Very Early Pulsed Dye Laser Intervention for Optimal Cosmetic Outcome in Post-Thyroidectomy Scars.

Purpose: Early intervention of surgical scars with a pulsed dye laser is known to effectively prevent pathologic scars. Despite multiple reports on the effectiveness of the treatment, very few studies have demonstrated its appropriate initiation timing. In this study, our objective was to determine the optimal timing for initiating laser treatment following thyroidectomy. Methods: This study retrospectively analyzed 91 patients undergoing pulsed dye laser treatment post-thyroidectomy, grouping them by treatment initiation timing. The patients underwent treatment at intervals of 3-4 weeks with at least five sessions. Those with a high pliability score were injected with intralesional corticosteroids. The Antera 3D® skin imaging analyzer was used to assess biophysical parameters. Results: The total Vancouver Scar Scale score significantly reduced after treatment in all groups. The Vancouver Scar Scale score reduction rate was significantly higher after treatment in the group for which the treatment was initiated within 3 weeks of surgery. The pigmentation and erythema score analyzed by Antera 3D® was also lower in this group. Conclusion: Early intervention using a pulsed dye laser within 3 weeks of thyroidectomy can substantially inhibit pathological scar development, providing physicians with a guide for optimal treatment commencement.

Effect of withdrawal of thyroid hormones versus administration of recombinant human thyroid-stimulating hormone on renal function in thyroid cancer patients.

This study was conducted to investigate the effects of thyroid hormone withdrawal (THW) and recombinant human thyroid-stimulating hormone (rhTSH) administration on renal function in patients with thyroid cancer after total thyroidectomy. This study included 202 patients who discontinued thyroid hormone therapy and/or received rhTSH after total thyroidectomy. Creatinine (Cr), blood urea nitrogen (BUN) levels, and estimated glomerular filtration rate (eGFR) were assessed at the following three time points: before thyroidectomy, at least 3 weeks after THW, and 1 day after the second injection of rhTSH. The median serum Cr level was significantly higher following THW compared to that before thyroidectomy (0.95 versus 0.70). In contrast, the median BUN level was significantly lower after THW compared to that before thyroidectomy (9.8 versus 11.3). Over a fifth (22.2%) of patients had abnormal eGFR values after THW, which was significantly greater than that before thyroidectomy. In contrast, renal parameter values after rhTSH administration were not significantly different than those before thyroidectomy. In conclusion, THW affects renal function in patients with thyroid cancer who have undergone total thyroidectomy. However, renal function in such patients is not affected by rhTSH administration.

Photobiomodulation therapy with an 830-nm light-emitting diode for the prevention of thyroidectomy scars: a randomized, double-blind, sham device-controlled clinical trial.

This randomized, double-blind, and sham device-controlled trial aimed to evaluate the efficacy and safety of home-based photobiomodulation therapy using an 830-nm light-emitting diode (LED)-based device for the prevention of and pain relief from thyroidectomy scars. Participants were randomized to receive photobiomodulation therapy using an LED device or a sham device without an LED from 1 week postoperatively for 4 weeks. Scars were assessed using satisfaction scores, the numeric rating scale (NRS) score for pain, Global Assessment Scale (GAS), and Vancouver Scar Scale (VSS) scores. The scars were also assessed using a three-dimensional (3D) skin imaging device to detect color, height, pigmentation, and vascularity. Assessments were performed at the 1-, 3-, and 6-month follow-ups. Forty-three patients completed this trial with 21 patients in the treatment group and 22 patients in the control group. The treatment group showed significantly higher patient satisfaction and GAS scores and lower NRS and VSS scores than the control group at 6 months. Improvements in color variation, height, pigmentation, and vascularity at 6 months were greater in the treatment group than in the control group, although the differences were not significant. In conclusion, early application of 830-nm LED-based photobiomodulation treatment significantly prevents hypertrophic scar formation and reduces postoperative pain without noticeable adverse effects.

Suspicious thyroid nodules 4 cm require a diagnostic lobectomy regardless of their benign fine needle aspiration results.

BACKGROUND/OBJECTIVE: The diagnostic accuracy of fine needle aspiration biopsy (FNAB) seems limited in large thyroid nodules with Bethesda Cat. 2 result. We aimed to determine the incidence of carcinoma with benign cytology and the reason for the high false-positive rate in thyroid nodules ≥4 cm. METHODS: The records of 103 patients with thyroid nodules ≥4 cm with preoperative cytological diagnosis of Bethesda Cat. 2 who underwent thyroidectomy were consecutively reviewed. Characteristics between patients with malignant vs. benign pathology were compared. RESULTS: Forty patients (38.8%) had malignancy. Malignancy was subclassified into follicular variant of papillary thyroid carcinoma (43%), minimally invasive follicular thyroid carcinoma (20.0%), and minimally invasive Hurthle cell thyroid carcinoma (10.9%). Patients with malignant cytology had significantly more suspicious ultrasound findings than those with benign cytology (p = 0.001). CONCLUSIONS: Preoperative FNAB showed high false-negative rates in patients with thyroid nodules ≥4 cm with benign cytology. These nodules have a high malignancy rate with suspicious ultrasound findings.

Presence of TERT ± BRAF V600E mutation is not a risk factor for the clinical management of patients with papillary thyroid microcarcinoma.

BACKGROUND: The management of papillary thyroid microcarcinomas with TERT ± BRAF V600E mutations remains controversial owing to their potential associations with tumor aggressiveness. This study evaluated the clinical implications of these mutations in management of patients with papillary thyroid microcarcinomas. METHODS: Between June 2019 and October 2020, surgical specimens from 504 consecutive patients with papillary thyroid microcarcinomas were obtained at a tertiary hospital. The mutation statuses of TERT promoter and BRAF V600E were assessed by polymerase chain reaction. The prevalence and relationships of TERT ± BRAF V600E mutations with clinical, radiological, and pathological characteristics were evaluated. RESULTS: Of 504 patients with papillary thyroid microcarcinomas, TERT ± BRAF V600E mutations were found in 3.2% (16/504). Of these 16 patients, 93.8% (15/16) of papillary thyroid microcarcinomas with TERT promoter mutations also harbored BRAF V600E mutations. Correlation analysis showed that TERT ± BRAF V600E mutations were not associated with aggressive clinical, radiological, or pathological features (P > .05). The presence of lymph node metastasis was not associated with mutation status (P = .834). CONCLUSION: TERT ± BRAF V600E mutations in patients with papillary thyroid microcarcinomas are not associated with any unfavorable clinicopathological features, including lymph node metastasis status.

Reoperations for structurally persistent or recurrent disease after thyroidectomy: analysis via preoperative CT.

The incidence rates of structural persistent disease (PD) and recurrent disease (RD) after thyroidectomy, and their clinicoradiological (CT) characteristics, remain poorly understood. Therefore, we characterized differentiated thyroid cancer (DTC) patients who underwent re-operations, with a focus on preoperative CT scans. We examined neck CT scans obtained prior to initial surgery and reoperation, and classified the disease into four categories according to the persistence/recurrence and neck dissection/non-dissection status. In total, 121 of 9,173 DTC patients underwent reoperations to treat PD or RD; the mean time to reoperation was 25.5 and 54.1 months, respectively. Of all reoperations, 19% (23/121) were performed to treat RD; 81% (98/121) were performed to treat PD. Compared to RD, PD was commonly detected in the non-dissected neck. Tumor multiplicity and the number of pathologically positive lymph nodes were greater in the non-dissected than dissected neck. A review of the CT data revealed more false-negative findings on the 60-s- versus 30-40-s-delay scans of PD patients with non-dissected necks. In conclusion, most of the reoperations performed on DTC patients were for management of PD. Improved preoperative CT assessments and initial surgery, based on the information of clinico-radiological characteristics, are required in the care of DTC patients.

Author Correction: Transcription Factor HOXA9 is Linked to the Calcification and Invasion of Papillary Thyroid Carcinoma.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

The Association Between Chronic Lymphocytic Thyroiditis and the Progress of Papillary Thyroid Cancer.

BACKGROUND: Whether chronic lymphocytic thyroiditis (CLT) influences the risk of development and the progression of papillary thyroid cancer (PTC) remains uncertain. We investigated the effects of CLT on the clinicopathologic features and prognosis of PTC. METHODS: Two thousand nine hundred twenty-eight consecutive patients with PTC treated between 2009 and 2017 were divided into two groups: one with chronic lymphocytic thyroiditis and one without; 1174 (40%) of the patients had coincident CLT. RESULTS: In univariate analysis, CLT correlated positively with small tumor size, frequent extrathyroidal extension, multifocal diseases, and p53 but negatively with central lymph node (LN) metastasis and BRAF mutation. In multivariate analysis, CLT was associated with extrathyroidal extension and multifocal disease; however, it was not a prognostic factor for recurrence even though it was associated with two aggressive factors. Compared with patients with PTC alone, there were more retrieved central LNs in the PTC + CLT group, and these patients also underwent more invasive diagnostic tests such as fine needle aspiration cytology and frozen biopsy of LN. CONCLUSIONS: The CLT patients with PTC had better behavior features and prognoses than did those with PTC alone despite frequent multifocality and extrathyroidal extension. However, precaution may be necessary to avoid performing invasive diagnostic procedures for lateral LN metastasis and to manage the patients appropriately.

Can the basal serum thyroglobulin level be used to predict the recombinant human TSH-stimulated thyroglobulin level in differentiated patients with thyroid cancer?

This study investigated the correlation between basal thyroglobulin (Tg) and recombinant human thyroid-stimulating hormone (rhTSH)-stimulated Tg in differentiated patients with thyroid cancer, and sought to determine whether the basal Tg level predicts the rhTSH-stimulated Tg level.We retrospectively enrolled 177 patients with papillary thyroid cancer (mean age = 44 years; 50 males, 127 females) who received rhTSH before radioiodine therapy (RIT). Serum Tg levels were measured 7 days before the 1st rhTSH injection (basal Tg) and on the days of RIT (rhTSH-stimulated Tg). Patients were divided into 3 groups according to rhTSH-stimulated Tg cut-off levels of 2, 5, and 10 ng/mL. The correlation between basal Tg and rhTSH-stimulated Tg levels was assessed, and whether basal Tg was useful in predicting the rhTSH-stimulated Tg level was determined.A significant positive correlation was observed between basal and rhTSH-stimulated Tg levels (|rho| = 0.48, P < .0001). The basal Tg level had significant diagnostic ability in predicting an rhTSH-stimulated Tg level of 2 ng/mL or higher, and the optimal basal Tg level for this prediction was 0.3 ng/mL (AUC = 0.77, P < .0001). A basal Tg level of 0.5 ng/mL was optimal for predicting rhTSH-stimulated Tg levels of 5 ng/mL or higher (AUC = 0.81, P < .0001), and of 10 ng/mL or higher (AUC = 0.82, P = .0171).The basal Tg level was significantly correlated with the rhTSH-stimulated Tg level. If the basal Tg level is >0.3 or 0.5 ng/mL, then the rhTSH-stimulated Tg level can be expected to be sufficiently high to necessitate clinical examination.

Transcription Factor HOXA9 is Linked to the Calcification and Invasion of Papillary Thyroid Carcinoma.

Calcification is important for the diagnosis of papillary thyroid carcinoma (PTC). Runt-related transcription factor 2 (RUNX2), a master transcription factor associated with osteogenic differentiation, is reportedly related to PTC calcification and invasiveness. However, its regulatory role in this process is somewhat uncharacterized. Here, we attempted to identify genes that regulate RUNX2 and clarify its function in PTC carcinogenesis and calcification. The expression of RUNX2-upstream genes was evaluated by real-time PCR in Nthy-Ori 3-1 normal thyroid cells and TPC1 and BHP10-3 PTC cell lines. Luciferase and chromatin immunoprecipitation assays were performed with candidate genes after cloning the RUNX2 promoter. We found that RUNX2 promoter activity was enhanced by homeobox family A9 (HOXA9). Over-expression of HOXA9 was found to enhance alkaline phosphatase activity, mineralization, and in vitro tumour cell migration and invasion, whereas downregulation had the opposite effects. These results indicate that HOXA9, a positive regulator of RUNX2, can enhance calcification, migration, and invasion in PTC. Our data improve the understanding of the molecular mechanisms of microcalcification in PTC as well as tumorigenesis.

BRAFwild papillary thyroid carcinoma has two distinct mRNA expression patterns with different clinical behaviors.

BACKGROUND: Using a large set of genomic data from The Cancer Genome Atlas (TCGA), we classified BRAFwild papillary thyroid carcinomas (PTCs) into 2 subtypes with distinct molecular patterns and different clinical behaviors. We also suggested gene signatures (RAS-score) to predict molecular subtypes and clinical behaviors of BRAFwild PTC. METHOD: Integrated genomic analysis was done using all genomic data of PTC in TCGA data portal (https://tcga-data.nci.nih.gov) and cancer browser (https://genome-cancer.ucsc.edu). Using Gene Ontology and a logistic regression test, we selected gene signatures (RAS-score) and applied this prediction model to the validation cohort (GSE60542). RESULT: When we performed multiplatform genomic analysis, BRAFwild PTCs were divided into 2 molecular subtypes. Each subtype showed distinct molecular patterns and clinical behaviors. Gene signatures successfully predicted molecular subtype in another validation cohort. CONCLUSION: We found that BRAFwild PTCs were divided into 2 molecular subtypes and each subtype showed distinct molecular patterns, different activated pathways, and different clinical behaviors.

Synergistic Activity of N-hydroxy-7-(2-naphthylthio) Heptanomide and Sorafenib Against Cancer Stem Cells, Anaplastic Thyroid Cancer.

Anaplastic thyroid carcinoma (ATC) although rare is the most deadly form of thyroid cancer. The fatality rate for ATC is high-pitched, the survival rate at 1 year after diagnosis is <20%. Control of ATC is severely hard and widespread with unpredictability. We Previous proved that histone gene reviser and epigenetic changes role significant parts in papillary and anaplastic thyroid cancer tumorigenesis. Herein, the goal of this study was to investigate the anti-tumor activities of a HDAC inhibitor, HNHA alone and in combination with sorafenib in ATC cells in vitro and in vivo and to explore its effects on apoptotic cell death pathways. Three ATC cell lines were exposed to sorafenib in the presence or absence of HNHA, and cell viability was determined by MTT assay. Effects of combined treatment on cell cycle and intracellular signaling pathways were assessed by flow cytometry and western blot analysis. The ATC cell lines xenograft model was used to examine the anti-tumor activity in vivo. Our data showed that HNHA and sorafenib synergistically decreased cell viability in ATC cells, and also significantly increased apoptotic cell death in these cells, as proved by the cleavage of caspase-3 and DNA fragmentation. HNHA and sorafenib combination was reduced anti-apoptotic factor in ATC. Thus, combination therapy with HNHA and sorafenib significantly decreased vessel density, and most significantly reduced tumor volume and increased survival in ATC xenografts. These results propose that HNHA in combination with sorafenib has significant anti-cancer activity in preclinical models, potentially suggesting a new clinical approach for patients of advanced thyroid cancer type.

Clinical Experience With n-Butyl-2-Cyanoacrylate in Performing Lateral Neck Dissection for Metastatic Thyroid Cancer.

Background Chyle leakage following lateral neck dissection (LND) is rare, but can induce metabolic disturbances, delay wound healing, and prolong hospitalization. n-Butyl-2-cyanoacrylate (NBCA) has been used to achieve hemostasis and seal tissues in several surgical settings. We here assessed whether application of NBCA to the thoracic duct area is effective in sealing chyle leakage. Methods The medical records of 163 patients who underwent total thyroidectomy with unilateral LND between March 2011 and September 2012 were reviewed. NBCA was applied to 84 patients and not applied to 79. Drainage volume, duration of hospital stay, and incidence of complications were compared between the 2 groups. Results The 2 groups were not different with regard to age, body weight, gender, primary tumor histology, and number of lateral neck nodes harvested. Mean hospital stay was significantly shorter (4.3 ± 1.8 vs 5.7 ± 3.0 days, P < .001), median total drainage volume was significantly smaller (270 mL; range: 97-931 mL vs 328 mL; range: 113-2636 mL; P < .001), and rate of chyle leakage was significantly lower (0% vs 6.3%, P = .025) in the NBCA than in the non-NBCA group. Conclusion NBCA application to the dissected area of the thoracic duct posterior to its angle of junction with the internal jugular and subclavian veins could be safe and effective in reducing surgical complications related to chyle leakage after LND.

Thyroidectomy without lateral neck dissection for papillary thyroid carcinoma with lateral neck lymph node metastases and negative intraoperative frozen section.

BACKGROUND: The purpose of this study was to investigate the outcomes of patients with papillary thyroid cancer (PTC) with lateral neck metastasis according to their permanent pathology report but negative frozen section findings who did not undergo lateral neck dissection. METHODS: Between September 2009 and December 2011, 575 patients at Gangnam Severance Hospital (Seoul, Korea) underwent frozen section analysis for a suspicious lateral neck lymph node. In 16 patients, the intraoperative findings were negative, but lateral neck metastasis was diagnosed on the basis of permanent pathology findings. The outcomes of these patients who underwent thyroidectomy but not lateral neck dissection were retrospectively investigated. RESULTS: One patient underwent a subsequent lateral neck dissection. After a mean (SD) follow-up period of 42.1 (8.5) months, none of the patients had distant metastasis. CONCLUSION: Total thyroidectomy with subsequent lateral neck dissection is not necessary in patients with PTC who are diagnosed with lateral neck metastasis according to their permanent pathology report but have negative intraoperative frozen section findings.

Potential anti-cancer effect of N-hydroxy-7-(2-naphthylthio) heptanomide (HNHA), a novel histone deacetylase inhibitor, for the treatment of thyroid cancer.

BACKGROUND: Thyroid cancer has been indicated to have a higher global proportion of DNA methylation and a decreased level of histone acetylation. Previous studies showed that histone gene reviser and epigenetic changes role significant parts in papillary and anaplastic thyroid cancer tumorigenesis. The goal of this research was to study the endoplasmic reticulum (ER) stress-mediated actions of the dominant histone deacetylase (HDAC) inhibitor, N-hydroxy-7-(2-naphthylthio) hepatonomide (HNHA), in thyroid cancer and to explore its effects on apoptotic cell death pathways. METHODS: Experiments were achieved to conclude the effects of HNHA in papillary thyroid cancer (PTC) and anaplastic thyroid cancer (ATC) cell lines and xenografts, as compared with two other established HDAC inhibitors (SAHA; suberoylanilide hydroxamic acid and TSA; trichostatin A). RESULTS: Apoptosis, which was induced by all HDAC inhibitors, was particularly significant in HNHA-treated cells, where noticeable B-cell lymphoma-2 (Bcl-2) suppression and caspase activation were observed both in vitro and in vivo. HNHA increased Ca(2+) release from the ER to the cytoplasm. ER stress-dependent apoptosis was induced by HNHA, suggesting that it induced caspase-dependent apoptotic cell death in PTC and ATC. PTC and ATC xenograft studies demonstrated that the antitumor and pro-apoptotic effects of HNHA were greater than those of the established HDAC inhibitors. These HNHA activities reflected its induction of caspase-dependent and ER stress-dependent apoptosis on thyroid cancer cells. CONCLUSIONS: The present study indicated that HNHA possibly provide a new clinical approach to thyroid cancers, including ATC.

Diagnostic Thyroidectomy May Be Preferable in Patients With Suspicious Ultrasonography Features After Cytopathology Diagnosis of AUS/FLUS in the Bethesda System.

Atypia/follicular lesion of undetermined significance (AUS/FLUS) is a new category in the Bethesda System for Reporting Thyroid Cytopathology (BSRTC) for which repeat fine-needle aspiration cytology (FNAC) is recommended. The aim of this study was to identify specific ultrasonography and clinical predictors of malignancy in a subset of thyroid nodules associated with cytology diagnoses of AUS/FLUS.Between January 2011 and December 2102, 5440 patients underwent thyroid surgery at our institution. Of these, 213 patients were diagnosed AUS/FLUS at the preoperative cytopathology diagnosis. The frequency of FNAC and ultrasonography images was compared between patients with cancerous and benign tumors based on their final pathology.Of the 213 patients, 158 (74.2%) were diagnosed with thyroid carcinoma in their final pathology reports. In univariate and multivariate analyses, the frequency of FNAC was not significantly correlated with the cancer diagnosis. Hypoechogenicity (odds ratio 2.521, P = 0.007) and microcalcification (odds ratio 3.247, P = 0.005) were statistically correlated with cancer risk.Although AUS/FLUS in cytopathology is recommended for repeating FNAC in BSRTC, we proposed that thyroid nodules with ultrasonography findings that suggest the possibility of cancer should undergo thyroidectomy with diagnostic intent.

Recovery from Permanent Hypoparathyroidism After Total Thyroidectomy.

BACKGROUND: Permanent hypoparathyroidism after total thyroidectomy is a rare but potentially serious iatrogenic complication. The aim of this study was to investigate the rate of recovery from postoperative, permanent hypoparathyroidism in patients undergoing thyroidectomy without parathyroid autotransplantation. METHODS: This study was a prospective case series with a postoperative follow-up of up to 3 years. We enrolled patients with thyroid cancer who underwent total thyroidectomy with central compartment dissection, with or without lateral neck dissection, and who had postoperative permanent hypoparathyroidism, defined as serum levels of intact parathyroid hormone (PTH) <15 pg/mL for at least 1 year. In the postoperative follow-up period, the serum levels of PTH and calcium were measured regularly. Recovery from permanent hypoparathyroidism was defined as return to normal serum levels of PTH (15-65 pg/mL) and calcium (8.5-10.1 mg/dL) without calcium and/or vitamin D supplementation. RESULTS: In the 1467 patients who underwent total thyroidectomy, 22 presented with permanent postoperative hypoparathyroidism. In 5 of these 22 patients, the PTH levels increased steadily and returned to normal in 27.6±2.9 months, after which supplementation of calcium and vitamin D could be discontinued. CONCLUSIONS: Although recovery from permanent hypoparathyroidism is rare, patients should be monitored for serum PTH levels so that unnecessary treatments such as calcium and vitamin D supplementation can be avoided.