Feasibility of active surveillance in patients with clinically T1b papillary thyroid carcinoma ≤1.5 cm in preoperative ultrasonography: MASTER study.

Objective: Active surveillance (AS) is generally accepted as an alternative to immediate surgery for papillary thyroid carcinoma (PTC) measuring ≤1.0 cm (cT1a) without risk factors. This study investigated the clinicopathologic characteristics of PTCs measuring ≤2.0 cm without cervical lymph node metastasis (cT1N0) by tumor size group to assess the feasibility of AS for PTCs between 1.0 cm and 1.5 cm (cT1b≤1.5). Design: This study enrolled clinically T1N0 patients with preoperative ultrasonography information (n= 935) from a cohort of 1259 patients who underwent lobectomy and were finally diagnosed with PTC from June 2020 to March 2022. Results: The cT1b≤1.5 group (n = 171; 18.3 %) exhibited more lymphatic invasion and occult central lymph node (LN) metastasis with a higher metastatic LN ratio than the cT1a group (n = 719; 76.9 %). However, among patients aged 55 years or older, there were no significant differences in occult central LN metastasis and metastatic LN ratio between the cT1a, cT1b≤1.5, and cT1b>1.5 groups. Multivariate regression analyses revealed that occult central LN metastasis was associated with age, sex, tumor size, extrathyroidal extension, and lymphatic invasion in patients under 55, while in those aged 55 or older, it was associated only with age and lymphatic invasion. Conclusion: For PTC patients aged 55 years or older with cT1b≤1.5, AS could be a viable option due to the absence of a significant relationship between tumor size and occult central LN.

Clinical impact of coexistent chronic lymphocytic thyroiditis on central lymph node metastasis in low- to intermediate-risk papillary thyroid carcinoma: The MASTER study.

BACKGROUND: The clinicopathological impact of chronic lymphocytic thyroiditis on patients with papillary thyroid carcinoma patients is still controversial. This study aimed to evaluate the clinicopathologic differences and risk factors for central lymph node metastasis based on the presence of coexistent chronic lymphocytic thyroiditis in patients with low- to intermediate-risk papillary thyroid carcinoma. METHODS: The medical records of 1,022 patients with low- to intermediate-risk papillary thyroid carcinoma who underwent lobectomy and central neck dissection between June 2020 and March 2022 were reviewed. Differences in clinicopathological factors were analyzed in patients with papillary thyroid carcinoma with or without chronic lymphocytic thyroiditis. Furthermore, risk factors for central lymph node metastasis in patients with low- to intermediate-risk papillary thyroid carcinoma with or without chronic lymphocytic thyroiditis were evaluated. RESULTS: Among the 1,022 patients with low to intermediate-risk papillary thyroid carcinoma, 102 (10.0%) had coexisting chronic lymphocytic thyroiditis. Female sex (odds ratio = 3.536, P = .001, 95% confidence interval 1.781-8.069), a multifocal tumor (odds ratio = 2.162, P = .001, 95% confidence interval 1.358-3.395), and angiolymphatic invasion (odds ratio = 0.365, P < .001, 95% confidence interval 0.203-0.625) were independent factors associated with patients who had coexisting chronic lymphocytic thyroiditis compared to those without chronic lymphocytic thyroiditis. There were 358 (35%) patients who had central lymph node metastasis. Multivariate analysis showed that younger age (odds ratio = 0.667, P = .013, 95% confidence interval 0.482-0.555), male sex (odds ratio = 0.549, P < .001, 95% confidence interval 0.402-0.751), tumor size >1 cm (odds ratio = 1.454, P = .022, 95% confidence interval 1.053-2.003), extrathyroidal extension (odds ratio = 1.874, P < .001, 95% confidence interval 1.414-2.486), and angiolymphatic invasion (odds ratio = 3.094, P < .001, 95% confidence interval 2.339-4.101) were risk factors for central lymph node metastasis. Angiolymphatic invasion (odds ratio = 11.184, P < .001, 95% confidence interval 3.277-46.199) was identified as the sole independent risk factor for central lymph node metastasis in patients with papillary thyroid carcinoma with coexisting chronic lymphocytic thyroiditis. CONCLUSION: Our data suggest that patients with low to intermediate-risk papillary thyroid carcinoma with coexistent chronic lymphocytic thyroiditis exhibit different clinical features than patients with papillary thyroid carcinoma without chronic lymphocytic thyroiditis. Additionally, the presence of chronic lymphocytic thyroiditis may be considered a potential factor against central lymph node metastasis.

NAT10-mediated ac4C tRNA modification promotes EGFR mRNA translation and gefitinib resistance in cancer.

Aberrant RNA modifications are frequently associated with cancers, while the underlying mechanisms and clinical significance remain poorly understood. Here, we find that the ac4C RNA acetyltransferase NAT10 is significantly upregulated in esophageal cancers (ESCAs) and associated with poor ESCA prognosis. In addition, using ESCA cell lines and mouse models, we confirm the critical functions of NAT10 in promoting ESCA tumorigenesis and progression in vitro and in vivo. Mechanistically, NAT10 depletion reduces the abundance of ac4C-modified tRNAs and decreases the translation efficiencies of mRNAs enriched for ac4C-modified tRNA-decoded codons. We further identify EGFR as a key downstream target that facilitates NAT10's oncogenic functions. In terms of clinical significance, we demonstrate that NAT10 depletion and gefitinib treatment synergistically inhibit ESCA progression in vitro and in vivo. Our data indicate the mechanisms underlying ESCA progression at the layer of mRNA translation control and provide molecular insights for the development of effective cancer therapeutic strategies.

Optimal value of lymph node ratio and metastatic lymph node size to predict risk of recurrence in pediatric thyroid cancer with lateral neck metastasis.

BACKGROUND: No specific guideline exists for risk stratification based on lymph node (LN) status in pediatric thyroid cancer. The purpose of our study is to identify optimal values of lymph node ratio (LNR) and largest metastatic LN size for predicting recurrent/persistent disease, especially in children with lateral neck metastasis (N1b). METHODS: We conducted a retrospective study from January 1997 to June 2018 at Samsung Medical Center. A total of 50 papillary thyroid carcinoma (PTC) patients who underwent total thyroidectomy + both central neck dissection (CND) + modified radical neck dissection (MRND) (unilateral or bilateral) was enrolled. RESULTS: The median follow-up duration was 60.8 months (range, 6.2-247 months). The mean age was 14.6 years, and the mean tumor size was 2.9 cm. Mean size of the largest metastatic LN was 1.5 cm. Mean value of central LNR was 0.6, and mean value of lateral LNR was 0.3. Largest metastatic LN size [HR = 2.0 (95% CI 1.0-4.0), p = 0.040] and lateral LNR [HR = 43.6 (95% CI 2.2-871.0), p = 0.014] were significant prognostic factors for recurrence. The optimal combination of lateral LNR and largest metastatic LN size to predict recurrence were 0.3 and 2.5 cm, respectively, with the largest AUC (AUC at 60 months = 77.4) and significant p-value (p = 0.009 and p = 0.021) (Table 3). Kaplan-Meier curves showed significant differences in recurrence-free survival (RFS) rates among four groups (Fig. 2A,2B). CONCLUSIONS: In pediatric PTC patients with N1b, lateral LNR and largest metastatic LN size are significant predictors for recurrence. Children with lateral LNR > 0.3 or any metastatic lymph node > 2.5 cm in the largest dimension have higher risk for recurrence. Children are classified as extensive N1b if lateral LNR > 0.3 or pathologic N1 with largest LN size > 2.5 cm, and vice versa.

Frequency of TERT Promoter Mutations in Real-World Analysis of 2,092 Thyroid Carcinoma Patients.

BACKGRUOUND: Telomerase reverse transcriptase (TERT) promoter mutations are associated with increased recurrence and mortality in patients with thyroid carcinoma. Previous studies on TERT promoter mutations were retrospectively conducted on a limited number of patients. METHODS: We prospectively collected data on all consecutive patients who underwent thyroid carcinoma surgery between January 2019 and December 2020 at the Samsung Medical Center, Seoul, Korea. We included 2,092 patients with thyroid carcinoma. RESULTS: Of 2,092 patients, 72 patients (3.4%) had TERT promoter mutations. However, the frequency of TERT promoter mutations was 0.5% in papillary thyroid microcarcinoma (PTMC) ≤1 cm and it was 5.8% in papillary thyroid carcinoma (PTC) >1 cm. The frequency of TERT promoter mutations was significantly associated with older age at diagnosis (odds ratio [OR], 1.12; P<0.001), larger primary tumor size (OR, 2.02; P<0.001), and aggressive histological type (OR, 7.78 in follicular thyroid carcinoma; OR, 10.33 in poorly differentiated thyroid carcinoma; OR, 45.92 in anaplastic thyroid carcinoma; P<0.001). Advanced T stage, advanced N stage, and distant metastasis at diagnosis were highly prevalent in mutated thyroid cancers. However, initial distant metastasis was not present in patients with TERT promoter mutations in PTMC. Although the C228T mutation was more highly detected than the C250T mutation (64 cases vs. 7 cases), there were no significant clinicopathological differences. CONCLUSION: This study is the first attempt to investigate the frequency of TERT promoter mutations in a real-world setting. The frequency of TERT promoter mutations in PTC was lower than expected, and in PTMC, young patients, and female patients, the frequency was very low.

Is total thyroidectomy with bilateral central neck dissection the only surgery for papillary thyroid carcinoma patients with clinically involved central nodes?

BACKGROUND: In clinical practice, we often observed that patients who underwent total thyroidectomy due to clinically involved nodal disease (cN1a) actually had less extensive CLNM on final pathology. This study investigates whether total thyroidectomy and therapeutic bilateral CND are necessary for all PTC patients with cN1a. METHODS: This study retrospectively reviewed 899 PTC patients who underwent total thyroidectomy with bilateral CND from January 2012 to June 2017. The patients were divided into two groups according to pre-operative central lymph node (CLN) status: cN0, no suspicious CLNM; cN1a, suspicious CLNM. We compared the clinicopathological features of these two groups. RESULTS: There was no significant difference in recurrence between cN0 and cN1a groups after a mean follow-up time of 59.1 months. Unilateral cN1a was related to the largest central LN size ≥ 2 mm (OR = 3.67, p < 0.001) and number of CLNM > 5(OR = 2.24, p = 0.006). On the other hand, unilateral cN1a was not associated with an increased risk of contralateral lobe involvement (OR = 1.35, p = 0.364) and contralateral CLNM (OR = 1.31, p = 0.359). Among 106 unilateral cN1a patients, 33 (31.1%) were found to be pN0 or had ≤ 5 metastatic CLNs with the largest node smaller than 2 mm. CONCLUSIONS: Most cN1a patients were in an intermediate risk group for recurrence and required total thyroidectomy. However, lobectomy with CND should have performed in approximately 30% of the cN1a patients. Pre-operative clinical examination, meticulous radiologic evaluation, and intra-operative frozen sections to check the nodal status are prerequisites for this approach.

N7-methylguanosine tRNA modification promotes esophageal squamous cell carcinoma tumorigenesis via the RPTOR/ULK1/autophagy axis.

Mis-regulated RNA modifications promote the processing and translation of oncogenic mRNAs to facilitate cancer progression, while the molecular mechanisms remain unclear. Here we reveal that tRNA m7G methyltransferase complex proteins METTL1 and WDR4 are significantly up-regulated in esophageal squamous cell carcinoma (ESCC) tissues and associated with poor ESCC prognosis. In addition, METTL1 and WDR4 promote ESCC progression via the tRNA m7G methyltransferase activity in vitro and in vivo. Mechanistically, METTL1 or WDR4 knockdown leads to decreased expression of m7G-modified tRNAs and reduces the translation of a subset of oncogenic transcripts enriched in RPTOR/ULK1/autophagy pathway. Furthermore, ESCC models using Mettl1 conditional knockout and knockin mice uncover the essential function of METTL1 in promoting ESCC tumorigenesis in vivo. Our study demonstrates the important oncogenic function of mis-regulated tRNA m7G modification in ESCC, and suggest that targeting METTL1 and its downstream signaling axis could be a promising therapeutic target for ESCC treatment.

Safety of pre-incisional low-dose ropivacaine infiltration in bilateral axillo-breast approach thyroidectomy: a retrospective study.

Introduction: Ropivacaine is widely used as a local analgesic, but it has toxicity that is related to the concentration, and highly concentrated ropivacaine can induce motor nerve blockage. Aim: To investigate the safety of low-concentration pre-incisional ropivacaine injection for postoperative pain control and compare postoperative adverse events between a low-concentration ropivacaine injection group and a high-concentration ropivacaine injection group. Material and methods: Patients who underwent thyroidectomy via the bilateral axillo-breast approach (BABA) between June 2017 and October 2021 performed by a single surgeon at Samsung Medical Center were retrospectively identified. These outcomes were compared between the two groups after 1 : 1 propensity score matching. Results: From a total of 633 patients, 620 patients were selected. There were 527 in the low-concentration ropivacaine group and 93 in the high-concentration ropivacaine group. After propensity score matching, two comparable groups with 93 patients in each were obtained. The incidence of ropivacaine-related adverse events was similar between the two groups (p = 0.186) but the occurrence of postoperative bradycardia (p = 0.048) was lower in the low-concentration ropivacaine group than in the high-concentration ropivacaine group. Other outcomes such as postoperative pain scores (p = 0.363), postoperative nausea and vomiting (p > 0.999), and postoperative opioid consumption (p = 0.699) were similar between the two groups. Conclusions: Pre-incisional low-concentration ropivacaine injection was effective for postoperative pain control and can be safely used in BABA thyroidectomy.

Total thyroidectomy can be overtreatment in cN1a papillary thyroid carcinoma patients whose tumor is smaller than 1 cm.

BACKGROUND: The 2015 American Thyroid Association (ATA) guidelines recommend pursuing total thyroidectomy with therapeutic central lymph-node dissection (CND) in patients with clinically apparent nodal disease (cN1a), regardless of tumor size. The aim of this study was to investigate whether total thyroidectomy is necessary for thyroid papillary microcarcinoma (PTMC) patients with preoperative unilateral cN1a. METHODS: This study included 295 papillary thyroid microcarcinoma patients who underwent total thyroidectomy with bilateral CND from January 2012 to June 2015. RESULTS: The median follow-up time was 42.5 months. Locoregional recurrence (LRR) was observed in only two (0.9%) patients. Among 70 cN1a patients, only 19 (27.1%) were at intermediate risk for disease recurrence and required total thyroidectomy per the ATA guidelines. Lobectomy can be considered as a treatment option for the remaining patients (72.9%). CONCLUSIONS: Our study showed that more than two-thirds of PTMC patients with clinical nodal disease who underwent total thyroidectomy and CND were actually lobectomy candidates. Total thyroidectomy as the first surgical option for cN1a, especially in PTMC patients, should be reconsidered.

The clinical impact of extrathyroidal extensions on prognoses in pediatric differentiated thyroid cancers.

BACKGROUND: The prognostic impact of extrathyroidal extensions (ETE) on clinical outcomes has not been well studied in pediatric thyroid cancers. The aim of this study was to analyze the clinicopathological characteristics and clinical outcomes according to the extent of ETE in pediatric and adolescent thyroid cancers. METHODS: This study retrospectively reviewed 89 papillary thyroid carcinoma (PTC) patients less than 19 years of age who underwent total thyroidectomy with central neck dissections (CND) between 1997 and 2018. We compared the clinicopathological features among three groups: no ETE, microscopic ETE, and gross ETE. RESULTS: The median follow-up time was 111 months. The mean age was 15.3 years and the mean tumor size was 2.4 cm. Tumor sizes larger than 2 cm (OR = 9.2, p = 0.001), exhibited bilaterality (OR = 4.3, p = 0.006), were an aggressive variant (OR = 5.8, p = 0.006), and exhibited central lymph node metastasis (OR = 1.3, p = 0.018), lateral lymph node metastasis (OR = 9.2, p = 0.001), recurrence (OR = 3.9, p = 0.038), and distant metastasis (OR = 4.4, p = 0.016) were associated with gross ETE. There was no remarkable difference in clinicopathological characteristics between the no ETE group and microscopic ETE group, except for aggressive variants (OR = 5.5, p = 0.008). There was a significant difference in recurrence-free survival (RFS) rates according to the extent of ETE (p = 0.025). Furthermore, the distant metastasis-free survival curve presented a significant difference among the three groups (p = 0.018). Both microscopic ETE and gross ETE were significantly associated with worse prognoses in pediatric thyroid cancers. CONCLUSIONS: We recommend that microscopic ETE should be included in the intermediate risk category and that gross ETE should be stratified in the high risk group in future revisions of ATA pediatric guidelines.

Feasibility of lateral sentinel lymph node biopsy in medullary thyroid cancer: Surrogate tool for determining prophylactic lateral neck dissection-A pilot study.

BACKGROUNDS: This study aimed to evaluate usefulness of lateral sentinel lymph node biopsy (SLNB) in determining lateral neck dissection (LND) of patients with medullary thyroid cancer (MTC). METHODS: Sixteen patients with MTC were enrolled in the study from January 2013 to June 2019. Intratumoral injection of technetium (Tc)-99m phytate followed by lymphoscintigraphy was performed preoperatively. Lateral sentinel lymph nodes were detected by a collimated gamma probe and underwent frozen analysis. Ipsilateral LND was performed in all patients to assess lateral LN status. RESULTS: The identification rate of sentinel lymph nodes (SLNs) detected by radioisotope was 87.5% (14 of 16 patients). The sensitivity, specificity, positive predictive value, and negative predictive value of frozen analyses were 66.7%, 100%, 100%, and 91.6%, respectively. Based on final histopathology, however, the diagnostic values of lateral SLNB were all 100%. CONCLUSIONS: This study showed that lateral SLNB can be a promising surgical tool for decisions on LND in patients with MTC.

Surgeon Volume and Long-Term Oncologic Outcomes in Patients with Medullary Thyroid Carcinoma.

BACKGROUND: Surgery is the most important curative treatment for medullary thyroid carcinoma (MTC). The relationship between surgeon volume (the number of surgeries performed) and short-term surgical outcomes, such as increased postoperative complication or costs, is well established. This study evaluated whether surgeon volume influenced long-term oncologic outcomes. METHODS: We retrospectively reviewed 246 patients diagnosed with MTC after initial thyroid surgery from 1995 to 2019. After exclusion, 194 patients were eligible for inclusion in the study. Surgeons were categorized as low/intermediate volume (fewer than 100 operations per year) or high volume (at least 100 operations per year). RESULTS: Of the 194 included patients, 60 (30.9%) developed disease recurrence, and 9 (4.6%) died of MTC during the median follow-up of 92.5 months. Having a low/intermediate-volume surgeon was associated with high disease recurrence (log-rank test, p < 0.001). After adjustment for age, sex, tumor type (sporadic versus hereditary), primary tumor size, presence of central lymph node metastasis (LNM), presence of lateral LNM, extrathyroidal extension, and positive resection margin, surgeon volume was a significant factor for disease recurrence (hazard ratio 2.28, p = 0.004); however, cancer-specific survival was not affected by surgeon volume (hazard ratio 4.16, p = 0.115). CONCLUSIONS: Surgeon volume is associated with long-term oncologic outcome. MTC patients will be able to make the best decisions for their treatment based on the results of this study.

Changes in Thyrotropin Receptor Antibody Levels Following Total Thyroidectomy or Radioiodine Therapy in Patients with Refractory Graves' Disease.

Background: The actions of thyrotropin-binding inhibitory immunoglobulins (TBIIs) against thyrotropin receptors in thyroid follicular cells have been studied as important etiological factors in Graves' disease (GD). The purpose of this study was to investigate changes in the TBII levels of patients undergoing total thyroidectomy (TTx) or radioactive iodine (RAI) therapy for GD refractory to antithyroid drugs (ATDs). Methods: We enrolled patients who underwent TTx or RAI for GD with previous ATD use between January 2011 and December 2017 at the Samsung Medical Center in Seoul, Korea. Thorough retrospective reviews of medical records were performed in 130 patients. Results: Patients with goiter, ophthalmopathy, high levels of TBIIs, and high doses of ATDs received TTx. Elderly patients with arrhythmia received RAI. We observed that TBII levels continued to decrease after TTx. On the contrary, TBIIs initially increased for 138 days (estimated median time) and then decreased slowly after RAI. A faster decline in TBII levels was observed in the TTx group than in the RAI group (p < 0.001). The estimated median time for TBIIs to decrease below 4.5 IU (3 × upper normal limit, which is known to be a risk factor for fetal hyperthyroidism) was 318 days in the TTx group and 659 days in the RAI group, respectively. In the RAI group, high levels of TBII (>4.5 IU/L) were present in 70 (82%) at 6 months, 57 (67%) at 1 year, and 3 (3%) at 2 years. In the TTx group, rapid decreases in TBII levels were observed in younger patients and those with lower baseline TBII levels. In the RAI group, smaller thyroid volume was correlated with more rapid decrease in TBII levels. Conclusions: The changes in TBII levels following TTx or RAI were different in patients with refractory GD. When deciding on TTx or RAI, this difference should be considered with patient age, severity of hyperthyroidism, goiter, ophthalmopathy, and future pregnancy plans (for young female patients).

Prognostic Value of the Neutrophil-to-Lymphocyte Ratio before and after Radiotherapy for Anaplastic Thyroid Carcinoma.

The neutrophil-lymphocyte ratio (NLR) is a marker of systemic inflammation, and its elevation has recently been associated with poor survival in many solid cancers. Leukocyte elevation and lymphocyte reduction are associated with a poor response to radiotherapy (RT). This study aimed to assess the prognostic value of NLR before and after RT for anaplastic thyroid carcinoma (ATC). This retrospective study analyzed 40 patients with ATC who received RT with available complete blood cell count data from November 1995 through May 2020 at Samsung Medical Center (Seoul, Korea). Patients were classified into two groups according to the NLR before and after RT. The median overall survival (OS) was 8.9 months (range, 3.5-18.2) in the low NLR group (<3.47) and 5.2 months (range, 2.7-7.5) months in the high NLR group (≥3.47). The association between NLR and OS was also observed in multivariable Cox regression analysis (hazard ratio, 3.18; 95% confidence interval, 1.15-8.85; p = 0.026). The OS curves differed significantly according to post-RT NLR (p = 0.036). A high NLR before and after RT may be significantly associated with poor OS in patients with ATC who receive RT.

Occult contralateral central neck metastasis in papillary thyroid carcinoma with preoperatively documented ipsilateral lateral neck metastasis.

BACKGROUND: This study was conducted to evaluate risk factors and long-term prognosis of contralateral central neck metastasis (CCNM) in papillary thyroid cancer (PTC) patients with ipsilateral lateral neck metastasis. We present clinical evidence to aid in surgical decision-making regarding the extent of central neck dissection (CND), focusing on separation between ipsilateral and contralateral sides. METHODS: A total of 379 PTC patients who underwent total thyroidectomy and concomitant bilateral central neck dissection with ipsilateral lateral neck dissection (LND) at a single institution was retrospectively included between January 1997 and December 2015. RESULTS: The median follow-up time was 83.2 months, the mean age was 44.3 years, and the mean tumor size was 1.5 cm. Among the study sample, 266 patients were female (70.2%) and 113 (29.8%) were male. Of 379 patients, CCNM was present in 34.6%. In multivariate analysis, male sex (adjusted OR = 2.46, p = 0.002), bilaterality (adjusted OR = 2.58, p = 0.004), number of metastatic ipsilateral central lymph nodes (adjusted OR = 1.15, p = 0.002), number of metastatic lateral lymph nodes (adjusted OR = 1.48, p < 0.001), and three-level metastasis (adjusted OR = 2.46, p = 0.012) were identified as risk factors of CCNM. Overall recurrence occurred in 6.0% and 11.5% of patients in the CCNM (-) group and CCNM (+) group, respectively. In addition, contralateral recurrence was observed in 1.2% patients and 0.8% patients in the CCNM (-) group and CCNM (+) group, respectively. However, CCNM did not significantly increase risk of recurrence (adjusted HR = 1.01, p = 0.981). CONCLUSIONS: Although the probability of pathological CCNM is not negligible, CCNM was not associated with higher risk of recurrence. This study suggest that central neck dissection may be limited to the ipsilateral side, and the result regarding prognosis of CCNM may help to avoid bilateral CND so that it could have potential to minimize unnecessary surgery-related complications such as recurrent laryngeal nerve(RLN) injury or hypoparathyroidism.

Deciphering the molecular mechanisms of epitranscriptome regulation in cancer.

Post-transcriptional regulation is an indispensable cellular mechanism of gene expression control that dictates various cellular functions and cell fate decisions. Recently, various chemical RNA modifications, termed the "epitranscriptome," have been proposed to play crucial roles in the regulation of post-transcriptional gene expression. To date, more than 170 RNA modifications have been identified in almost all types of RNA. As with DNA modification-mediated control of gene expression, regulation of gene expression via RNA modification is also accomplished by three groups of proteins: writers, readers, and erasers. Several emerging studies have revealed that dysregulation in RNA modification is closely associated with tumorigenesis. Notably, the molecular outcomes of specific RNA modifications often have opposite cellular consequences. In this review, we highlight the current progress in the elucidation of the mechanisms of cancer development due to chemical modifications of various RNA species. [BMB Reports 2021; 54(2): 89-97].

The mRNA m6A reader YTHDF2 suppresses proinflammatory pathways and sustains hematopoietic stem cell function.

The mRNA N6-methyladenosine (m6A) modification has emerged as an essential regulator of normal and malignant hematopoiesis. Inactivation of the m6A mRNA reader YTHDF2, which recognizes m6A-modified transcripts to promote m6A-mRNA degradation, results in hematopoietic stem cell (HSC) expansion and compromises acute myeloid leukemia. Here we investigate the long-term impact of YTHDF2 deletion on HSC maintenance and multilineage hematopoiesis. We demonstrate that Ythdf2-deficient HSCs from young mice fail upon serial transplantation, display increased abundance of multiple m6A-modified inflammation-related transcripts, and chronically activate proinflammatory pathways. Consistent with the detrimental consequences of chronic activation of inflammatory pathways in HSCs, hematopoiesis-specific Ythdf2 deficiency results in a progressive myeloid bias, loss of lymphoid potential, HSC expansion, and failure of aged Ythdf2-deficient HSCs to reconstitute multilineage hematopoiesis. Experimentally induced inflammation increases YTHDF2 expression, and YTHDF2 is required to protect HSCs from this insult. Thus, our study positions YTHDF2 as a repressor of inflammatory pathways in HSCs and highlights the significance of m6A in long-term HSC maintenance.

Highly Sensitive and Specific Molecular Test for Mutations in the Diagnosis of Thyroid Nodules: A Prospective Study of BRAF-Prevalent Population.

Molecular testing offers more objective information in the diagnosis and personalized decision making for thyroid nodules. In Korea, as the BRAF V600E mutation is detected in 70-80% of thyroid cancer specimens, its testing in fine-needle aspiration (FNA) cytology specimens alone has been used for the differential diagnosis of thyroid nodules until now. Thus, we aimed to develop a mutation panel to detect not only BRAF V600E, but also other common genetic alterations in thyroid cancer and to evaluate the diagnostic accuracy of the mutation panel for thyroid nodules in Korea. For this prospective study, FNA specimens of 430 nodules were obtained from patients who underwent thyroid surgery for thyroid nodules. A molecular test was devised using real-time PCR to detect common genetic alterations in thyroid cancer, including BRAF, N-, H-, and K-RAS mutations and rearrangements of RET/PTC and PAX8/PPARr. Positive results for the mutation panel were confirmed by sequencing. Among the 430 FNA specimens, genetic alterations were detected in 293 cases (68%). BRAF V600E (240 of 347 cases, 69%) was the most prevalent mutation in thyroid cancer. The RAS mutation was most prevalently detected for indeterminate cytology. Among the 293 mutation-positive cases, 287 (98%) were diagnosed as cancer. The combination of molecular testing and cytology improved sensitivity from 72% (cytology alone) to 89% (combination), with a specificity of 93%. We verified the excellent diagnostic performance of the mutation panel applicable for clinical practice in Korea. A plan has been devised to validate its performance using independent FNA specimens.

Diverse molecular functions of m6A mRNA modification in cancer.

N6-methyladenosine (m6A), the most prevalent chemical modification found on eukaryotic mRNA, is associated with almost all stages of mRNA metabolism and influences various human diseases. Recent research has implicated the aberrant regulation of m6A mRNA modification in many human cancers. An increasing number of studies have revealed that dysregulation of m6A-containing gene expression via the abnormal expression of m6A methyltransferases, demethylases, or reader proteins is closely associated with tumorigenicity. Notably, the molecular functions and cellular consequences of m6A mRNA modification often show opposite results depending on the degree of m6A modification in specific mRNA. In this review, we highlight the current progress on the underlying mechanisms of m6A modification in mRNA metabolism, particularly the functions of m6A writers, erasers, and readers in the context of tumorigenesis.

Preoperative Serum Thyroglobulin and Its Correlation with the Burden and Extent of Differentiated Thyroid Cancer.

Lymph node metastasis (LNM) in differentiated thyroid cancer (DTC) is usually detected with preoperative ultrasonography; however, this has limited sensitivity for small metastases, and there is currently no predictive biomarker that can help to inform the extent of surgery required. We evaluated whether preoperative serum thyroglobulin levels can predict tumor burden and extent. We retrospectively reviewed the clinical records of 4029 DTC cases diagnosed and treated at a Samsung Medical Center between 1994 and 2016. We reviewed primary tumor size, number and location of LNM, and presence of distant metastases to reveal relationships between tumor burden and extent and preoperative serum thyroglobulin levels. We found a linear association between increasing preoperative thyroglobulin levels, the size of the primary tumor, and the number of LNM (r = 0.34, p < 0.001, r = 0.20, p < 0.001, respectively). Tumor extent also increased with each decile of increasing preoperative thyroglobulin level (r = 0.18, p < 0.001). Preoperative thyroglobulin levels of 13.15 ng/mL, 30.05 ng/mL, and 62.9 ng/mL were associated with the presence of ipsilateral lateral LNM, contralateral lateral LNM, and distant metastasis, respectively. Our results suggest that preoperative measurement of serum thyroglobulin may help to predict LNM and help to tailor surgery.