Golgi export of the Kir2.1 channel is driven by a trafficking signal located within its tertiary structure.

Mechanisms that are responsible for sorting newly synthesized proteins for traffic to the cell surface from the Golgi are poorly understood. Here, we show that the potassium channel Kir2.1, mutations in which are associated with Andersen-Tawil syndrome, is selected as cargo into Golgi export carriers in an unusual signal-dependent manner. Unlike conventional trafficking signals, which are typically comprised of short linear peptide sequences, Golgi exit of Kir2.1 is dictated by residues that are embedded within the confluence of two separate domains. This signal patch forms a recognition site for interaction with the AP1 adaptor complex, thereby marking Kir2.1 for incorporation into clathrin-coated vesicles at the trans-Golgi. The identification of a trafficking signal in the tertiary structure of Kir2.1 reveals a quality control step that couples protein conformation to Golgi export and provides molecular insight into how mutations in Kir2.1 arrest the channels at the Golgi.

Risk of cardiovascular disease associated with long-term use of non-steroidal anti-inflammatory drugs in ankylosing spondylitis.

OBJECTIVE: To examine the risk of cardiovascular disease associated with long-term use of non-steroidal anti-inflammatory drugs (NSAIDs) in a large real-world ankylosing spondylitis (AS) cohort. METHODS: This nationwide population-based cohort study used data from the Korean National Health Insurance Database. Patients aged ≥18 years old who were newly diagnosed with AS without prior cardiovascular disease between January 2010 and December 2018 were included in this study. Controls without AS were randomly selected by age, sex, and index year. The primary outcome was cardiovascular disease, a composite outcome of ischemic heart disease, stroke, or congestive heart failure. Long-term use of NSAIDs was defined as use of NSAIDs for >365 cumulative defined daily doses. The association between long-term use of NSAIDs and incident cardiovascular disease was examined in both AS and non-AS populations. RESULTS: Among 19 775 patients with AS and 59 325 matched controls without AS, there were 1,663 and 4,308 incident cases of cardiovascular disease, showing an incidence of 16.9 and 13.8 per 1,000 person-years, respectively. Long-term use of NSAIDs was associated with increased risk of cardiovascular disease in non-AS controls (adjusted hazard ratio [aHR], 1.64; 95% CI, 1.48-1.82). In contrast, long-term use of NSAIDs did not increase the risk of cardiovascular disease in AS patients (aHR, 1.06; 95% CI, 0.94-1.20; adjusted for age, sex, socioeconomic status, body mass index, smoking status, hypertension, diabetes, hyperlipidemia, and tumor necrosis factor inhibitor use). CONCLUSION: Prolonged NSAID treatment in AS patients may not be as harmful as in the general population regarding cardiovascular risk.

Atheroma-Relevant 7-Oxysterols Differentially Upregulate Cd14 Expression.

The expression of CD14 in monocytic cells is elevated in atherosclerotic lesions where 7-oxyterols are abundant. However, it remains unknown whether atheroma-relevant 7-oxysterols are involved in receptor expression. Therefore, we investigated the effects of 7α-hydroxycholesterol (7αOHChol), 7ß-hydroxycholesterol (7ßOHChol), and 7-ketocholesterol (7K) on CD14 levels in THP-1 cells. The three 7-oxysterols increased CD14 transcript levels at a distinct time point, elevated cellular CD14 protein levels, and promoted the release of soluble CD (sCD14) from THP-1 cells. Our data revealed that CD14 expression was most strongly induced after treatment with 7αOHChol. Moreover, 7αOHChol alone upregulated membrane-bound CD14 levels and enhanced responses to lipopolysaccharides, as determined by CCL2 production and monocytic cell migration. The 7-oxysterols also increased the gelatinolytic activity of MMP-9, and a cell-permeable, reversible MMP-9 inhibitor, MMP-9 inhibitor I, significantly impaired sCD14 release. These results indicate that 7-oxysterols differentially induce CD14 expression in vascular cells and contribute to the monocytic cell expression of CD14 via overlapping, but distinct, mechanisms.

A Case of Diffuse Thyroid Hematoma after Ultrasound-Guided Fine Needle Aspiration.

Ultrasound-guided fine needle aspiration is an easy, safe, and efficient method of diagnosing thyroid diseases. Recent guidelines and studies have demonstrated that this test has a low incidence of complications; thus, most guidelines do not provide recommendations for post-exam care. However, the risk of serious and fatal bleeding in selected patients with bleeding tendency exists. Although screening tests for coagulation are not always necessary, a thorough assessment of past medical history needs to be made to identify disorders affecting coagulation function and bleeding risk factors, such as the use of antithrombotic drugs. This is a case report of a 70-year-old female patient who continued to take edoxaban and suffered bilateral thyroid hematoma a few hours after ultrasound-guided thyroid fine needle aspiration. The patient successfully recovered after undergoing conservative treatment.

Development of an Accurate and Sensitive Diagnostic System Based on Conventional PCR for Detection of African Swine Fever Virus in Food Waste.

African swine fever virus (ASFV), a highly contagious virus, can cause diseases with high mortality rates in pigs, making it a pathogen of social and economic significance. ASFV has been reported to show potential long-term survival in living livestock, such as pigs, but also in leftover cooking meat and undercooked pork meat. Hence, it is possible that there could be direct reinfection or secondary infection through feed produced from household food waste and treatment facilities. Many polymerase chain reaction (PCR)-based molecular diagnostic techniques to detect ASFV in clinical swine samples have been reported. However, those with applicability for food waste samples, which contain relatively low viral copy numbers and may contain various unknown inhibitors of PCR, are still lacking. In this study, we developed a conventional PCR-based diagnostic system that can detect ASFV with high sensitivity from food waste sample types. The technique shows a 10-100 times higher limit of detection compared to that of previously reported methods based on conventional PCR and quantitative real-time PCR. It is also capable of amplifying a sequence that is approximately 751 nucleotides, which is advantageous for similarity analysis and genotyping. Moreover, a ASFV-modified positive material different from ASFV that could synthesize 1400 nucleotide amplicons was developed to identify false-positive cases and thus enhance diagnostic accuracy. The method developed herein may be applicable for future ASFV monitoring, identification, and genotyping in food waste samples. Supplementary Information: The online version contains supplementary material available at 10.1007/s12088-022-01007-y.

27-Hydroxycholesterol induces macrophage gene expression via LXR-dependent and -independent mechanisms.

27-Hydroxycholesterol (27OHChol) exhibits agonistic activity for liver X receptors (LXRs). To determine roles of the LXR agonistic activity in macrophage gene expression, we investigated the effects of LXR inhibition on the 27OHChol-induced genes. Treatment of human THP-1 cells with GSK 2033, a potent cell-active LXR antagonist, results in complete inhibition in the transcription of LXR target genes (such as LXRα and ABCA1) induced by 27OHChol or a synthetic LXR ligand TO 901317. Whereas expression of CCL2 and CCL4 remains unaffected by GSK 2033, TNF-α expression is further induced and 27OHChol-induced CCL3 and CXCL8 genes are suppressed at both the transcriptional and protein translation levels in the presence of GSK 2033. This LXR antagonist downregulates transcript levels and surface expression of CD163 and CD206 and suppresses the transcription of CD14, CD80, and CD86 genes without downregulating their surface levels. GSK 2033 alone had no effect on the basal expression levels of the aforementioned genes. Collectively, these results indicate that LXR inhibition leads to differential regulation of 27-hydroxycholesterolinduced genes in macrophages. We propose that 27OHChol induces gene expression and modulates macrophage functions via LXR-dependent and -independent mechanisms.

Simple differentiation method using FBS identifies DUSP6 as a marker for fine-tuning of FGF-ERK signaling activity in human pluripotent stem cells.

Assessment of differentiation potential is a basic requirement to obtain qualified human pluripotent stem cells (hPSCs). Here, we report a simple differentiation method using fetal bovine serum (FBS) to estimate differentiation potential and propensity of hPSCs. PluriTest using RNA-sequencing showed that cells differentiated after treatment with 5% FBS. Expression patterns of three germ layer markers revealed that cells cultured in Knockout Serum Replacement-containing medium (KSR) with mouse feeder cells had higher differentiation potential than cells cultured in a chemically defined medium (E8) with recombinant matrix proteins, especially into the mesoderm and endoderm lineages. Analysis of differentially expressed genes between KSR and E8 identified DUSP6 as a marker for where cells had been cultured. Expression of DUSP6 correlated with FGF-ERK signaling activity. Fine-tuning of FGF-ERK signaling activity to a range that can shut down DUSP6 transcription but sustain NANOG transcription partially increased the differentiation potential. Our data suggest that differentiation with 5% FBS is good to estimate differentiation potential and propensity at the early stage, and that DUSP6 is an excellent marker to monitor ERK signaling activity.

"New classification of late and delayed complications after dermal filler: Localized or Generalized?"

Background: As filler injections have become very common procedures worldwide, the number of complications has increased. However, there is a lack of systematized studies and precise classification of late and delayed complications. This study aimed to suggest new and reliable classifications and to characterize the clinical manifestations of late and delayed complications after filler injections.Methods: This retrospective study analyzed patients and suggested a new classification of delayed adverse effects related to filler injection. Several demographic and clinical findings were analyzed. Patients were classified into two types according to their clinical presentation: Type I (Localized) or Type II (Generalized).Results: Twenty-five patients were evaluated during a clinically active adverse event suspected to be related to fillers. The most common injected filler substance was hyaluronic acid (HA, 68.8%). 76% of the patients were classified with Localized complications. In the Generalized complications group, systemic symptoms were more common (p=0.002), the treatment response was poor (p=0.010), and fewer patients showed complete remission (p=0.007) than in the Localized complications group.Conclusions: We propose a simple new classification method for late and delayed complications after dermal filler: Localized and Generalized. We expect that this new classification could help provide appropriate treatment and predict patient prognosis.

Randomized trial of prophylactic ipsilateral central lymph node dissection in patients with clinically node negative papillary thyroid microcarcinoma.

PURPOSE: This study aimed to evaluate the role of prophylactic ipsilateral central neck dissection (pCND) in patients with clinically node-negative (cN0) papillary thyroid microcarcinoma (PTMC). METHODS: In this randomized control trial, a total of 164 consecutive patients were enrolled. By double-blinded randomization protocol, patients were allocated into hemithyroidectomy with pCND (n = 82) or without pCND (n = 82). With intention-to-treat analysis, post-surgical pathological and clinical course, surgery-related complications, causes and clinical course of protocol-violated cases and 5-year recurrence-free survival were compared. RESULTS: Operation time, hospital stay, and post-surgical complication were not significantly different between the two groups. In the pCND (+) group, occult lymph node metastasis rate was 50.0%, and lymph node ratio (metastatic/harvested lymph nodes) was 45.2%. Ten patients in the pCND (+) group had converted to undergo onsite or staged completion total thyroidectomy due to the presence of metastatic central lymph nodes and/or positive resection margin. Until last follow-up (mean 73.4 months), one regional recurrence developed in the pCND (-) group, and three regional recurrences occurred in the pCND (+) group. Five-year recurrence-free survival was similar between the two groups. CONCLUSION: Although ipsilateral pCND could clear occult lymph node metastasis in the central compartment, it failed to provide any oncological benefit for cN0 PTMC patients.

The endosomal trafficking factors CORVET and ESCRT suppress plasma membrane residence of the renal outer medullary potassium channel (ROMK).

Protein trafficking can act as the primary regulatory mechanism for ion channels with high open probabilities, such as the renal outer medullary (ROMK) channel. ROMK, also known as Kir1.1 (KCNJ1), is the major route for potassium secretion into the pro-urine and plays an indispensable role in regulating serum potassium and urinary concentrations. However, the cellular machinery that regulates ROMK trafficking has not been fully defined. To identify regulators of the cell-surface population of ROMK, we expressed a pH-insensitive version of the channel in the budding yeast Saccharomyces cerevisiae We determined that ROMK primarily resides in the endoplasmic reticulum (ER), as it does in mammalian cells, and is subject to ER-associated degradation (ERAD). However, sufficient ROMK levels on the plasma membrane rescued growth on low-potassium medium of yeast cells lacking endogenous potassium channels. Next, we aimed to identify the biological pathways most important for ROMK regulation. Therefore, we used a synthetic genetic array to identify non-essential genes that reduce the plasma membrane pool of ROMK in potassium-sensitive yeast cells. Genes identified in this screen included several members of the endosomal complexes required for transport (ESCRT) and the class-C core vacuole/endosome tethering (CORVET) complexes. Mass spectroscopy analysis confirmed that yeast cells lacking an ESCRT component accumulate higher potassium concentrations. Moreover, silencing of ESCRT and CORVET components increased ROMK levels at the plasma membrane in HEK293 cells. Our results indicate that components of the post-endocytic pathway influence the cell-surface density of ROMK and establish that components in this pathway modulate channel activity.

Midazolam Premedication Facilitates Mask Ventilation During Induction of General Anesthesia: A Randomized Clinical Trial.

BACKGROUND: During induction of general anesthesia, proper mask ventilation is crucial for supplying sufficient oxygen to unconscious patients. Midazolam has a relaxing effect on airway muscles. We hypothesized that sedative premedication with midazolam would facilitate mask ventilation during anesthetic induction. METHODS: Patients undergoing elective surgery under general anesthesia were randomized into 2 groups. The midazolam group received midazolam premedication at the reception area, 3 minutes before transfer to the operating room. Patients in the control group were treated with normal saline as a placebo. The primary outcome was difficulty of mask ventilation during induction, as evaluated using the Warters scales. RESULTS: A total of 97 patients completed the analysis: 49 in the control group and 48 in the midazolam group. The patients in the midazolam group showed a significantly lower mask ventilation difficulty score on the Warters scale than that of the control group (mean [standard deviation], 0.92 [1.13] vs 0.19 [0.57]; estimated difference [95% confidence interval], 0.73 [0.37-1.09]; P < .001). The incidence of difficult mask ventilation (≥2 Warters scale) was significantly lower in the midazolam group than in the control group (risk ratio [95% confidence interval], 0.15 [0.03-0.72]; P = .015). CONCLUSIONS: This randomized clinical trial demonstrated that midazolam premedication enhanced mask ventilation during induction of general anesthesia.

Needle-free pneumatic injection device; histologic assessment using a rat model and parameter comparison in predicting collagen synthesis degree.

BACKGROUND: Needle-free pneumatic injections have been recently introduced to the field of dermatology to inject such substances as hyaluronic acid. However, data on the influence of various pneumatic injection parameters on collagen synthesis are lacking. OBJECTIVE: Compare the effect of diameter, pressure, and volume of a pneumatic injection jet on collagen synthesis and fluid dispersion pattern using a rat model. Investigate if the total work force of the injection jet is useful in predicting the degree of collagen synthesis. MATERIALS AND METHODS: We injected fluid with 1 mg/ml of hyaluronic concentration to adult rats. Different injection pressures and volumes were tested using devices with nozzles of different diameters. Collagen synthesis areas were then measured, and statistical analyses were performed. RESULTS: The area of collagen fibers increased for up to two months. The injection pressure and volume did not correlate with the degree of collagen synthesis. The nozzle diameter showed a significant after two and four weeks of injection. The total work force correlated with collagen synthesis 2, 4, and 8 weeks post-injection. (P = 0.043, 0.027, and 0.000, respectively). CONCLUSION: Collagen formation is more prominent 2 months post-hyaluronic acid injection than after 1 month when using a needle-free pneumatic injection device. The total work force, which is affected by both the nozzle diameter and injection pressure, can be helpful in predicting the degree of collagen synthesis. Lasers Surg. Med. 51:278-285, 2019. © 2019 Wiley Periodicals, Inc.

Prospective Evaluation of Atrophic Acne Scars on the Face With Needle-Free High-Pressure Pneumatic Injection: Quantitative Volumetric Scar Improvement.

BACKGROUND: Atrophic acne facial scars still pose a treatment challenge. Needle-free high-pressure pneumatic injection has recently been introduced; however, few studies exist regarding its effectiveness. OBJECTIVE: To evaluate the efficacy and safety of pneumatic injection for treating atrophic acne scars using a 3-dimensional optical profiling system. METHODS AND MATERIALS: A pneumatic injection device with a 0.2-mm nozzle diameter, 50% pressure power, and 85-µL injection volume was used. The degree of depression was examined and analyzed using a 3-dimensional optical profiling system and clinical photographs. The patients also evaluated any side effects. Each subject underwent a single treatment session and was followed up after 1 and 2 months. RESULTS: A total of 13 atrophic acne scars from 10 Korean men and women aged 20 to 29 (mean age 25.8 ± 2.4) years were studied. The mean scar volume values were 0.964, 0.741, and 0.566 mm, respectively, at baseline, 1 month, and 2 months after the injection. Scar volumes after 2 months were significantly different compared with baseline volumes. However, there was no significant difference between the baseline and 1-month volumes. CONCLUSION: Treatment with pneumatic injection is safe and effective in reducing atrophic acne facial scars; it results in quantitative improvement in scar volumes.

Comparative efficacy of short-pulsed intense pulsed light and pulsed dye laser to treat rosacea.

Background: Laser and light-based therapies have often been used successfully to treat rosacea. Recently, short-pulsed intense pulsed light (IPL) that emitted pulse durations down to 0.5 ms was found to be effective for rosacea treatment. Objective: This study evaluated the efficacy of short-pulsed IPL in the treatment of rosacea compared with pulsed dye laser (PDL) using same pulse duration and fluence. Materials and Methods: Nine patients with rosacea were enrolled in a randomized, split-face trial. Each treatment consisted of four sessions at three-week intervals and followed up until three weeks after the last treatment. Efficacy was assessed by erythema, melanin index, physician's subjective evaluation, and patient's satisfaction. Results: The mean change in erythema index was -4.93 ± 1.59 for the short-pulsed IPL group and -4.27 ± 1.23 for the PDL group. The mean change in melanin index was -2.52 ± 2.45 for the short-pulsed IPL group and -1.95 ± 1.41 for the PDL group. There was no significant difference in either melanin or erythema index between short-pulsed IPL and PDL treatments, and there were no noticeable adverse events. Conclusions: There was no significant difference between PDL and short-pulsed IPL treatment using the same energies and pulse. Both PDL and short-pulsed IPL were satisfactory and safe for rosacea treatment.

Double stacking cryolipolysis treatment of the abdominal fat with use of a novel contoured applicator.

Background: Cryolipolysis is a noninvasive method for the selective reduction of subcutaneous fat. The abdomen and flank area are most commonly treated sites and now the treatment efficacy became the important issue. Objectives: To evaluate the effectiveness and safety of double stacking cryolipolysis treatment with the novel contoured applicator for abdominal fat reduction. Materials and methods: 12 healthy Korean were treated using cryolipolysis contact device. The device was applied on participant's left lower abdomen. Performance was held for 35 minutes and immediately repeated the second performance. The right abdomen was left untreated. Participants were examined with high resolution ultrasound and the depth of subcutaneous fat layer was measured initially and 8 weeks after the sessions. Any adverse events were assessed during the entire study period. Results: The subjective reduction of abdominal fat was noted in most participants. No serious adverse events was reported. Reduction of subcutaneous fat layer depth was confirmed in high resolution ultrasound after 8 weeks of treatment. Conclusion: The results of this study indicate that abdominal fat can be reduced effectively by the novel cryolipolysis applicator. With subjective satisfaction of participants our study shows that double stacking treatment appears safe and well tolerated with enhanced treatment outcomes.

Comparative effects of various absorbable threads in a rat model.

BACKGROUND: Conventional procedures including botulinum toxin and filler injections have their limitations in improving deep wrinkles and decreasing tissue laxity, and possess the propensity for vascular accidents. Absorbable thread is a recently commercialized field, but there is little evidence on comparative superiority. OBJECTIVES: We observed the effects of polydiaxanone (PDO) threads with different number of strands in relation to collagen production and histopathology in a rat model. MATERIALS AND METHODS: Dorsal skin of rat was divided into five different compartments and four different PDO threads and monofilament poly-lactic acid (PLA) thread were inserted. Tissue samples were obtained at week 1, 2, and 12 after the procedure for histopathologic review and real-time PCR for quantification of collagen. RESULTS: Multiple PDO filaments produced more collagen at 2 weeks. Single-stranded PLA thread insertion resulted in more Col1α1 levels than the double PDO thread and also showed the most Col1α3 production at week 2. The amount of collagen showed a sharp decline at week 12. Histologic evaluation showed retained threads surrounded by fibrous capsule-like structure at week 12. CONCLUSION: We were able to observe more collagen production in multiple stranded PDO threads compared to a single strand and that increasing number of threads leads to more collagen synthesis.

Incidence of postoperative facial weakness in parotid tumor surgery: a tumor subsite analysis of 794 parotidectomies.

BACKGROUND: The reported incidence of facial weakness immediately after parotid tumor surgery ranges from 14 to 65%. The purpose of this study was to evaluate the incidence of postoperative facial weakness related to parotidectomy with use of preoperative computed tomography (CT), intraoperative facial nerve monitoring, and surgical magnification. Also, we sought to elucidate additional information about risk factors for postoperative facial weakness in parotid tumor surgery, particularly focusing on the tumor subsites. METHODS: We retrospectively reviewed 794 cases with parotidectomy for benign and malignant tumors arising from the parotid gland (2009-2016). Patients with pretreatment facial palsy were excluded from the analyses. Tumor subsites were stratified based on their anatomical relations to the facial nerve as superficial, deep, or both. Multivariable logistic regression analyses were conducted to identify risk factors for postoperative facial weakness. RESULTS: The overall incidences of temporary and permanent (more than 6 months) facial weakness were 9.2 and 5.2% in our series utilizing preoperative CT, intraoperative facial nerve monitoring, and surgical magnification. Multivariable analysis revealed that old age, malignancy, and recurrent tumors (revision surgery) were common independent risk factors for both temporary and permanent postoperative facial weakness. In addition, tumor subsite (tumors involving superficial and deep lobe) was associated with postoperative facial weakness, but not tumor size. Extent of surgery was strongly correlated with tumor pathology (malignant tumors) and tumor subsite (tumors involving deep lobe). CONCLUSION: Aside from risk factors for facial weakness in parotid tumor surgery such as old age, malignant, or recurrent tumors, the location of tumors was found to be related to postoperative facial weakness. This study result may provide background data in a future prospective study and up-to-date information for patient counseling.

A zero-thermal-quenching phosphor.

Phosphor-converted white light-emitting diodes (pc-WLEDs) are efficient light sources used in lighting, high-tech displays, and electronic devices. One of the most significant challenges of pc-WLEDs is the thermal quenching, in which the phosphor suffers from emission loss with increasing temperature during high-power LED operation. Here, we report a blue-emitting Na3-2xSc2(PO4)3:xEu2+ phosphor (λem = 453 nm) that does not exhibit thermal quenching even up to 200 °C. This phenomenon of zero thermal quenching originates from the ability of the phosphor to compensate the emission losses and therefore sustain the luminescence with increasing temperature. The findings are explained by polymorphic modification and possible energy transfer from electron-hole pairs at the thermally activated defect levels to the Eu2+ 5d-band with increasing temperature. Our results could initiate the exploration of phosphors with zero thermal quenching for high-power LED applications.

Genetic analysis of parathyroid and pancreatic tumors in a patient with multiple endocrine neoplasia type 1 using whole-exome sequencing.

BACKGROUND: Multiple endocrine neoplasia type 1 (MEN1) syndrome is an autosomal dominant hereditary disorder characterized by the presence of endocrine tumors affecting the parathyroid, pancreas, and pituitary. A heterozygous germline inactivating mutation in the MEN1 gene (first hit) may be followed by somatic loss of the remaining normal copy or somatic mutations in the MEN1 gene (second hit). Whole-exome sequencing has been successfully used to elucidate the mutations associated with the different types of tumors. CASE PRESENTATION: We performed whole-exome sequencing (WES) on three parathyroid tumors, one pancreatic insulinoma, and a blood sample taken from the same patient with MEN1 to study tumor heterogeneity in MEN1 originating from different tumors. We identified a novel frame-shift deletion (c.1382_1383delAG, p.E461GfsX69) in the MEN1 gene using WES, which was confirmed by Sanger sequencing. WES and the SNP array revealed somatic LOH on chromosome 11 in parathyroid tumors (left upper, left lower, and right upper parathyroid). However, we did not detect a somatic MEN1 gene mutation or LOH in the pancreatic insulinoma. WES revealed two somatic functional variants outside the MEN1 gene in the pancreatic insulinoma. CONCLUSIONS: This study revealed heterogeneity among tumors in the same patient with MEN1, suggesting that different tumor-specific tumorigenic mechanisms may contribute to the pathogenesis of MEN1 tumors. The present study supports the clinical applicability of the WES strategy to research on multiple tumor samples and blood.

Prognostic factors for recurrence of locally advanced differentiated thyroid cancer.

Background and Objectives To present treatment outcomes and prognostic factors for surgical management of locally advanced differentiated thyroid cancer (DTC). METHODS: Retrospective review of 70 patients in a single, tertiary referral institution was done. Clinical pathology characteristics were analyzed to investigate prognosticators, based on primary endpoints; locoregional recurrence alone (LRR), total recurrence (LRR or distant metastasis (DM)), and recurrence-free survival. RESULTS: Recurrent laryngeal nerve (n = 31) and trachea (n = 30) were most commonly invaded organs by tumor. At the mean follow-up of 81.7 months, LRR occurred in 15 patients and/or DM was detected in 15 patients (10 developed LRR and DM). By multivariate analysis, R1 resection (positive margin) and pN1b stage increased risk of LRR with a fold of 3.16 [95%CI 1.08-9.24, P = 0.03] and 5.92 [1.61-21.7, P = 0.007], respectively. Also, they increased risk of total recurrence with a fold of 3.04 [95%CI 1.26-7.31, P = 0.01] and 3.42 [95%CI 1.16-10.0, P = 0.02], respectively. Patients with pN1b stage showed better LRR-free survival than pN0/N1a stage (P = 0.03). Conclusions Along with careful preoperative evaluation of the extent of primary and neck disease, obtaining negative resection margin and aggressive neck management is critical to improve oncologic outcomes of locally advanced DTC.