Τετάρτη 23 Ιουνίου 2021

Correlation of tumour and treatment characteristics to dose received by cochlea in volumetric arc therapy

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Eur Arch Otorhinolaryngol. 2021 Jun 23. doi: 10.1007/s00405-021-06950-y. Online ahead of print.

ABSTRACT

PURPOSE: This is a radiation field simulation study using CT images designed to see the cochlear dosimetry and its correlation with tumour and treatment characteristics during radiotherapy for head and neck cancers (HNC) for identifying the factors associated with a higher dose delivered to the cochlea.

METHODS: From 2018 to 2020, 80 patients with HNC underwent volumetric arc therapy (VMAT) to a dose of 66-70 Gy at 2 Gy per fraction with bilateral cochlea contoured for VMAT optimization as an organ at risk. Minimum, mean and maximum planned radiation dose to the cochlea based on tumour and treatment characteristics and dose-volume histogram variables of VMAT plans were analysed.

RESULTS: Mean (standard deviation, SD) cochlear volume was 0.14 (0.06) cm3 with maximum and mean planned doses of 10.3 (SD = 11.6) Gy and 8.5 (SD = 9.8) Gy, respectively. We found a statistically significant correlation between mean dose received by bilateral cochlea (P-0.000, rright-0.84, rleft-0.78, rmidline-0.92). Tumours of the paranasal sinuses, and the parotids and more advanced T stages were associated with a higher mean dose to cochlea but was not significant statistically. The dose received by the 95% target nodal volume (D95%) showed a significant correlation with the cochlear mean dose (P-0.000, rright-0.85, rleft-0.77, rmidline-0.93) CONCLUSION: With VMAT we have achieved a better sparing of cochlea. The mean dose to the cochlea of one side significantly differed from the other side in patients with lateralized cancers. D95% of nodal volume also showed a significant correlation with the cochlear mean dose.

PMID:34160665 | DOI:10.1007/s00405-021-06950-y

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Deep neck infections with and without mediastinal involvement: treatment and outcome in 218 patients

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Eur Arch Otorhinolaryngol. 2021 Jun 23. doi: 10.1007/s00405-021-06945-9. Online ahead of print.

ABSTRACT

PURPOSE: Infections of the deep neck, although becoming scarcer due to the widespread use of antibiotics, still represent a dangerous and possibly deadly disease, especially when descending into the mediastinum. Due to the different specialities involved in the treatment and the heterogenous presentation of the disease, therapeutic standard is still controversial. This study analyzes treatment and outcome in these patients based on a large retrospective review and proposes a therapeutic algorithm.

METHODS: The cases of 218 adult patients treated with deep neck abscesses over a 10-year period at a tertiary university hospital were analyzed retrospectively. Clinical, radiological, microbiological and laboratory findings were compared between patients with and without mediastinal involvement.

RESULTS: Forty-five patients (2 0.64%) presented with abscess formation descending into the mediastinum. Those patients had significantly (all items p < 0.0001) higher rates of surgical interventions (4.27 vs. 1.11) and tracheotomies (82% vs. 3.4%), higher markers of inflammation (CRP 26.09 vs. 10.41 mg/dl), required more CT-scans (3.58 vs. 0.85), longer hospitalization (39.78 vs 9.79 days) and more frequently needed a change in antibiotic therapy (44.44% vs. 6.40%). Multi-resistant pathogens were found in 6.67% vs. 1.16%. Overall mortality rate was low with 1.83%.

CONCLUSION: Despite of the high percentage of mediastinal involvement in the present patient collective, the proposed therapeutic algorithm resulted in a low mortality rate. Frequent CT-scans, regular planned surgical revisions with local drainage and lavage, as well as an early tracheotomy seem to be most beneficial regarding the outcome.

PMID:34160666 | DOI:10.1007/s00405-021-06945-9

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Can fractal dimension analysis be used in quantitating collagen structure?

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Abstract

It is well known that collagen tissue, especially the collagen structure, plays an important role in wound healing. However, most research on collagen has been qualitative and morphological, based on sections, and cannot be used for real-time monitoring and clinical prediction. There are no standardized methods of quantitative analysis based on the whole skin sample in three dimensions (3-D). In order to explore a 3-D quantitative analysis, we developed a method that was derived from that of material science and physics, combined with our previous technique, X-ray scattering (SAXS). We hypothesized that the dermis might be analyzed by fractal dimensions. To test this hypothesis, we performed the analysis in different pathological conditions, such as scar tissue, different time points after wounding, skin in different degrees of burns, and skin in diabetes. The results showed that fractal dimension analysis could detect differences in different locations of the scar tissue, in diff erent time points after wounding, and in a different extent of the severity of skin in diabetes. The research demonstrated that fractal dimension analysis can describe the 3-D structure of the collagen tissue of the skin, which will be beneficial for studying wound healing and finding new clinical treatments.

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Graves disease and metastatic hormonal-active Hürthle cell thyroid cancer: A case report

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Medicine (Baltimore). 2021 Jun 25;100(25):e26384. doi: 10.1097/MD.0000000000026384.

ABSTRACT

RATIONALE: A hormone-active metastatic Hürthle cell thyroid carcinoma (HCTC) and Graves disease (GD) present a therapeutic challenge and is rarely reported.

PATIENT CONCERNS: We present a 64-year-old male patient, who had dyspnea and left hip pain lasting 4 months. He had clinical signs of hyperthyroidism and a tumor measuring 9 cm in diameter of the left thyroid lobe, metastatic nec k lymph node and metastases in the lungs, mediastinum, and bones.

DIAGNOSIS: Laboratory findings confirmed hyperthyroidism and GD. Fine-needle aspiration biopsy and cytological investigation revealed metastases of HCTC in the skull and in the 8th right rib. A CT examination showed a thyroid tumor, metastatic neck lymph node, metastases in the lungs, mediastinum and in the 8th right rib measuring 20 × 5.6 × 4.5 cm, in the left acetabulum measuring 9 × 9 × 3 cm and parietooccipitally in the skull measuring 5 × 4 × 2 cm. Histology after total thyroidectomy and resection of the 8th right rib confirmed metastatic HCTC.

INTERVENTIONS: The region of the left hip had been irradiated with concomitant doxorubicin 20 mg once weekly. When hyperthyroidism was controlled with thiamazole, a total thyroidectomy was performed. Persistent T3 hyperthyroidism, most likely caused by TSH-R-stimulated T3 production in large metastasis in the 8th right rib, was eliminated by rib resection . Thereafter, the patient was treated with 3 radioactive iodine-131 (RAI) therapies (cumulative dose of 515 mCi). Unfortunately, the tumor rapidly progressed after treatment with RAI and progressed 10 months after therapy with sorafenib.

OUTCOMES: Despite treatment, the disease rapidly progressed and patient died due to distant metastases. He survived for 28 months from diagnosis.

LESSONS: Simultaneous hormone-active HCTC and GD is extremely rare and prognosis is dismal. Concomitant external beam radiotherapy and doxorubicin chemotherapy, followed by RAI therapy, prevented the growth of a large metastasis in the left hip in our patient. However, a large metastasis in the 8th right rib presented an unresolved problem. Treatment with rib resection and RAI did not prevent tumor recurrence. External beam radiotherapy and sorafenib treatment failed to prevent tumor growth.

PMID:34160415 | DOI:10.1097/MD.0000000000026384

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A rare tumor manifestation in the head and neck region

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HNO. 2021 Jun 23. doi: 10.1007/s00106-021-01071-8. Online ahead of print.

NO ABSTRACT

PMID:34160625 | DOI:10.1007/s00106-021-01071-8

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Perfusion analysis in parotid gland tumors using contrast-enhanced ultrasound (CEUS)

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HNO. 2021 Jun 23. doi: 10.1007/s00106-021-01077-2. Online ahead of print.

ABSTRACT

OBJECTIVE: The diagnosis of parotid gland tumors is challenging due to their rarity and heterogenity. Neither conventional ultrasound nor magnetic resonance imaging (MRI) nor computed tomography (CT) allow a reliable pretherapeutic diagnosis. In addition to conventional ultrasound, contrast-enhanced ultrasound (CEUS) enables a more detailed assessment of perfusion in parotid gland tumors, ther eby improving evaluation of this tumor entity. Extensive studies with analysis of perfusion characteristics in different regions of interest (ROI) in parotid gland tumors are currently lacking. This study analysed and compared perfusion parameters in different intratumoral areas of malignant and benign parotid gland tumors using CEUS.

MATERIALS AND METHODS: A total of 100 patients with tumors in the parotid gland were examined using B‑mode sonography, colour Doppler sonography and CEUS. The parameters magnitude, echogenicity, demarcation, vascularisation and in particular perfusion characteristics were measured and analysed. Analysis of quantitative CEUS parameters was performed using a specific method for perfusion analysis with certain ROI, which were allocated in a standardized manner in the entire parotid gland tumors. The perfusion parameters were compared between intratumoral ROI in the tumors and between particular tumor entities. Qualitative CEUS analysis with an est imation of perfusion patterns was additionally performed.

RESULTS: Histologically benign tumors were found in 92 cases, and malignant tumors in eight cases. CEUS analysis of perfusion patterns revealed a centripetal perfusion pattern in malignant tumors significantly more frequently than in benign tumors. In the perfusion analysis of quantitative CEUS parameters, all tumors showed higher perfusion intensities in the peripheral ROI. In benign tumors, more differences in perfusion intensity between the intratumoral ROIs were detected compared to malignant tumors.

CONCLUSION: The perfusion parameters (centripetal perfusion pattern; area under the curve) evaluated in this study have the potential to improve pretherapeutic diagnostics of parotid gland tumors in terms of differentiation of tumor entity. Further studies with larger patient cohorts are required for subsequent investigation and validation of the diagnostic accuracy of particular parameters to detect perfusion pat terns potentially specific to particular tumor entities.

PMID:34160626 | DOI:10.1007/s00106-021-01077-2

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The histopathological 'fingerprint' of the paradigm shift in the treatment of parotid pleomorphic adenoma

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HNO. 2021 Jun 23. doi: 10.1007/s00106-021-01074-5. Online ahead of print.

NO ABSTRACT

PMID:34160627 | DOI:10.1007/s00106-021-01074-5

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Effects of a food preparation program on dietary well-being for stroke patients with dysphagia: A pilot study

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Medicine (Baltimore). 2021 Jun 25;100(25):e26479. doi: 10.1097/MD.0000000000026479.

ABSTRACT

BACKGROUND: Dysphagia is one of the common issues observed in patients with stroke. Stroke patients with dysphagia have to eat blended food or similar types of food for each meal, resulting in dietary dissatisfaction. The purpose of this study was to investigate the effects of a food preparation program on dietary well-being for stroke patients with dysphagia.

METHODS: This study was a pilot randomized clinical trial. Twenty-two patients were assigned randomly into the food preparation group (n = 11) and control group (n = 11). The food preparation group received oral motor exercises, recognition of food texture and thickener, and hands-on food preparation for 6 weeks. Outcome measures included the Dietary Well-Being Scale, brief version of the World Health Organization Quality of life, Swallowing Quality of Life Questionnaire, and Mini Nutritional Assessment.

RESULTS: Patients in the food preparation group showed significant improvements in the Dietary Well-Being Scale, psychological and environmental domains of the brief version of the World Health Organization Quality of life (P = .001-.024) with small to large effect sizes (success rate difference = 0.23-0.46). The Swallowing Quality of Life Questionnaire and Mini Nutritional Assessment displayed non-significant differences (P = .053-.092) and revealed small to moderate effect sizes (success rate diffe rence = 0.23-0.32).

CONCLUSIONS: The food preparation program showed a positive impact on dietary well-being and a potential improvement in the health-related quality of life, quality of life related to the process of swallowing, and nutritional status for stroke patients with dysphagia. We recommend that stroke patients with dysphagia receive adequate knowledge and hands-on food preparation training to increase their dietary intake and well-being.

PMID:34160459 | DOI:10.1097/MD.0000000000026479

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Progress in Treating Advanced Thyroid Cancers in the Era of Targeted Therapy

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Abstract
Background: Thyroid cancer is a common malignancy whose detection has increased significantly in past decades. Most of the increased incidence is due to detection of early well-differentiated thyroid cancer, but the incidence of more advanced thyroid cancers has increased as well. Recent methodological advancements have allowed for a deep understanding of the molecular underpinnings of the various types of thyroid cancer.

Summary: Thyroid cancers harbor a high frequency of potential druggable molecular alterations, including the highest frequency of oncogenic driver kinase fusions seen across all solid tumors. Analyses of poorly differentiated and anaplastic thyroid carcinoma confirmed that these tumors develop from more well-differentiated follicular-derived thyroid cancers through acquired additional mutations. The recognition of driver genomic alterations in thyroid cancers not only predicts tumor phenotype but also now can inform treatment approaches.

Conclusions: Major progress in understanding the oncogenic molecular underpinnings across the array of thyroid cancers has led to considerable gains in gene-specific systemic therapies for many cancers. This article focuses on the molecular characteristics of aggressive follicular-derived thyroid cancers and medullary thyroid cancer and highlights advancements in treating thyroid cancer in the era of targeted therapy.

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Thyroid, Ahead of Print.
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Repeat Fine Needle Aspiration Cytology Refines the Selection of Thyroid Nodules for Afirma Gene Expression Classifier Testing

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Abstract
Background: Molecular testing (MT) refines risk stratification for thyroid nodules that are indeterminate for cancer by fine needle aspiration (FNA) cytology. Criteria for selecting nodules for MT vary and remain largely untested, raising questions about the best strategy for maximizing the usefulness of MT while minimizing the harms of overtesting. We used a unique data set to examine the effects of repeat FNA cytology-based criteria for MT on management decisions and nodule outcomes.

Methods: This was a study of adults (age 25–90 years; 281 women and 72 men) with cytologically indeterminate (Bethesda III/IV) thyroid nodules who underwent repeat FNA biopsy and Afirma Gene Expression Classifier (GEC) testing (N = 363 nodules from 353 patients) between June 2013 and October 2017 at a single institution, with follow-up data collected until December 2019. Subgroup analysis was performed based on classification of repeat FNA cytology. Outcomes of GEC testing, clinical/sonographic surveillance of unresected nodules, and histopathologic diagnoses of thyroidectomies were compared between three testing approaches: (i) Reflex (MT sent on the basis of the initial Bethesda III/IV FNA), (ii) SemiRestrictive (MT sent if repeat FNA is Bethesda I–IV), and (iii) Restrictive (MT sent only if repeat FNA is Bethesda III/IV) testing approaches.

Results: Restricting MT to nodules that remain Bethesda III/IV on repeat FNA would have missed 4 low-risk cancers and 3 noninvasive follicular thyroid neoplasms with papillary-like nuclear features (NIFTP) (collectively 2% of the test population) but would have avoided diagnostic surgery for 42 benign nodules (12% of the test population). The Restrictive testing strategy was more specific (delta 0.126 confidence interval [CI 0.093 to 0.159] and 0.129 [CI 0.097 to 0.161], respectively) but less sensitive (delta −0.339 [CI −0.424 to −0.253] and −0.340 [CI −0.425 to −0.255], respectively) than the Reflex and SemiRestrictive approaches for detecting NIFTP or cancer.

Conclusions: Repeat FNA cytology can guide the selection of cytologically indeterminate thyroid nodules that warrant MT. The Restrictive model of performing Afirma GEC only on nodules with two separate biopsies showing Bethesda III/IV cytology would reduce the rate of diagnostic surgery for histologically benign nodules while missing only rare low-risk tumors. Given the low but nontrivial risks of thyroidectomy, the higher specificity of the Restrictive testing approach disproportionately outweighs the potential harms.

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Thyroid, Ahead of Print.
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Patient-Tailored Levothyroxine Dosage with Pharmacokinetic/Pharmacodynamic Modeling: A Novel Approach after Total Thyroidectomy

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Abstract
Background: After seven decades of levothyroxine (LT4) replacement therapy, dosage adjustment still takes several months. We have developed a decision aid tool (DAT) that models LT4 pharmacometrics and enables patient-tailored dosage. The aim of this was to speed up dosage adjustments for patients after total thyroidectomy.

Methods: The DAT computer program was developed with a group of 46 patients post-thyroidectomy, and it was then applied in a prospective randomized multicenter validation trial in 145 unselected patients admitted for total thyroidectomy for goiter, differentiated thyroid cancer, or thyrotoxicosis. The LT4 dosage was adjusted after only two weeks, with or without application of the DAT, which calculated individual free thyroxine (fT4) targets based on four repeated measurements of fT4 and thyrotropin (TSH) levels. The individual TSH target was either <0.1, 0.1–0.5, or 0.5–2.0 mIU/L, depending on the diagnosis. Initial postoperative LT4 dosage was determined according to clinical routine without using algorithms. A simplified DAT with a population-based fT4 target was used for thyrotoxic patients who often went into surgery after prolonged TSH suppression. Subsequent LT4 adjustments were carried out every six weeks until target TSH was achieved.

Results: When clinicians were guided by the DAT, 40% of patients with goiter and 59% of patients with cancer satisfied the narrow TSH targets eight weeks after surgery, as compared with only 0% and 19% of the controls, respectively. The TSH was within the normal range in 80% of DAT/goiter patients eight weeks after surgery as compared with 19% of controls. The DAT shortened the average dosage adjustment period by 58 days in the goiter group and 40 days in the cancer group. For thyrotoxic patients, application of the simplified DAT did not improve the dosage adjustment.

Conclusions: Application of the DAT in combination with early postoperative TSH and fT4 monitoring offers a fast approach to LT4 dosage after total thyroidectomy for patients with goiter or differentiated thyroid cancer. Estimation of individual TSH-fT4 dynamics was crucial for the model to work, as removal of this feature in the applied model for thyrotoxic patients also removed the benefit of the DAT.

Introduction
An estimated 5% of the population require thyroxine replacement therapy due to thyroid dysfunction or surgery (1,2). In the United States, levothyroxine (LT4) has been among the three most prescribed medications for years (3). Surprisingly, dosage adjustment remains a significant clinical problem even though LT4 has been on the market for almost seven decades and was first synthesized in 1927 (4). The time to achieve euthyroidism after thyroidectomy is often more than a year (5,6). The long interval could be due to the long half-life of LT4 (about one week), the narrow therapeutic window, variations in bioavailability and pharmacodynamics, and nonadherence. Long-term hypothyroidism and iatrogenic thyrotoxicosis have implications for cardiovascular disease, osteoporosis, quality of life, neurological disease, dementia, cancer treatment, and even mortality (7–16). Shorter periods with suboptimal dosage are more likely to affect quality of life, work capacity and have social consequen ces (17,18).

Several attempts have been made to predict the required LT4 dosage after thyroidectomy or in treatment of hypothyroidism (5,6,19–23). The published dosage schemes are variations of weighted relationships between LT4 dosage and person weight, height, sex, age, and drug interactions. At best, they retrospectively predict the correct dosage for 60–65% of the patients (1,23). However, prospective testing of the formulas is limited and often provides inferior results. Leaving a priori dosage estimates behind, we decided to use a patient-tailored approach that estimates the free thyroxine (fT4) pharmacokinetics and the thyrotropin (TSH)/fT4 relationship for each individual patient based on repeated blood samples. We hypothesized that rather than waiting six to eight weeks for hormone levels to stabilize, dosage adjustments after only two weeks would be feasible if the clinician was assisted by a computerized decision aid tool (DAT) predicting the future fT4 and TSH responses. We furthe r assumed that the best prediction could be done by combining population data and the results of individual blood samples drawn during the first two weeks after thyroidectomy. The objective of the study was to test whether application of the DAT led to more efficient dosage adjustments for patients starting LT4 therapy after total thyroidectomy, as compared with randomized controls.

Methods
Participants
Patients >18 years old admitted for total thyroidectomy or completion thyroidectomy after previous hemithyroidectomy were recruited consecutively, after obtaining informed consent. Their diagnosis was nontoxic goiter, thyroid malignancy Graves' disease, or toxic multinodular goiter. Exclusion criteria were pregnancy, use of liothyronine, or inability to cooperate on later follow-up by telephone. First, 46 patients were recruited for collection of pilot data that were used to develop the DAT algorithms. Second, a validation group of 145 new patients (103 female) were consecutively recruited in a randomized controlled trial (RCT): 84 from the University Hospital of North Norway, 28 from Haukeland University Hospital, Norway, and 33 from Västervik Hospital, Sweden. Ten patients were excluded after enrolment in the RCT, because they did not take the blood samples required by the study design (n = 7), because of technical problems with the DAT (server crash, n = 2), or because of other health emergencies (n = 1). The excluded patients were evenly distributed between the DAT and control groups (Table 1). This left 135 participants for data analysis. Of these, all completed the 8 weeks postoperative checkpoint and 122 successfully completed dosage adjustment according to the TSH goals in the study. The thyrotoxicosis/DAT group consisted of 21 patients with Graves' disease and 5 patients with toxic nodular goiter, while the thyrotoxicosis/control group contained 20 patients with Graves' disease and 5 patients with toxic nodular goiter.

Table 1. Patient Characteristics for Validation Randomized Controlled Trial

Variable Goiter Cancer Thyrotoxicosis
DAT Control DAT Control DAT Control All
No. total 16 18 29 28 28 26 145
No. exclusions 1 2 2 2 2 1 10
No. analyzed 15 16 27 26 26 25 135
Age (years) 55 ± 4.6 55.9 ± 4.1 57.5 ± 2.3 55.7 ± 2.6 51.5 ± 2.8 53.8 ± 2.9 54.8 ± 1.2
Height (cm) 167 ± 2 165 ± 2 169 ± 1 173 ± 2 171 ± 2 168 ± 2 169 ± 1
Weight (kg) 76.7 ± 5.7 77.5 ± 5 79.7 ± 2.8 83.6 ± 3.2 78.5 ± 3.3 80.2 ± 3.7 79.7 ± 1.5
BMI (kg/cm2) 27.1 ± 1.6 28.2 ± 1.6 27.6 ± 0.7 28 ± 1.1 26.6 ± 0.8 28.4 ± 1.2 27.6 ± 0.5
% Female 80 88 70 54 73 72 71
Initial LT4 dose (μg/day) 112 ± 3 109 ± 4 131 ± 4 137 ± 3 113 ± 3 117 ± 4 121 ± 2
Final LT4 dose (μg/day) 117 ± 9 118 ± 12 144 ± 7 150 ± 7 119 ± 5 114 ± 7 129 ± 3
TSH target <0.1 mIU/L 0 0 21 17 1 0 39
TSH target 0.1–0.5 mIU/L 0 0 5 8 4 4 21
TSH target 0.5–2.0 mIU/L 15 16 1 1 21 21 75
Baseline characteristics and dosage data for participants in the study. There was no statistical difference between the DAT groups and control groups within each diagnosis group (all p-values <0.15). The lower three rows show the number of patients assigned to each possible TSH target within each group.

BMI, body mass index; DAT, decision aid tool; LT4, levothyroxine; TSH, thyrotropin.

DAT development and validation study design
The DAT was developed on pilot data as described in Supplemental Data. Briefly, the model parameters were derived from four blood draws analyzed for TSH and fT4 obtained during the first two weeks of LT4 therapy. We assumed a log-linear relationship between TSH and fT4 (24), and we modeled individual TSH-fT4 response and fT4 pharmacokinetics informed by population data. Individual TSH-fT4 responses are illustrated in Figure 1. We tested the DAT in a prospective multicenter trial where participants were randomized to either application of the DAT or not (controls). We used an automated stratified randomization based on diagnosis and participating hospital. After surgery, and before randomization, all participants were prescribed an LT4 starting dosage, usually between 100 and 150 μg/day depending on diagnosis, body weight, age, and comorbidity. They were then asked to give pre-LT4 ingestion blood samples twice per week for two weeks postoperatively (Fig. 2). To reduce variation in the measurements and model, patients were instructed to take the medicine and give all blood samples in the morning. On days of blood samples, patients were instructed to delay intake of LT4 until the blood was drawn. Two to three weeks after surgery, the participants received a follow-up call advising them to either keep the current dosage or change it. In the DAT group, the responsible surgeon was assisted by the DAT with a graphical plot of the predicted fT4 and TSH given a suggested dosage change (Fig. 3). The DAT was disabled in the control group, but the same blood samples were available to the clinician. We collected preoperative data about diagnosis, TSH-target, height, weight, age, sex, surgery date, creatinine, albumin, TSH, fT4, and free triiodothyronine. Postoperative data were collected about LT4 dosage, TSH, and fT4.

FIG. 1.
FIG. 1. Measurements of TSH and fT4 from a subset of the RCT population (left) and two example patients (center and right) during the first two weeks after thyroidectomy. Hyper parameters of the Bayesian regression lines estimated from the pilot population used to develop our model. For estimation of individual TSH/fT4 relationships a Bayesian regression model was used instead of OLS to compensate for the low number of samples and for censoring. Center: A patient without detectable TSH, naive OLS would give flat/no response. The Bayesian model gives more plausible estimate with response extending below censoring limit, slope is informed by population data. Right: Bayesian slope is less steep than naive patient specific OLS as informed by population data. fT4, free thyroxine; OLS, ordinary least squares; RCT, randomized controlled trial; TSH, thyrotropin.

FIG. 2.
FIG. 2. Study design for randomized controlled validation trial. After total thyroidectomy, the surgeon chose an LT4 starting dosage based on diagnose and clinical routine. TSH and fT4 was measured four times the next two weeks to allow early dosage adjustment. The patients were randomized to the application of a DAT or not (control) for dosage adjustments that were supervised by an experienced endocrine surgeon in either case. Eight weeks after surgery, successful dosage adjustment was evaluated based on TSH measurements. If the TSH target was not achieved, the patient continued six-week dosage adjustment cycles. DAT, decision aid tool.

FIG. 3.
FIG. 3. Output from the DAT guided the clinician to increase LT4 dosage 20 days after thyroidectomy, when the DAT was applied in this example patient (same as in Fig. 1, right). A near twofold increase in dosage is suggested to reach the target of TSH <0.10 mIU/L. The plots show the actual measurements of fT4 (A) and TSH (B) alongside the model estimates. The suggested dosages and the projected responses are also shown to facilitate evaluation from the clinician before deciding on the final dosage.

Eight weeks after surgery (i.e., 5–6 weeks after the first follow-up), blood tests were again evaluated. If the TSH target was reached, they left the study and continued follow-ups by surgeons, endocrinologists, or general practitioners, according to local routines. If the TSH target was not reached, the participants entered loops of follow-up every six weeks until the TSH target was reached (Fig. 2). On each follow-up, the DAT was applied only to the DAT group.

Outcome measures
The primary endpoint in the study was the number of patients who reached their clinically determined TSH target eight weeks after thyroidectomy. Before discharge, the surgeon assigned each patient to either substitution treatment (TSH 0.5–2.0 mIU/L), mild suppression (TSH 0.1–0.5 mIU/L), or full suppression (TSH <0.1 mIU/L and fT4 < 30 pmol/L), depending on a clinical evaluation. Usually, patients with goiter and thyrotoxicosis received substitution therapy, while patients with cancer received suppression therapy (Table 1). The secondary endpoint was the number of days from surgery to the completion of LT4 dosage adjustment.

Ethical considerations and patient consent
The study was approved by the Norwegian Regional Ethics Committee (2016/1782) and by the Swedish Ethical Review Authority (443-17). All participants, including the ones contributing to pilot data, signed a written consent form. Very few (<5%) declined the invitation to participate. Patients reported no perceived ethical dilemma participating in the study and did not receive any financial compensation.

Statistical methods and data analysis
All values are reported mean ± standard error of the mean. We used two-tailed Student's t-tests, univariate analysis of variance, and Pearson Chi-square tests for all statistics. The Markov Chain Monte Carlo model (25) is written in JAGS (26), with pre- and postprocessing in Julia (https://julialang.org). Data were collected by using Microsoft Access for the pilot study, and using REDCap for the multicenter study. Final results were exported for statistical analysis in Microsoft Excel, SPSS, and Julia. The dosage optimization was calculated by using JuMP (27) and Couenne (https://github.com/coin-or/Couenne).

Results
The DAT was tested in a validation RCT on patients diagnosed with goiter and differentiated thyroid cancer, and the simplified DAT was tested on patients with thyrotoxicosis. There was no statistical difference between the DAT and control groups in the basic characteristics of the groups, nor in the initial and final dosages of LT4 (Table 1, multiple t-tests, uncorrected p-values >0.15 for all variables). Most patients with cancer received TSH suppression, while all patients with goiter and most patients with thyrotoxicosis received replacement therapy. There was no difference in clinically decided TSH targets between DAT and controls (all patients with goiter had the same TSH target, Pearson Chi-square p = 0.58 for cancer and p = 0.61 for thyrotoxicosis).

Faster dosage adjustment with DAT in patients with goiter and cancer
For all RCT-groups together, 24 of 68 patients (35%) had reached their narrow TSH targets eight weeks after surgery if the dosage adjustment was assisted by the DAT, in contrast to 10 of 67 patients (15%) in the control group (Chi-square = 7.43, p = 0.006). As the applied DAT for thyrotoxic patients used a simplified population based fT4 target, in contrast to the individually estimated fT4 targets for patients with goiter and cancer, all further analysis was done on subgroups. Forty percent of patients with goiter and 59% of patients with cancer in DAT groups were within the TSH target after 8 weeks compared with 0% and 19% in control groups, respectively (Fig. 4A, Chi-squares 7.94, p = 0.005 and 8.87, p = 0.003). To make our results more comparable with other published dosage schemes, we also calculated the proportion of patients with goiter with TSH within the normal reference range rather than within the narrower TSH goal (0.5–2.0 mIU/L) used in the study. The r eference range was 0.2–4.3, 0.3–3.7 or 0.4–4.5 mIU/L depending on the recruiting hospital. After 8 weeks, 80% of patients with DAT had TSH values within the normal range, which was significantly higher than 19% of controls (Chi-square 9.31, p = 0.002).

FIG. 4.
FIG. 4. Number of patients (above bars) who achieved their TSH goals eight weeks after thyroidectomy and initiation of LT4 replacement therapy. (A) When the DAT was applied, more patients reached their narrow TSH goal after 8 weeks in patients treated for goiter (p = 0.005) and cancer (p = 0.003). For goiter patients, light color illustrates the proportion of patients with TSH within the normal reference range as compared with the narrower TSH target in the study (0.5–2.0 mIU/L, dark colors). (B) Dynamics of LT4 dosage adjustments and total distance to reach TSH goals. Distance to final LT4 dosage during the first 20 weeks of follow-up for patients with goiter and cancer. Light colors indicate CIs. The distance to the final dosage dropped significantly after 2 weeks in DAT groups [goiter t(15) = 3.16, p = 0.003, cancer t(27) = 3.52, p = 0.001], but not in controls (n.s.). (C) Violin plots showing time to achieve TSH targets (black dots for individual patient s). Median is indicated in white lines, and quartiles are indicated in black dotted lines. The TSH targets were reached earlier in the goiter (p = 0.016) and cancer (p = 0.017) groups that used the DAT. CI, confidence interval.

To evaluate how the DAT impacted the clinician's decision after two to three weeks, we classified the early adjustments as either in the "right direction" (toward what later became the final dosage) or in the opposite "wrong direction," or as "no change" (Table 2). For all control groups, "no change" was the preferred choice, while adjustments in the right direction was far more common than wrong direction adjustments for all groups. For statistical analysis, the difference between LT4 dosage at any timepoint and the final dosage was calculated for the first 20 weeks (Fig. 4B). After 2 weeks, clinicians made significant adjustments toward the "correct" final dosage for patients with DAT [t(65) = 3.31, p = 0.002], but not for controls [t(65) = 1.00, p = 0.32]. Subgroup analysis revealed that the effect of DAT was present in both goiter [t(15) = 3.16, p = 0.006] and cancer [t(27) = 3.52, p = 0.002] groups. The results from control gro ups indicate that the experienced clinicians were not able to make significant dose adjustments based on the TSH and fT4 values from the first two weeks without assistance of the DAT. The effect of the DAT in goiter and cancer groups was reflected in the total time to reach TSH targets (Fig. 4C). The average time to reach the TSH targets in the DAT/goiter group was 105 ± 13 days compared with 162 ± 17 days in the control/goiter group [t = t(25) = 2.59, p = 0.016]. The DAT/cancer group reached TSH targets on average 87 ± 10 days after surgery, significantly shorter than 127 ± 13 days in controls [t(49) = 2,48, p = 0.017].

Table 2. Classification of Early Dosage Adjustments

Variable Goiter Cancer Thyrotoxicosis
DAT Control DAT Control DAT Control
No adjustment 3 7 5 13 6 16
Right direction 11 6 20 8 12 8
Wrong direction 1 2 2 4 5 1
The dosage adjustments that were performed after two to three weeks, based on early blood samples after thyroidectomy, showed that less adjustments were made in control groups compared with DAT groups. Most adjustments were made in the direction of the final dosage for each patient, termed "right direction," while a few were made in the opposite "wrong direction."

No effect of population-based DAT version for thyrotoxic patients
In the thyrotoxicosis group, we could not reliably estimate individual fT4 targets due to frequent TSH suppression. Instead, we applied a simplified DAT version with a population-based fT4 target. The number of patients who reached their TSH target after 8 weeks was not different between the DAT and control groups (Fig. 5A; Chi-square 1.63, p = 0.20).

FIG. 5.
FIG. 5. Number of thyrotoxic patients (above bars) who achieved their TSH goals eight weeks after thyroidectomy and initiation of LT4 replacement therapy. (A) Application of a simplified DAT, which only used population-based fT4 targets, had no effect on the number of patients who reached their TSH target after eight weeks (p = 0.20). (B) Distance to final LT4 dosage during the first 20 weeks of follow-up for patients with thyrotoxicosis. Light colors indicate CI. Distance to final dosage was not significantly reduced in the DAT group after 2 weeks [t(21) = 0.99, p = 0.34]. (C) Violin plots for time to achieve TSH targets with black dots for individual patients. Median is indicated in white lines, and quartiles are indicated in black dotted lines. It took longer to reach the TSH targets when the simplified DAT was used, as compared with controls [t(42) = −2,96, p = 0.005].

The DAT group spent longer than controls to finalize dosage adjustment [182 ± 20 days vs. 115 ± 12 days, t(42) = −2.96, p = 0.005], indicating that clinicians were misinformed by the DAT for this group (Fig. 5B). Undetectable TSH levels was a significant problem in this group, as 16 out of 26 patients had TSH below the laboratory's detection level (0.01–0.05 mIU/L depending on hospital) preoperatively, of whom 10 remained with undetectable TSH values during blood samples the first 2 weeks. Excluding these 10 DAT patients from analysis eliminated the group difference regarding time to finalize dosage adjustment [t(34) = 1.76, p = 0.09].

To check whether the surgeons responsible for dosage adjustment followed the suggestions of the DAT, we calculated the difference between DAT suggestion and the actual prescribed dosage at the two-week follow-up. The deviation was 16.4 ± 4.6 μg/day in the thyrotoxicosis group, in contrast to 4.9 ± 2.3 μg/day in the goiter group and 7.7 ± 2.4 μg/day in the cancer group. There was a significant effect of group [one-way analysis of variance F(2,64) = 4.19, p = 0.019], and subsequent orthogonal testing revealed that the surgeons deviated significantly more from the suggested dosage in the thyrotoxicosis group compared with the two other groups [t(64) = 2.47, p = 0.016]. There was no significant difference between the goiter and cancer groups [t(64) = 1.18, p = 0.24].

Cost versus benefit
The average follow-up period in the study was 127 ± 6.4 days, or ∼18 weeks, ranging from 47 to 468 days. The average number of postoperative blood draws in this period was 6.6 ± 0.15, and the average number of follow-up visits was 3.6 ± 0.14 (Table 3). For goiter and cancer groups, the application of the DAT reduced the number of blood draws needed [t(25) = 2.47, p = 0.02 and t(50) = 3.14, p = 0.003 respectively] and the number of follow-up visits [t(25) = 2.16, p = 0.04 and t(50) = 3.15, p = 0.003] as compared with their respective controls. As our RCT did not have a control arm with an ordinary standard of care, we made a comparison with retrospective data from a similar population operated three years before the DAT study (Supplementary Table S1). Lab records from these patients showed that the average number of blood draws before the TSH targets were reached was 8.6, which is higher than for patients in the current RCT (Supplementa l Data).

Table 3. Biochemical Data

Variable Goiter Cancer Thyrotoxicosis
DAT Control DAT Control DAT Control All
TSH preoperative (mIU/L) 1.23 ± 0.2 1.13 ± 0.2 2.88 ± 0.5 2.74 ± 0.42 0.78 ± 0.31 1.37 ± 0.57 1.77 ± 0.19
TSH 8 weeks (mIU/L) 2.03 ± 0.50 4.88 ± 2.35 0.42 ± 0.24 0.50 ± 0.15 5.75 ± 1.83 1.49 ± 0.44 2.36 ± 0.49
TSH final (mIU/L) 1.16 ± 0.18 1.15 ± 0.13 0.15 ± 0.06 0.14 ± 0.03 1.17 ± 0.23 0.95 ± 0.11 0.71 ± 0.07
fT4 preoperative (pmol/L) 16.3 ± 0.6 15.1 ± 0.5 15.8 ± 0.6 16.8 ± 0.7 22.1 ± 3.4 17.8 ± 1.4 17.6 ± 0.8
fT4 8 weeks (pmol/L) 19.0 ± 1.0 20.2 ± 1.1 24.6 ± 1.0 24.3 ± 1.3 19.3 ± 1.2 19.1 ± 0.7 21.3 ± 0.5
fT4 final (pmol/L) 19.3 ± 1.0 18.0 ± 0.9 24.3 ± 0.8 22.6 ± 0.7 20.1 ± 0.9 18.3 ± 0.4 20.8 ± 0.4
No. of postoperative blood draws 5.8 ± 0.38 7.1 ± 0.40 5.8 ± 0.17 6.9 ± 0.30 7.8 ± 0.52 6.2 ± 0.27 6.6 ± 0.15
No. of postoperative visits 3.1 ± 0.31 4.1 ± 0.34 2.8 ± 0.17 3.8 ± 0.30 4.67 ± 0.48 3.3 ± 0.25 3.6 ± 0.14
Biochemical data preoperatively, after eight weeks and at the end of the study period (final), and the total number of blood draws and follow-up visits for the validation RCT (average ± SEM). The TSH reference range for TSH was 0.2–4.3, 0.3–3.7, and 0.4–4.5 mIU/L in the three recruiting hospitals. fT4 reference range was 9–22, 12–22, and 9.5–22 pmol/L.

fT4, free thyroxine; LT4, levothyroxine; SEM, standard error of the mean.

Discussion
This is the first study to suggest LT4 dosage adjustment based on repeated fT4 and TSH measurements during the first two weeks after thyroidectomy. Application of the DAT enabled the clinician to make appropriate dosage adjustments after only two weeks. It is hard to compare the performance of our model directly against other published dosage schemes, because they all use the entire TSH reference range as goal achievement (5,6), while we used a narrower TSH target also for replacement therapy. The reason we did not include TSH range >2.0 mIU/L in our targets was that high normal TSH values are associated with comorbidity (12,28–31), and to make our TSH targets more applicable to all diagnoses in the study, including cancer. The study was thus not designed to evaluate our model against other published dosage schemes, but to evaluate whether computerized modeling would allow meaningful early LT4 dose adjustments, before a steady state is reached. When recalculating our eight-week dat a for patients with goiter using the entire TSH reference range as goal achievement, we found, however, that our model outperforms other published dosage schemes. Care must be taken when interpreting these data, as the number of patients is low both in our study groups and in comparable studies.

The consequences of efficient dosage adjustments after thyroidectomy in terms of work capacity, sick leave, quality of life, or other patient-reported outcomes have to be determined before we know whether a minimum of five postoperative blood draws is acceptable. The number is comparable with routine follow-up in the first author's clinic before development of the DAT (Supplemental Data). There is, however large variation in the reported number of necessary dosage adjustments after thyroidectomy (32–34), probably reflecting that optimal care is yet to be established. We believe that the advantages of the DAT outweigh the extra cost of early blood samples, for example by reducing the number of follow-up visits and shortening the dosage adjustment period. In addition, further refinement of our model could lower the number of needed samples.

The failure of the simplified DAT to improve dosage for thyrotoxic patients suggests that individual fT4-TSH estimations are necessary to achieve successful dosage with our model. The majority of the patients in the thyrotoxicosis group had a totally suppressed TSH before surgery and were still on anti-thyroid hormone drugs. Slow recovery of normal TSH dynamics after prolonged suppression made our model vulnerable to mistakes, as it relied heavily on initial blood samples. In addition, our assumption that a log-linear relationship exists between TSH and fT4 (32–34) may not be valid for this group. The overall altered metabolism in patients with Graves' disease could also be changing during the course of follow-up, making initial estimations invalid later on.

In conclusion, application of the DAT for LT4 dosage was superior to clinician dosage adjustment in patients who were euthyroid before total thyroidectomy. Further studies should include patient-reported outcome measures and investigate whether faster dosage adjustment has direct implications for health or quality of life.

Authors' Contributions
V.H.B. and L.H. conceived the idea, developed the study design, and raised funding. L.H. and M.K. developed computational models and software. A.H.E., R.S., K.J., B.D., and R.V. collected data, and they followed up patients. A.H.E., V.H.B., and L.H. analyzed the data. V.H.B. wrote the article.

Acknowledgment
The authors thank Leif Svensson for coordinating laboratory tests and follow-up.

Author Disclosure Statement
No competing financial interests exist.

Funding Information
This work was supported by grants from Regional Research Funds North Norway (project 357035) and Northern Norway Regional Health Authority (project HNI0004-17).

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Supplementary Table S1

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© Vegard Heimly Brun, et al. 2021; Published by Mary Ann Liebert, Inc.

To cite this article:
Vegard Heimly Brun, Amund H. Eriksen, Ruth Selseth, Kenth Johansson, Renate Vik, Benedicte Davidsen, Michal Kaut, and Lars Hellemo.Thyroid.ahead of printhttp://doi.org/10.1089/thy.2021.0125
Online Ahead of Print:June 22, 2021
Online Ahead of Editing: May 12, 2021
Keywords
decision aid toollevothyroxine dosagepatient tailoredpharmacokinetic modelingthyroidectomy
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