Robotic parathyroidectomy is a feasible technique for primary hyperparathyroidism.

PURPOSE: Focused parathyroidectomy is the gold standard treatment modality for primary hyperparathyroidism, which allows accurate preoperative localization. Robotic parathyroidectomy has emerged as a feasible procedure for focused parathyroidectomy. This study aimed to report the experiences of gasless robotic transaxillary parathyroidectomy for primary hyperparathyroidism in a single center. METHODS: We assessed the data obtained from patients who underwent gasless robotic parathyroidectomy with the transaxillary approach between December 2013 and August 2022 and were diagnosed with primary hyperparathyroidism at our institute. The data included clinical, biochemical, and pathological features and operation time. RESULTS: Of the 12 patients, 11 were women and one was a man. The median age of the patients was 44.5 years (range: 15-65 years). The median preoperative maximum mass diameters on ultrasonography and neck computed tomography were 1.2 ± 0.5 and 1.1 ± 0.6 cm, respectively. The median size of the postoperative maximum mass diameter in gross pathology was 1.3 ± 0.4 cm. The location of the enlarged parathyroid was left superior in five patients, right inferior in four, left inferior in three, and no right superior in one. In the final pathological examination, all cases were parathyroid adenomas. Only one case experienced a postoperative bleeding complication. At six months from surgery, average of an axillary scar length was 5.85 cm, and an average width was 0.21 cm. The mean operative time was 113 ± 48 min. The mean robot docking and console times were 9 ± 5 and 47 ± 52 min, respectively. CONCLUSIONS: Robotic transaxillary parathyroidectomy is a feasible technique in select patients with primary hyperparathyroidism and preoperatively localized disease. The gasless robotic transaxillary approach provides procedural safety as well as superior cosmetic results without a neck scar.

Anti-Cancer SERCA Inhibitors Targeting Sorafenib-Resistant Human Papillary Thyroid Carcinoma.

Thyroid cancer is generally curable and, in many cases, can be completely treated, although it can sometimes recur after cancer therapy. Papillary thyroid cancer (PTC) is known as one of the most general subtypes of thyroid cancer, which take up nearly 80% of whole thyroid cancer. However, PTC may develop anti-cancer drug resistance via metastasis or recurrence, making it practically incurable. In this study, we propose a clinical approach that identifies novel candidates based on target identification and validation of numerous survival-involved genes in human sorafenib-sensitive and -resistant PTC. Consequently, we recognized a sarco/endoplasmic reticulum calcium ATPase (SERCA) in human sorafenib-resistant PTC cells. Based on the present results, we detected novel SERCA inhibitor candidates 24 and 31 via virtual screening. These SERCA inhibitors showed remarkable tumor shrinkage in the sorafenib-resistant human PTC xenograft tumor model. These consequences would be clinically worthwhile for the development of a new combinatorial strategy that effectively targets incredibly refractory cancer cells, such as cancer stem cells and anti-cancer drug-resistant cells.

Effects of Anti-Cancer Drug Sensitivity-Related Genetic Differences on Therapeutic Approaches in Refractory Papillary Thyroid Cancer.

Thyroid cancer (TC) includes tumors of follicular cells; it ranges from well differentiated TC (WDTC) with generally favorable prognosis to clinically aggressive poorly differentiated TC (PDTC) and undifferentiated TC (UTC). Papillary thyroid cancer (PTC) is a WDTC and the most common type of thyroid cancer that comprises almost 70-80% of all TC. PTC can present as a solid, cystic, or uneven mass that originates from normal thyroid tissue. Prognosis of PTC is excellent, with an overall 10-year survival rate >90%. However, more than 30% of patients with PTC advance to recurrence or metastasis despite anti-cancer therapy; consequently, systemic therapy is limited, which necessitates expansion of improved clinical approaches. We strived to elucidate genetic distinctions due to patient-derived anti-cancer drug-sensitive or -resistant PTC, which can support in progress novel therapies. Patients with histologically proven PTC were evaluated. PTC cells were gained from drug-sensitive and -resistant patients and were compared using mRNA-Seq. We aimed to assess the in vitro and in vivo synergistic anti-cancer effects of a novel combination therapy in patient-derived refractory PTC. This combination therapy acts synergistically to promote tumor suppression compared with either agent alone. Therefore, genetically altered combination therapy might be a novel therapeutic approach for refractory PTC.

Synergistic Anticancer Activity of N-Hydroxy-7-(2-Naphthylthio) Heptanomide, Sorafenib, and Radiation Therapy in Patient-Derived Anaplastic Thyroid Cancer Models.

Anaplastic thyroid cancer (ATC) is an undifferentiated and advanced form of thyroid cancer, accompanied with a high ratio of epigenetic adjustment, which occurs more than genetic mutations. In this study, we aimed to evaluate the synergistic anticancer effect (in vitro and in vivo) of the new combination of N-hydroxy-7-(2-naphthylthio) heptanomide (HNHA) and sorafenib with radiation therapy in pre-clinical models of ATC. The ATC cell lines, YUMC-A1 and YUMC-A2, were isolated from the current patients who were treated with HNHA and sorafenib, either as monotherapy or combination therapy. Synergistic anticancer effect of the combination therapy on the intracellular signaling pathways and cell cycle was assessed via flow cytometry and immunoblot analysis. To examine tumor shrinkage activity in vivo, an ATC cell line-derived mouse xenograft model was used. Results showed that the combination therapy of HNHA and sorafenib with radiation promoted tumor suppression via caspase cleavage and cell cycle arrest in patient-derived ATC. In addition, the combination therapy of HNHA and sorafenib with radiation was more effective against ATC than therapy with HNHA or sorafenib with radiation. Thus, the combination of HNHA and sorafenib with radiation may be used as a novel curative approach for the treatment of ATC.

Amelioration of amyloid ß-FcγRIIb neurotoxicity and tau pathologies by targeting LYN.

SRC-family kinases (SFKs) have been implicated in Alzheimer's disease (AD), but their mode of action was scarcely understood. Here, we show that LYN plays an essential role in amyloid ß (Aß)-triggered neurotoxicity and tau hyperphosphorylation by phosphorylating Fcγ receptor IIb2 (FcγRIIb2). We found that enzyme activity of LYN was increased in the brain of AD patients and was promoted in neuronal cells exposed to Aß 1-42 (Aß1-42). Knockdown of LYN expression inhibited Aß1-42-induced neuronal cell death. Of note, LYN interacted with FcγRIIb2 upon exposure to Aß1-42 and phosphorylated FcγRIIb2 at Tyr273 within immunoreceptor tyrosine-based inhibitory motif in neuronal cells. With the use of the structure-based drug design, we isolated KICG2576, an ATP-competitive inhibitor of LYN. Determination of cocrystal structure illustrated that KICG2576 bound to the cleft in the LYN kinase domain and inhibited LYN with a half-maximal inhibitory concentration value of 0.15 µM. KICG2576 inhibited Aß- or FcγRIIb2-induced cell death, and this effect was better than pyrazolopyrimidine 1, a widely used inhibitor of SFK. Upon exposure to Aß, KICG2576 blocked the phosphorylation of FcγRIIb2 and translocation of phosphatidylinositol 3,4,5-trisphosphate 5-phosphatase 2, a binding protein to the phosphorylated FcγRIIb2, to the plasma membrane, resulting in the inhibition of tau hyperphosphorylation, the downstream event of Aß1-42-FcγRIIb2 binding. Furthermore, intracerebroventricular injection of KICG2576 into mice ameliorated Aß-induced memory impairment. These results suggest that LYN plays a crucial role in Aß1-42-mediated neurotoxicity and tau pathology, providing a therapeutic potential of LYN in AD.-Gwon, Y., Kim, S.-H., Kim, H. T., Kam, T.-I., Park, J., Lim, B., Cha, H., Chang, H.-J., Hong, Y. R., Jung, Y.-K. Amelioration of amyloid ß-FcγRIIb neurotoxicity and tau pathologies by targeting LYN.

Transoral endoscopic thyroidectomy using the vestibular approach with an endoscopic retractor in thyroid cancer: experience with the first 132 patients.

BACKGROUND: Transoral endoscopic thyroidectomy using the vestibular approach (TOETVA) is a novel technique for thyroid cancer surgery. We aimed to review our initial experiences with TOETVA for the management of thyroid carcinoma, using retrospective analyses of a larger single-center case series. METHODS: From September 2016 to April 2018, 132 patients with thyroid cancer underwent TOETVA. A three-port technique through the oral vestibule was used to perform endoscopic thyroidectomy with ipsilateral central compartment dissection using conventional laparoscopic instruments, and an endoscopic retractor that we developed. RESULTS: All patients had papillary thyroid carcinoma. Less-than total or total thyroidectomy with ipsilateral central compartment node dissection was performed (124 vs. 8). The mean operation time was 87.6 min (range 56-213 min). The average number of lymph nodes resected was 2.6 (range 1-12). Six patients experienced transient hoarseness, which was resolved within 3 months. Most of the patients were discharged within 3 days after surgery. CONCLUSIONS: In this large series from a single center, we found that TOETVA with the endoscopic retractor can be performed safely and radically in selected patients with thyroid cancer.

SoLAT (Sorafenib Lenvatinib alternating treatment): a new treatment protocol with alternating Sorafenib and Lenvatinib for refractory thyroid Cancer.

BACKGROUND: In the last decade, several tyrosine kinase inhibitors (TKIs), which disrupt pathways involved in the proliferation and tumorigenesis of thyroid cancer, have been extensively studied. Two different TKIs, lenvatinib and sorafenib, were recently approved by both the US FDA and European Medicine Agency. Until date, the duration of the TKI response is not sufficient and resistance eventually occurs. The goal of this study was to investigate a new treatment protocol, SoLAT, using sorafenib and lenvatinib alternatively on refractory thyroid cancer. METHODS: Patient-derived aggressive papillary thyroid cancer (PTC) cell lines from patients with biochemical and histologically proven aggressive RAI-refractory papillary thyroid cancer were exposed to sorafenib and lenvatinib alternatively. Human thyroid cancer cell xenografts were obtained by injecting patient-derived aggressive PTC cell lines into the flank of female BALB/c nude mice. Tumor-bearing mice were treated with sorafenib and lenvatinib alternatively. Cell viability assay, immunofluorescence analysis, confocal imaging, immunoblot analysis, flow cytometry analysis of cell cycle and a tube formation assay were performed. RESULTS: SoLAT was more effective for advanced PTC cell lines than individual treatment. Immunoblot analysis showed that SoLAT markedly increased levels of cell cycle inhibitors (p53 and p21), and pro-apoptotic factors (Apaf-1 and cleaved caspase 3) and decreased levels of positive cell cycle regulators (cyclin D1, CDK4, CDK6) and anti-apoptotic factors (p-NFκB, Bcl-2). Increased sub-G0/G1 population was observed in the SoLAT group, leading to apoptosis, cell cycle arrest, and strong inhibition of advanced PTC cell viability. SoLAT reduced the level of EMT markers such as vimentin, E-cadherin, Snail and Zeb1 by FGFR inhibition. In the xenograft model, individual treatment with sorafenib or lenvatinib did not markedly suppress patient-derived aggressive PTC cell xenograft tumors, whereas SoLAT significantly suppressed the proliferation of these tumors. CONCLUSIONS: SoLAT was more effective than individual treatment with sorafenib or lenvatinib in inhibiting PTC progression by inducing cell cycle arrest. Studies using both in vitro cell culture and an in vivo xenograft model provided evidence of tumor shrinkage with SoLAT. We suggest that these effects may be due to reduced EMT-mediated drug resistance in the aggressive PTC model.

Long-term outcomes of ethanol injection therapy for locally recurrent papillary thyroid cancer.

The standard treatment regimen for locally recurrent lesions is total thyroidectomy, or complete removal of the recurrent thyroid lesion within the thyroid bed. However, reoperation increases the risk of complications and patients have to undergo general anesthesia. Percutaneous ethanol injection therapy represents a far less invasive procedure without general anesthesia and with lower risk of complications. Thirty-four patients who received PEIT at Yonsei University Medical Center between October 2002 and August 2009 for recurrent cervical nodal metastases of differentiated papillary thyroid cancer were included in this retrospective study. During a minimum follow-up of 60 months, treatment outcomes were determined by measuring the lesion size prior to the first injection and 3 months after the last injection. A total of 46 recurrent lesions were detected in 34 patients. Five patients underwent surgery and PEIT was administered to the remaining 19 and 22 lesions in the central compartment and lateral neck lymph nodes, respectively. Size increases were observed in seven (17.1%) lesions, whereas no changes in size and decreases were detected in 10 (24.4%) and 24 (58.5%) lesions. Patients with increased lymph nodes were significantly older (65.3 ± 14.4 vs. 48.2 ± 16.3 years; p = 0.02) and had smaller sizes (9.3 ± 1.0 vs. 12.3 ± 6.4 mm; p = 0.012). Although reoperation remains the first-line treatment for recurrent thyroid cancer, PEIT may be considered as a treatment option in selected patients with lesions larger than 1 cm who are ineligible for surgery or have refused reoperation.

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.

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.

Compensatory growth and recovery of cartilage cytoarchitecture after transient cell death in fetal mouse limbs.

A major question in developmental and regenerative biology is how organ size and architecture are controlled by progenitor cells. While limb bones exhibit catch-up growth (recovery of a normal growth trajectory after transient developmental perturbation), it is unclear how this emerges from the behaviour of chondroprogenitors, the cells sustaining the cartilage anlagen that are progressively replaced by bone. Here we show that transient sparse cell death in the mouse fetal cartilage is repaired postnatally, via a two-step process. During injury, progression of chondroprogenitors towards more differentiated states is delayed, leading to altered cartilage cytoarchitecture and impaired bone growth. Then, once cell death is over, chondroprogenitor differentiation is accelerated and cartilage structure recovered, including partial rescue of bone growth. At the molecular level, ectopic activation of mTORC1 correlates with, and is necessary for, part of the recovery, revealing a specific candidate to be explored during normal growth and in future therapies.

No Change in Complications Following Thyroidectomy Despite Increase in Thyroid Cancer Surgeries: A Meta-Regression Analysis.

PURPOSE: The increase in thyroid cancer incidence has inevitably led to an increase in thyroid cancer surgeries. This meta-regression analysis aimed to determine if the rate of post-thyroidectomy complications changes by year. MATERIALS AND METHODS: PubMed and Embase databases were used to perform a systematic literature search of studies published from January 1, 2005, using the keywords "thyroidectomy" and "complication." A meta-regression was performed for post-thyroidectomy hypocalcemia and bleeding. RESULTS: This meta-analysis included 25 studies involving 927751 individuals. Through the years of publications in this study, there was no significant difference in the proportion of post-thyroidectomy hypocalcemia and bleeding (p=0.9978, 0.6393). CONCLUSION: Although the number of thyroid surgeries has recently increased, the incidence of post-thyroidectomy hypocalcemia and bleeding did not significantly increase.

Preoperative Ultrasonography Predicts Level II Lymph Node Metastasis in N1b Papillary Thyroid Carcinoma: Implications for Surgical Planning.

PURPOSE: To investigate whether preoperative ultrasonographic (US) features of the index cancer and metastatic lymph nodes (LNs) are associated with level II LN metastasis in N1b papillary rmfthyroid carcinoma (PTC) patients. MATERIALS AND METHODS: We enrolled 517 patients (mean age, 42 [range, 6-80] years) who underwent total thyroidectomy and lateral compartment LN dissection between January 2009 and December 2015. We reviewed the clinicopathologic and US features of the index cancer and metastatic LNs in the lateral neck. Logistic regression analysis was performed to analyze features associated with level II LN metastasis. RESULTS: Among the patients, 196 (37.9%) had level II metastasis on final pathology. In the preoperative model, larger tumor size (odds ratios [ORs], 1.031; 95% confidence interval [CI]: 1.011-1.051, p = 0.002), nonparallel tumor shape (OR, 1.963; 95% CI: 1.322-2.915, p = 0.001), multilevel LN involvement (OR, 1.906; 95% CI: 1.242-2.925, p = 0.003), and level III involvement (OR, 1.867; 95% CI: 1.223-2.850, p = 0.004), were independently associated with level II LN metastasis. In the postoperative model, non-conventional pathology remained a significant predictor for level II LN metastasis (OR, 1.951; 95% CI: 1.121-3.396; p = 0.018), alongside the presence of extrathyroidal extension (OR, 1.867; 95% CI: 1.060-3.331; p = 0.031), and higher LN ratio (OR, 1.057; 95% CI: 1.039-1.076; p < 0.001). CONCLUSIONS: Preoperative US features of the index tumor and LN may be helpful in guiding surgery in N1b PTC. These findings could enhance preoperative planning and decision-making, potentially reducing surgical morbidities by identifying those at higher risk of level II LN metastasis and tailoring surgical approaches accordingly.

Aggressive Subtypes of Papillary Thyroid Carcinoma Smaller Than 1 cm.

CONTEXT: Tumor size is important in determining the range of surgery in papillary thyroid carcinomas (PTCs), especially those smaller than 1 cm. OBJECTIVE: We aimed to analyze the features of small PTCs with aggressive subtypes based on histological characteristics. METHODS: In this retrospective study, we reviewed the medical records of 11 570 patients with PTCs smaller than or equal to 1 cm who underwent thyroidectomy between January 2009 and December 2016. Aggressive subtypes included diffuse sclerosing, solid, tall cell, columnar cell, and hobnail subtypes. RESULTS: Among the 11 570 patients with PTCs smaller than or equal to 1 cm, 177 aggressive PTC subtypes were identified. Propensity score matching revealed 110 tumors (62.1%) with extrathyroidal extension of aggressive PTC subtypes and 451 (51.1%) nonaggressive PTC subtypes (95% CI, 0.41-0.80; P < .001). Metastatic central and lateral neck lymph nodes constituted 3.06 ± 3.67 and 3.81 ± 5.39 of aggressive PTC subtypes and 1.22 ± 2.14 and 2.85 ± 3.79 of nonaggressive PTC subtypes, respectively (central neck nodes: 95% CI, 1.42-2.26; P < .001; lateral neck nodes: 95% CI, 2.9-5.90; P < .001). Seven patients with aggressive PTC subtypes (3.95%) and 12 with nonaggressive PTC subtypes (1.7%) exhibited recurrence. CONCLUSION: Aggressive subtypes of small PTC tumors smaller than or equal to 1 cm exhibited more extrathyroidal extension and neck node metastasis. This study suggests that surgeons should consider the aggressive subtypes as important factors when deciding the range of surgery in PTCs smaller than 1 cm.

Primary thyroid lymphoma: A single-center experience.

Background: Primary thyroid lymphoma (PTL) is a very rare entity accounting for 5% of all thyroid malignancies and less than 2% of lymphomas. PTLs are classified as non-Hodgkin's B-cell lymphomas in the majority of cases, although Hodgkin's lymphoma of the thyroid has also been identified. This study aimed to identify the clinical, biochemical, and pathological features of primary thyroid lymphomas. Methods: From January 2008 to December 2020, data from patients diagnosed with PTL treated at the Gangnam Severance Hospital, including clinical, biochemical, and pathological features of thyroid lymphomas, were assessed. Results: Of 10 patients, nine women and one man, with a median age of 62 (range, 44-82) years were included. Fine needle aspiration biopsy was performed in nine patients and surgical resection was performed in one patient without biopsy. Excisional and surgical biopsies were performed in all patients, including five who underwent excisional biopsy and five who underwent thyroidectomy. Histological analyses revealed that all 10 lymphomas were non-Hodgkin B-cell lymphoma; six patients had diffuse large B-cell lymphoma, three had mucosa-associated lymphoid tissue lymphoma, and one had Burkitt lymphoma. Four patients received chemotherapy, two were treated with chemoradiation therapy, one received radiation therapy only, one did not require more treatment after surgery, one refused treatment, and one was transferred to another hospital. Conclusions: Although PTLs are scarce, clinicians should be aware of this rare entity and evaluate and treat PTLs on an individual basis.

Lateral neck dissection for the treatment of synchronous and metachronous lateral neck metastasis of N1b papillary thyroid cancer.

Introduction: Metachronous lateral neck recurrence after thyroidectomy for N1b papillary thyroid cancer is accompanied by high morbidity and increased difficulty of reoperation. From the perspective of recurrence, the objective of this study was to compare patients who underwent metachronous lateral neck dissection (mLND) despite initial thyroidectomy and patients who underwent synchronous lateral neck dissection (sLND) for papillary thyroid cancer and analyze the risk factors for recurrence after mLND. Method: This retrospective study involved 1,760 patients who underwent lateral neck dissection for papillary thyroid cancer at the Gangnam Severance Hospital, a tertiary medical center in Korea, from June 2005 to December 2016. The primary outcome was structural recurrence, and secondary outcome measures were risk factors of recurrence in the mLND group. Result: A total of 1,613 patients underwent thyroidectomy and sLND at diagnosis. In 147 patients, thyroidectomy alone was performed at the time of diagnosis, and mLND was performed when recurrence to the lateral neck lymph node was confirmed. During a median follow-up of 102.1 months, 110 (6.3%) patients experienced a recurrence. There was no significant difference in the recurrence between the sLND and mLND groups (6.1% vs 8.2%, P=.32). The period from lateral neck dissection to recurrence was longer in the mLND group than in the sLND group (113.6 ± 39.4 months vs 87.0 ± 33.8 months, respectively, P<.001). Age ≥50 years (adjusted HR=5.209, 95% CI=1.359-19.964; P=.02), tumor size >1.45 cm (adjusted HR=4.022, 95% CI=1.036-15.611; P=.04), and lymph node ratio in the lateral compartment (adjusted HR=4.043, 95% CI=1.079-15.148; P=.04) were independent variables predictive of recurrence after mLND. Conclusion: mLND is suitable for treating lateral neck recurrence in patients with N1b papillary thyroid cancer who previously underwent thyroidectomy. Lateral neck recurrence after treatment in patients who underwent mLND was predicted by age, tumor size, and lymph node ratio in the lateral compartment.

Comparison of delayed bleeding to immediate bleeding following thyroidectomy.

It is important to identify risk factors for post-thyroidectomy bleeding requiring airway intervention or reoperation. Therefore, we aimed to compare the characteristics of patients with postoperative bleeding after thyroid surgery according to the period until reoperation. We conducted a retrospective study analyzing data between April 2009 and July 2022 and included 126 patients who had postoperative bleeding. The patients were grouped according to the period between thyroidectomy and reoperation due to bleeding (0 day, 1-7 days, > 7 days). We performed among-group comparisons of patient characteristics and surgical aspects, including the extent of surgery. The ratios of male-female and lateral neck dissection were higher in the post-operative bleeding group than in the group without bleeding. In the analysis of patients with postoperative bleeding, grouped according to period between thyroidectomy and reoperation, there was a significant among-group difference in the male-female ratio. The male sex was positively correlated with the reoperation period. Further, the reoperation period was also positively correlated with total thyroidectomy and lateral neck dissection and the operation time showed a significant among-group difference. Our results indicate that the male sex and lateral neck dissection are risk factors for postoperative bleeding after thyroidectomy. Furthermore, male sex, total thyroidectomy, and lateral neck dissection are risk factors for delayed bleeding. Therefore, clinicians should consider these factors for interventions against immediate or delayed bleeding after thyroidectomy.

Clinicopathological and Genetic Characteristics of Patients of Different Ages with Diffuse Sclerosing Variant Papillary Thyroid Carcinoma.

Diffuse sclerosing variant papillary thyroid carcinoma (DSVPTC) is commonly observed in young patients, with a median age at diagnosis in the third decade of life. Further, the risk of recurrence is higher for DSVPTC than for classical PTC. Therefore, this study aimed to describe the clinicopathological and genetic characteristics of patients of different ages with DSVPTC. We retrospectively reviewed 397 patients who underwent thyroidectomy for DSVPTC at Gangnam Severance Hospital, Yonsei University, from January 2005 to December 2017. The mean age at diagnosis was 36.7 ± 11.6 years, with most patients (163, 41.1%) aged 31-40 years. DSVPTC was predominant in women (276, 69.5%). We observed recurrence in 46 (11.6%) patients, with regional nodal recurrence being the most common type of recurrence (32 patients, 69.6%). The mean tumour size was larger in younger patients than in older patients. DSVPTC was more aggressive in paediatric patients with a larger-sized tumour, more common multiplicity, and lateral neck metastasis. Through random sampling, we selected 41 patients by age group and examined the mutations in 119 genes using next-generation sequencing. BRAF, KRAS, and TERT displayed relatively higher mutation rates than other genes. DSVPTC displays different clinical, pathological, and molecular profiles than classical PTC. The BRAF, KRAS, and TERT mutations are the most important, with age-specific differences.

Molecular mechanism of activation of human Cdc7 kinase: bipartite interaction with Dbf4/activator of S phase kinase (ASK) activation subunit stimulates ATP binding and substrate recognition.

Cdc7 is a serine/threonine kinase conserved from yeasts to human and is known to play a key role in the regulation of initiation at each replication origin. Its catalytic function is activated via association with the activation subunit Dbf4/activator of S phase kinase (ASK). It is known that two conserved motifs of Dbf4/ASK are involved in binding to Cdc7, and both are required for maximum activation of Cdc7 kinase. Cdc7 kinases possess unique kinase insert sequences (kinase insert I-III) that are inserted at defined locations among the conserved kinase domains. However, precise mechanisms of Cdc7 kinase activation are largely unknown. We have identified two segments on Cdc7, DAM-1 (Dbf4/ASK interacting motif-1; amino acids 448-457 near the N terminus of kinase insert III) and DAM-2 (C-terminal 10-amino acid segment), that interact with motif-M and motif-C of ASK, respectively, and are essential for kinase activation by ASK. The C-terminal 143-amino acid polypeptide (432-574) containing DAM-1 and DAM-2 can interact with Dbf4/ASK. Characterization of the purified ASK-free Cdc7 and Cdc7-ASK complex shows that ATP binding of the Cdc7 catalytic subunit requires Dbf4/ASK. However, the "minimum" Cdc7, lacking the entire kinase insert II and half of kinase insert III, binds to ATP and shows autophosphorylation activity in the absence of ASK. However, ASK is still required for phosphorylation of exogenous substrates by the minimum Cdc7. These results indicate bipartite interaction between Cdc7 and Dbf4/ASK subunits facilitates ATP binding and substrate recognition by the Cdc7 kinase.

Design, synthesis and biological evaluation of novel imidazopyridines as potential antidiabetic GSK3ß inhibitors.

Design, synthesis and biological evaluation of the imidazopyridine analogs as novel GSK3ß inhibitors for treatment of type 2 diabetes mellitus are described. Most of the analogs exhibited excellent inhibitory activities (IC50<44 nM) against glycogen synthase kinase 3ß (GSK3ß). The structure-activity relationship (SAR) of the imidazopyridine analogs and the binding mode of analog 23 in the catalytic domain of GSK3ß, based on our X-ray crystallography study, are described. In particular, analog 28, which was selected as a potential drug candidate for treatment of type 2 diabetes mellitus, exhibited excellent GSK3ß inhibition, pharmacokinetic profiles and blood glucose lowering effect in mouse.