P = 0.002). The goiter enlargement had reverted at d 7. Nine patients had symptoms of hyperthyroidism and/or cervical compression after rhTSH, as opposed to one during placebo treatment (P < 0.02)., Conclusions: A transient average goiter enlargement of up to 24% is seen after 0.3 mg rhTSH. This may lead to a significant cervical compression when used for augmentation of (131)I therapy in patients with goiter. The use of lower doses of rhTSH needs to be explored.

Objective: According to European recommendations, the external dose rate (ED) in radioiodine-treated goitre patients can be determined by estimating from calculation of the residual activity (RA) in the patient based on radioiodine uptake measurements or by measuring ED directly. In the European guidelines, "Radiation Protection 97", it is assumed that an RA of 600 MBq (131)I causes an ED of 30 microSv/h at a distance of 1 m. This implies a slope of 0.05 microSv/h/MBq for the ratio ED/RA relationship, but, theoretically, this ratio is higher, at 0.07, a difference that is due to measurement in air versus in a scattering medium. We sought to investigate what the true ratio might be., Material and Methods: Sixty-six patients scheduled for radioiodine treatment of benign goitre (mean size 102 mL, range 20-440), who received (131)I orally (mean 984 MBq, range 173-3700) were examined. After 24 h and 96 h iodine uptake percentage we examined 7269 patients scheduled for radioiodine treatment of benign goitre (mean size 1042 mL, range 20-440) who received (131)I orally (mean 101,100 MBq, range 180-3700). After 24 h and 96 h, the iodine uptake was determined, RA calculated and ED measured using a hand-held dosimeter., Results: At 24 and 96 h, we observed a slope ratio of 0.103 microSv/h/MBq (95 % CI: 0.09564-0.111) and 0.101 microSv/h/MBq (95 % CI: 0.0915-0.11107), respectively, for the ED/RA relationship. None of the confidence intervals included the value 0.05 microSv/h/MBq, reflecting that the observed slopes differed significantly from the expected slope (p < 0.001). Consequently, an RA of 600 MBq typically causes an ED of 60 and not 30 microSv/h, and therefore dose rates based on radioiodine uptake measurements and established assumptions were only about half as high as the directly measured values. We noticed that with an RA roughly below 450 MBq, the anticipated slope of 0.05 microSv/h/MBq is within the prediction interval of our claimed ratio, therefore we cannot rebut the anticipated slope for lower doses., Conclusions: Dose-rate estimates based on radioiodine uptake measurements and established assumptions were only about half as high as the directly measured values in patients receiving doses higher than the widely accepted limits for outpatient treatment. This finding may have substantial implications for us, in that it makes a considerable difference whether the radiation precautions are taken to limit doses to the patient's surroundings and for deciding if a patient may or may not be regarded as an outpatient, as well as for the safe discharge of an inpatient from hospital.

There is no consensus regarding the optimum treatment of benign non-toxic goitre. L-thyroxine suppressive therapy is widely used, but there is poor evidence of its efficacy, and it may have serious adverse effects on health. Surgery is first choice in large goitres or if malignancy is suspected. 131I therapy results in a one-year goitre reduction of around 40% in multinodular goitres, usually with a high degree of patient satisfaction and improvement of the inspiratory capacity. The effect is attenuated with increasing goitre size. The risk of hypothyroidism is 22-58% within 5-8 years. A sufficient thyroid 131I uptake is mandatory for 131I therapy to be feasible and pre-stimulation with recombinant human TSH (rhTSH) increases this considerably. This leads to an increased absorbed thyroid dose by approx.75%, mainly in those patients with the lowest thyroid 131I uptake, and a more homogeneous intrathyroidal isotope distribution. Pre-stimulation with even a small dose of rhTSH seems to allow a reduction of the 131I activity while still achieving a mean goitre reduction of approximately 40% within a year. A significantly lower extrathyroidal radiation is achieved by this approach. With an unchanged 131I activity, rhTSH pre-stimulation improves the goitre reduction by 30-50%. However, this is at the expense of a higher rate of hypothyroidism, cervical pain and transient thyrotoxicosis. Of particular concern is the observation made in healthy persons, that rhTSH results in a transient average thyroid volume increase of 35%. A similar goitre swelling may cause problems in susceptible patients during rhTSH-augmented 131I therapy. Thus, this concept still needs a closer evaluation before routine use.

The present study compares, in a randomized double-blinded design, the expected and the actual absorbed thyroid radioactive dose in response to 0.3 mg recombinant human (rh)TSH (n = 35) or placebo (n = 28) given 24 h before (131)I therapy in patients with nodular goiter (median volume, 69 ml; range, 20-440 ml). The (131)I activity calculation was based on thyroid (131)I uptake (RAIU) at 24 and 96 h after a tracer dose of 0.5 MBq (131)I. After (131)I therapy, 24- and 96-h RAIU were repeated allowing a more exact assessment of the actual absorbed thyroid dose. The median (131)I activity was 617 and 632 MBq, respectively, in the rhTSH and the placebo group. At baseline, the 24- and 96-h RAIU and the expected thyroid dose were 32.8 +/- 9.1%, 32.1 +/- 8.2%, and 96.3 +/- 16.3 Gy, respectively, in the rhTSH group and 35.7 +/- 11.8%, 35.2 +/- 11.3%, and 94.1 +/- 18.5 Gy, respectively, in the placebo group (P value not significant between groups). After (131)I therapy, the 24- and 96-h RAIU and the actual absorbed thyroid dose were 46.9 +/- 11.7%, 45.0 +/- 12.1%, and 136.7 +/- 47.9 Gy, respectively, in the rhTSH group and 33.0 +/- 11.4%, 31.0 +/- 11.3%, and 76.9 +/- 27.5 Gy, respectively, in the placebo group (P < 0.001 between groups). Comparing the expected with the actual absorbed thyroid dose, this corresponds to a mean increase of 36.4% (95% confidence interval, 21.3-53.4) in the rhTSH group and a decrease of 21.5% (95% confidence interval, -33.9 to -6.6) in the placebo group (P < 0.001), equivalent to an increase of 73.8% in the absorbed thyroid dose in the rhTSH-treated group. We have thus for the first time shown that stimulation with rhTSH before (131)I therapy not only hinders the decrease in the thyroid RAIU observed with conventional (131)I therapy but in fact also significantly enhances the absorbed thyroid dose. Whether this also leads to a significant increase in goiter size reduction needs additional study.

The effect of recombinant human TSH (rhTSH) on thyroid function and ultrasonically determined thyroid volume was investigated in nine healthy euthyroid male volunteers. Each received either 0.9 mg rhTSH or isotonic saline in a randomized order, and thyroid volume and function were closely monitored during the following 28 d. No significant changes were observed after saline injection. After rhTSH stimulation, the median serum TSH increased from 2.03 mU/liter (range, 0.99-3.07 mU/liter) to more than 200 mU/liter (range, 78.9 to >200.0 mU/liter) after 4 h, with a subsequent rapid decline. Mean (+/-SEM) serum free T(4) and free T(3) peaked at 48 h with levels 204.7 +/- 26.1% and 226.9 +/- 31.4%, respectively, above baseline (P < 0.001). Twenty-four hours after rhTSH stimulation, mean (+/-SEM) thyroid volume was significantly increased by 23.3 +/- 5.8% (P = 0.003) and after 48 h by 35.5 +/- 18.4% (P = 0.02). On d 4 the mean thyroid enlargement had reverted to baseline values. One individual developed a 90-ml tender thyroid enlargement (initially 21 ml) 36 h after rhTSH administration, associated with a very high level of serum thyroglobulin. It is concluded that 0.9 mg rhTSH may result in a profound stimulation of not only thyroid function but also of thyroid size, appearing in the period 1-4 d after injection. Further dose-response studies are needed to clarify the potential hazards before routine use, for example in the context of (131)I therapy and goiter.

A middle-aged native Danish man became aphonic with chronic laryngitis. The symptoms persisted despite antibiotic treatment, and chest X-ray disclosed a central pulmonary infiltrate. Histopathology on specimens from the larynx and lung and microscopy and culture of the sputum revealed primary lung tuberculosis with spread to the larynx. At presentation, laryngeal tuberculosis often mimics non-specific chronic laryngitis or laryngeal carcinoma. It should be suspected when the clinical course is unusual. Tuberculosis may develop in the absence of risk factors.