Preoperative prediction of metastatic pheochromocytoma and paraganglioma using clinical, genetic, and biochemical markers: A cohort study.

BACKGROUND: The prevalence of metastatic pheochromocytoma and paraganglioma (PPGL) is approximately 15%-20%. Although there are indicators to assess metastatic risks, none of them predict metastasis reliably. Therefore, we aimed to develop and validate a scoring system using clinical, genetic, and biochemical risk factors to preoperatively predict the metastatic risk of PPGL. METHODS: In the cross-sectional cohort (n = 180), clinical, genetic, and biochemical risk factors for metastasis were identified using multivariate logistic regression analysis, and a novel scoring system was developed. The scoring system was validated and compared with the age, size of tumor, extra-adrenal location, and secretory type (ASES) score in the longitudinal cohort (n = 114). RESULTS: In the cross-sectional cohort, pseudohypoxia group-related gene variants (SDHB, SDHD, or VHL), methoxytyramine >0.16 nmol/L, and tumor size >6.0 cm were independently associated with metastasis after multivariate logistic regression. Using them, the gene variant, methoxytyramine, and size of tumor (GMS) score were developed. In the longitudinal cohort, Harrell's concordance index of the GMS score (0.873, 95% confidence interval [CI]: 0.738-0.941) was higher than that of the ASES score (0.713, 95% CI: 0.567-0.814, p = 0.007). In the longitudinal cohort, a GMS score ≥2 was significantly associated with a higher risk of metastasis (hazard ratio = 25.07, 95% CI: 5.65-111.20). A GMS score ≥2 (p < 0.001), but not ASES score ≥2 (p = 0.090), was associated with shorter progression-free survival. CONCLUSION: The GMS scoring system, which integrates gene variant, methoxytyramine level, and tumor size, provides a valuable preoperative approach to assess metastatic risk in PPGL.

Comparative outcomes and prognostic indicators in adrenalectomy for adrenal metastasis.

PURPOSE: The indications for adrenalectomy and feasibility of laparoscopic adrenalectomy for adrenal metastasis are controversial. This study aimed to compare the surgical outcomes between open adrenalectomy (OA) and laparoscopic adrenalectomy (LA) and to evaluate the prognostic factors for oncological outcomes of adrenal metastasis. MATERIALS AND METHODS: We conducted a retrospective chart review of 141 consecutive patients who underwent adrenalectomy for adrenal metastasis at Seoul National University Hospital from April 2005 to February 2021. Surgical and oncological outcomes were compared between OA and LA. RESULTS: OA was performed in 95 (67.4%) patients, and 46 (32.6%) patients underwent LA. Among the patients who underwent adrenalectomy without adjacent organ resection for adrenal tumors less than 8 cm, LA was associated with a shorter operation time (100.1 ± 48.8 vs. 158.6 ± 81.2, P = 0.001), less blood loss (94.8 ± 93.8 vs. 566.8 ± 1156.0, P = 0.034), and a shorter hospital stay (3.7 ± 1.3 vs. 6.9 ± 5.8, P = 0.003). For locoregional recurrence-free survival (LRRFS), on multivariate analysis, a positive pathological margin (hazard ratio [HR]: 5.777, P = 0.002), disease activity at the primary site (HR: 6.497, P = 0.005), other metastases (HR: 4.154, P = 0.015), and a relatively larger tumor size (HR: 1.198, P = 0.018) were significantly associated with poor LRRFS. Multivariate analysis indicated that metachronous metastasis (HR: 0.51, P = 0.032) was associated with a longer overall survival (OS), whereas a positive pathological margin (HR: 2.40, P = 0.017), metastases to other organs (HR: 2.08, P = 0.025), and a relatively larger tumor size (HR: 1.11, P = 0.046) were associated with a shorter OS. CONCLUSIONS: LA is a feasible treatment option for adrenal metastasis in selected patients. The pathological margin, metastases to other organs, and tumor size should be considered in adrenalectomy for adrenal metastasis.

Surgical Outcomes in Patients With Low-risk Papillary Thyroid Microcarcinoma From MAeSTro Study: Immediate Operation Versus Delayed Operation After Active SurveillanceA Multicenter Prospective Cohort Study.

OBJECTIVE: To investigate surgical, and clinical outcomes in patients with low-risk papillary thyroid microcarcinoma (PTMC) according to treatment options [immediate operation (IOP) vs delayed operation after active surveillance (AS) (DOP)]. BACKGROUND: AS has been adopted as an alternative to immediate surgery in patients with low-risk PTMC. Although some patients undergo surgery during AS, there is little information on surgical, and clinical outcomes after delayed operation after AS. METHODS: A multicenter prospective cohort study including 1177 patients was conducted at 3 tertiary hospitals in Korea from June 2016 to January 2020. Patients with low-risk PTMC were enrolled. The participants were self-assigned into AS or IOP, and during AS, the patients underwent surgery if there were signs of disease progression or if the patient's choice changed. RESULTS: A total of 516 patients underwent operation; 384 (74.4%) in the IOP group and 132 (25.6%) in the DOP group. Compared with the IOP group, the DOP group was significantly associated with a larger tumor size ( P =0.002), higher rates of lymphatic invasion ( P =0.002), and multifocality ( P =0.008). However, the rates of total thyroidectomy, postoperative hypoparathyroidism and vocal cord palsy did not differ significantly between the groups ( P = 0.283, P =0.184, and P =0.284, respectively). Of the 132 patients in the DOP group, disease progression was present in 39 (29.5%) patients. The DOP group with disease progression had a significantly higher rate of lymph node metastasis ( P =0.021) and radioiodine therapy ( P =0.025) than the DOP group without disease progression. CONCLUSIONS: These results suggest that AS might be considered an alternative treatment option for patients with low-risk PTMC regarding the extent of thyroidectomy and postoperative complications in the DOP group. To assess oncologic outcomes, long-term follow-up will be needed. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02938702.

US Predictors of Papillary Thyroid Microcarcinoma Progression at Active Surveillance.

Background Active surveillance (AS) is an accepted strategy for patients with low-risk papillary thyroid microcarcinoma (PTMC). While previous studies have evaluated the prognostic value of US features, results have been inconsistent. Purpose To determine if US features can help predict tumor progression in patients with low-risk PTMC undergoing AS. Materials and Methods This prospective study enrolled 1177 participants with PTMC from three hospitals between June 2016 and January 2021. Participants were self-assigned to either immediate surgery or AS, and those with two or more US examinations in the absence of surgery were included in the analysis. A χ2 test was used to compare estimated tumor progression rate at 4 years between participants stratified according to US features. Multivariable Cox regression analysis was used to assess the association of clinical and US features with overall tumor progression and specific progression criteria. Results Among 699 participants included in the analysis, 68 (mean age, 49 years ± 12 [SD]; 40 female participants) showed tumor progression (median follow-up, 41.4 months ± 16 [SD]). Tumor progression was associated with the US features of diffuse thyroid disease (DTD) (hazard ratio [HR], 2.3 [95% CI: 1.4, 3.7]; P = .001) and intratumoral vascularity (HR, 1.7 [95% CI: 1.0, 3.0]; P = .04) and the participant characteristics of male sex (HR, 2.8 [95% CI: 1.7, 4.6]; P < .001), age less than 30 years (HR, 2.9 [95% CI: 1.2, 6.8]; P = .01), and thyroid-stimulating hormone level of 7 µU/mL or higher (HR, 6.9 [95% CI: 2.7, 17.4]; P < .001). The risk of tumor progression was higher for participants with DTD (14%, P = .001) or intratumoral vascularity (14%, P = .02) than for participants without these features (6%). DTD and intratumoral vascularity were associated with tumor enlargement (HR, 2.7 [95% CI: 1.4, 5.1]; P = .002) and new lymph node metastasis (HR, 5.0 [95% CI: 1.3, 19.4]; P = .02), respectively. Conclusion DTD and intratumoral vascularity were associated with an increased risk of tumor progression in participants with PTMC undergoing AS. Clinical trial registration no. NCT02938702 © RSNA, 2023 Supplemental material is available for this article. See also the editorial by Reuter and the review "International Expert Consensus on US Lexicon for Thyroid Nodules" by Durante et al in this issue.

Effect of postoperative radiotherapy for patients with differentiated thyroid cancer.

OBJECTIVE: We evaluated the efficacy and safety of postoperative radiotherapy (PORT) for differentiated thyroid cancer (DTC) with high risk features. MATERIALS AND METHODS: This retrospective study analyzed 187 patients treated for DTC from 1985 to 2019. DTC referred to nonanaplastic thyroid cancer originating from follicular cells. PORT was defined as the administration of external beam radiation to the thyroid and regional lymph nodes following surgery for initially diagnosed DTC. The patients were included in the analysis if they received PORT or exhibited any of the following features: (a) pT4 or pN1b according to the 8th American Joint Committee on Cancer, (b) poorly differentiated thyroid cancer (PDTC), or (c) unfavourable variants such as anaplastic foci and etc. After 1:1 propensity matching, a total of 108 patients were analyzed according to PORT receipt. The median follow-up duration of the matched group was 10.4 years. RESULTS: After matching, most of the variables became balanced, but the PORT group still had more PDTC and DTC with anaplastic foci. Radioactive iodine (RAI) was less frequently administered in the PORT group. PORT yielded a significantly higher 5-year locoregional recurrence free survival (LRFS) than the No PORT group (5-year LRFS 86.1% vs. 72.7%, p = 0.022), but the 10-year cancer specific survival (CSS) was similar between them (97.8% vs. 85.9%, p = 0.122). The multivariable analysis indicated that PORT was a favourable prognostic factor (Hazard ratio 0.3, 95% Confidence interval 0.1-0.8, p = 0.02) for LRFS, but not for CSS. Among 133 patients without PORT for initial disease, 39 of them received salvage surgery followed by salvage PORT. No severe toxicity after PORT was reported. CONCLUSION: PORT reduced locoregional recurrence in DTC patients without severe toxicity. PORT can be an effective and safe treatment to improve locoregional control in DTC with high risk features. However, further study is warranted to identify those who can benefit from PORT.

A Time Trend Analysis of 5,000 Robotic Thyroidectomies via Bilateral Axillo-Breast Approach.

BACKGROUND: This study aimed to investigate the time trends of surgical outcomes in patients who underwent bilateral axillo-breast approach robotic thyroidectomy (BABA RT) over the last 14 years. METHODS: From February 2008 to September 2021, we conducted a retrospective medical chart review of 5,011 consecutive patients who underwent BABA RT at three Seoul National University-affiliated hospitals. The patients were divided into three groups based on the main model of the da Vinci robotic surgical system to evaluate trends in surgical treatment strategies and outcomes after BABA RT. RESULTS: Of the 5,011 patients (4,706 malignant and 305 benign), the most common histological subtype was papillary thyroid carcinoma (n = 4,584; 97.4%). The mean tumor size significantly increased from 0.8 cm to 1.2 cm (p < 0.05). The mean numbers of metastatic and harvested lymph nodes from the central neck dissection and the lateral neck dissection showed a significant difference and tendency to increase (from 0.9 to 1.6, 4.7 to 6.2, p < 0.05, and from 0.6 to 3.9, 5.3 to 17.9, p < 0.05), respectively, throughout the study period. Permanent hypoparathyroidism decreased from 3.4 to 2.9%. The rate of transient and permanent vocal cord palsy decreased from 15.2 to 2.7% and from 0.7 to 0.2%, respectively. CONCLUSION: With advancements in robotic surgical systems and improvements in the BABA RT technique, surgical indications have expanded to include more advanced thyroid diseases, and surgical outcomes have improved over the last 14 years.

Characteristics of germline mutations in Korean patients with pheochromocytoma/paraganglioma.

BACKGROUND: Pheochromocytomas and paragangliomas (PPGLs) are catecholamine-producing neuroendocrine tumours. PPGLs are a rare but important cause of secondary hypertension owing to their high morbidity and mortality. Patients with PPGL exhibit an increased prevalence of mutations in one of the PPGL susceptibility genes according to previous studies. We aimed to investigate the characteristics of germline mutations in the largest number of Korean patients with PPGL. METHODS: In this study, 161 patients with PPGL were evaluated. Phenotype data, including biochemical, pathological and anatomical imaging results, were collected. Germline mutations in 10 PPGL-related genes were tested by targeted next-generation sequencing (NGS), Sanger sequencing and multiplex ligation-dependent probe amplification. RESULTS: Approximately 21% of apparently sporadic PPGLs harboured germline mutations of the PPGL-related genes. The mutation carriers were younger at the first diagnosis and had more bilateral (28.6% vs 4.0%, p<0.001) and multifocal (11.4% vs 1.6%, p=0.027) PPGLs, but showed no metastatic risk (17.1% vs 11.1%, p=0.504), than non-mutation carriers. Missense mutation of SDHD p.V111I was found in this cohort of Asian patients, which was associated with unilateral pheochromocytoma with dominantly epinephrine production. CONCLUSION: This study covered the largest number of Korean patients with PPGL. To our knowledge, it is the first to compare results of targeted NGS panel with those of conventional sequencing methods in Asia. We demonstrated that the variant type, as well as the mutated gene, may determine the phenotype and prognosis of PPGLs.

Expression of CYP11B1 and CYP11B2 in adrenal adenoma correlates with clinical characteristics of primary aldosteronism.

OBJECTIVE: Primary aldosteronism (PA) shows histological heterogeneity and clinical variability, including the coexistence of hypercortisolemia. Immunohistochemical analyses of steroidogenic enzymes in adrenal tissues have provided new insights into the pathogenesis of PA. However, a comprehensive analysis of the association between enzyme expression and clinical characteristics of PA has rarely been conducted. We aimed to investigate the correlation between clinical characteristics and steroidogenic enzyme expression in PA. DESIGN: A retrospective case-control study. PATIENTS: Consecutive patients who underwent unilateral adrenalectomy for PA (n = 180). Patients with adrenal Cushing's syndrome (CS) (n = 29) and nonfunctioning adenoma (n = 6) as comparator groups. MEASUREMENTS: A tissue microarray of adrenal adenomas was constructed and immunostained for CYP11B1, CYP11B2 and CYP17A1. The expression of the three enzymes was compared between PA and other adrenal diseases and between PA with and without mild autonomous cortisol excess (MACE). RESULTS: Adrenal adenomas in PA showed lower CYP11B1, higher CYP11B2 and lower CYP17A1 expression than those in adrenal CS (p < .001). Nonfunctioning adenomas showed low expression of the three enzymes. PA with MACE showed higher CYP11B1 expression than PA without MACE. CYP11B1 expression was positively correlated with the severity of hypercortisolemia, and CYP11B2 was positively correlated with that of hyperaldosteronism. The expression of CYP11B1 and CYP11B2 had a negative correlation. Patients with absent clinical improvement after adrenalectomy had lower CYP11B2 expression than those with complete success. CONCLUSIONS: Variable expression of steroidogenic enzymes in adrenal adenoma underlies the clinical heterogeneity of PA and is associated with treatment outcomes.

Indices of ACTH-stimulated adrenal venous sampling as predictors of postsurgical outcomes in primary aldosteronism.

OBJECTIVE: This study aimed to investigate the impact of indices of adrenal venous sampling (AVS) on postsurgical outcomes in patients with primary aldosteronism (PA). DESIGN AND PATIENTS: This retrospective study determined biochemical and clinical outcomes based on ACTH-stimulated AVS parameters (lateralisation index [LI], contralateral ratio [CLR], and ipsilateral ratio [ILR]) in 251 patients with PA at 3 months after surgery. RESULTS: Modified complete biochemical success was achieved in 8 of 12 (66.7%) patients with LI = 3-4, 39 of 47 (83.0%) with LI = 4-10, and 155 of 169 (91.7%) with LI ≥ 10 (p = .004 for trend). Modified complete biochemical success was achieved in 29 of 38 (76.3%) patients with CLR ≥ 1 and ILR ≤ 2, 73 of 86 (84.9%) with CLR = 0.25-1 and ILR > 2, and 100 of 104 (96.2%) with CLR < 0.25 and ILR > 2 (p = .001 for trend). After adjusting for confounders, modified complete biochemical success was associated with an LI ≥ 10 (odds ratio [OR] = 6.32; 95% confidence interval [CI] = 1.33-29.93) using LI = 3-4 as a reference and combined CLR < 0.25 and ILR > 2 (OR = 11.49; 95% confidence interval [CI] = 2.49-53.01) using combined CLR ≥ 1 and ILR ≤ 2 as a reference. Using combined CLR ≥ 1 and ILR ≤ 2 as a reference, complete clinical success was associated with combined CLR < 0.25 and ILR > 2 (OR = 3.10; 95% CI = 1.03-9.28) and combined CLR = 0.25-1 and ILR > 2 (OR = 4.92; 95% CI = 1.64-14.76). CONCLUSION: LI ≥ 10 may be appropriate for achieving biochemical success. With ILR > 2, CLR < 0.25, and CLR < 1 may be appropriate for achieving biochemical and clinical success, respectively.

Comparison of Recurrent Laryngeal Nerve Identification Time in the Lower Central Triangle during Thyroid Surgery Using Neurophysiological Mapping and Monitoring.

Background and Objectives: Preserving the recurrent laryngeal nerve (RLN) is important in thyroid surgery. However, no standardized surgical method for locating the RLN has been established. We defined a new anatomical definition termed "lower central triangle" (LCT) for consistent identification of RLN and used intraoperative nerve monitoring (IONM) to aid in identification and dissection of RLN. Materials and Methods: Patients undergone thyroidectomy were reviewed retrospectively in Seoul National University Bundang Hospital from January to September 2017. Patients with papillary thyroid carcinoma, follicular neoplasm, and Graves' Disease were included while right side non-RLN in arteriosus lusoria, cancer invasion, pre-existing vocal cord palsy, or under the age of 18 were excluded. RLNs were tested with IONM within LCT consisting of the lower pole as the apex and the common carotid artery as the opposite side. The samples were divided into two groups, IONM and non-IONM. Results: Forty lobes in total were included, 22 in IONM group and 18 in non-IONM group. Groups were not significantly different in age, cancer proportion, and accompanying thyroiditis while sex and nodule size differed. RLN detection time was 10.43 s shorter (p < 0.001), and confirmation time was 10.67 s shorter (p = 0.09) in IONM group than in non-IONM group. Both right and left RLNs were located predominately in the middle of LCT. No transient or permanent vocal cord palsy occurred. Conclusions: While IONM is an appropriate aid for thyroidectomy, our approach using LCT to locate the RLN is a novel definition of anatomy that provides prompt identification of the RLN in thyroid surgery.

Comparison of Perioperative Outcomes Using the da Vinci S, Si, X, and Xi Robotic Platforms for BABA Robotic Thyroidectomy.

Background and Objectives: Robotic thyroidectomy via the bilateral axillo-breast approach (BABA), first introduced in Korea in 2008, has become a standard method of thyroid removal worldwide. The introduction of robotic surgical systems has enabled more patients to benefit from BABA robotic thyroidectomy, with good postoperative and excellent cosmetic results. To date, no studies have compared the benefits of the four currently available da Vinci robotic systems (S, Si, X, and Xi) for BABA robotic thyroidectomy. To determine the da Vinci model most suitable for BABA robotic thyroidectomy, the present study compared the perioperative outcomes in patients who underwent BABA robotic thyroidectomy using the four da Vinci models. Materials and Methods: This retrospective study evaluated outcomes in patients (n = 750) who underwent BABA robotic thyroidectomy using the four da Vinci systems from 2013 to 2019. The clinicopathologic data, including operation time, were compared. Substudy A compared the da Vinci models S and Si from 2013 to 2017, and substudy B compared models Si, X, and Xi from 2018 to 2019. Results: Substudy A, comparing the da Vinci S and Si systems, found no statistically significant differences between the two groups, whereas substudy B found that operation time was shorter in patients who underwent BABA robotic thyroidectomy with the da Vinci Xi system than with the Si and X systems. Conclusions: The da Vinci model Xi system can benefit patients undergoing BABA robotic thyroidectomy by shortening the operation time.

Functional Voice and Swallowing Outcome Analysis After Thyroid Lobectomy: Transoral Endoscopic Vestibular Versus Open Approach.

BACKGROUND: The transoral endoscopic thyroidectomy vestibular approach (TOETVA) is a scarless remote-access thyroidectomy technique. This study compared subjective and objective voice outcomes and swallowing outcomes of patients who underwent thyroid lobectomy using the TOETVA versus conventional open thyroidectomy (OT). METHODS: In addition to questionnaires, acoustic and aerodynamic analyses were performed to compare subjective and objective voice outcomes of the two groups. Swallowing outcome analyses were conducted using Swallowing Impairment Index-6 (SIS-6) scores. Assessments were performed preoperatively and 3 and 6 months after surgery. Propensity score matching was performed to compare the outcomes of the two groups. RESULTS: One hundred and two patients were included in this study (52 TOETVA and 50 OT). Excluding two patients who had vocal cord palsy and open conversion in the TOETVA group, 100 patients completed 3-month postoperative surveys. There were no significant differences between the groups in VAS, GRBAS, or VHI-10 scores at the preoperative and 3- and 6-month assessments. For both groups, there were no significant changes in acoustic or aerodynamic parameters during the 3-6-month postoperative period. The TOETVA group had lower SIS-6 scores at the postoperative 6-month assessment, but the SIS-6 scores after 12 months were similar between groups before and after propensity score matching. CONCLUSIONS: Following TOETVA lobectomy, there were no significant changes in voice outcomes 3 and 6 months after surgery, and the outcomes were comparable with those of OT. The TOETVA group also had swallowing outcomes that were comparable with the OT group.

Does Thyroidectomy Impact Quality of Life: Retrospective Case-Control Study of Post-Thyroidectomy Patients and Matched Individuals from the General Population.

Background and objectives: The study assesses quality of life (QoL) in patients who underwent thyroidectomy compared to the general population. Materials and Methods: QoL data from post-thyroidectomy patients and individuals with no subjective health concerns, who had attended a routine health screening visit, were evaluated. QoL was assessed using the modified version of Korean Short Form 12 questionnaire (SF-12). Patients and controls were matched using the propensity score approach and a ratio of 1:4. Results: Data from a total of 105 patients and 420 controls were analyzed. For five SF-12 items, lower QoL was found in patients (p < 0.05). Multivariate analysis revealed that a follow-up duration of <1-year, female sex, and an age of >50 years were independent risk factors. No significant difference was found between controls and patients who were >1-year post-surgery. Conclusions: For specific SF-12 items, QoL was lower in post-thyroidectomy patients than in controls. No intergroup difference in QoL was found >1-year post-surgery.

Postoperative Chylothorax after Modified Radical Neck Dissection for Thyroid Carcinoma: A Missable Rare Complication of Thyroid Surgery.

Background and objectives: Currently, few studies have been conducted on postoperative chylothorax, specifically in total thyroidectomy with modified radical neck dissection (MRND) in papillary thyroid carcinoma patients. This study provides the actual incidence, etiology, and clinical features of postoperative chylothorax and reports the clinical outcomes after treatment, which were dependent upon the severity of the complications. Materials and Methods: The medical charts of 111 papillary thyroid cancer (PTC) patients who underwent total thyroidectomy with modified radical neck dissection from January 2016 to December 2018 were reviewed retrospectively. The results were compared in three groups: the no chylothorax group, the subclinical (asymptomatic) group, and the clinical (symptomatic) group. Results: Chylothorax occurred in 23 patients (20.7%, 23/111). Nineteen (82.6%, 19/23) were subclinical chylothorax cases, which implies a small amount of chyle leakage with no respiratory symptoms. Four (17.4%, 4/23) were clinical, meaning they had either respiratory symptoms, such as dyspnea, desaturation, or a large amount of chylothorax in the images. The incidence was significantly higher in patients who underwent left modified radical neck dissection, and this corresponds to the side in which chylothorax occurred. There were also statistical differences in the drainage color, peak amount, or drain removal time. Conclusions: Postoperative chylothorax is a rare complication following neck dissection. However, it can be fatal if the condition progresses. Therefore, patients who undergo total thyroidectomy with modified radical neck dissection, especially on the left side, should be monitored for respiratory symptoms, and serial chest x-ray images obtained.

Anti-PD-1/PD-L1 therapy augments lenvatinib's efficacy by favorably altering the immune microenvironment of murine anaplastic thyroid cancer.

Patients with anaplastic thyroid cancer (ATC) have an extremely poor prognosis despite multimodal therapy with surgery and chemoradiation. Lenvatinib, a multi-targeted tyrosine kinase inhibitor, as well as checkpoint inhibitors targeting the programmed cell death pathway, have proven effective in some patients with advanced thyroid cancer. Combination of these therapies is a potential means to boost effectiveness and minimize treatment resistance in ATC. We utilized our novel immunocompetent murine model of orthotopic ATC to demonstrate that lenvatinib led to significant tumor shrinkage and increased survival, while combination therapy led to dramatic improvements in both. Lenvatinib monotherapy increased tumor-infiltrating macrophages, CD8+ T-cells, regulatory T-cells, and most notably, polymorphonuclear myeloid derived suppressor cells (PMN-MDSCs). While both combination therapies led to further increases in CD8+ T-cells, only the lenvatinib and anti-PD-1 combination decreased PMN-MDSCs. PMN-MDSC expansion was also seen in the blood of mice and one patient receiving lenvatinib therapy for ATC. RNA-Seq of the ATC cell line used in our mouse model demonstrated that lenvatinib has multifaceted effects on angiogenesis, response to hypoxia, the epithelial-to-mesenchymal transition, and on multiple pathways implicated in inflammation and host immunity. Combination of lenvatinib with anti-Gr-1 antibody ameliorated lenvatinib's expansion of MDSCs and significantly improved lenvatinib's anti-tumor effect. These data suggest that MDSCs play a negative role in ATC's response to lenvatinib and support future study of their role as a potential biomarker and treatment target.

Lateral Transperitoneal Adrenalectomy Versus Posterior Retroperitoneoscopic Adrenalectomy for Benign Adrenal Gland Disease: Randomized Controlled Trial at a Single Tertiary Medical Center.

OBJECTIVE: The aim of this study was to compare the surgical outcomes of lateral transperitoneal adrenalectomy (LTA) and posterior retroperitoneoscopic adrenalectomy (PRA) for benign adrenal tumor. BACKGROUND: Although LTA is the standard treatment for benign adrenal gland tumor, PRA has recently gained popularity. Studies comparing the surgical outcomes of the 2 approaches have reported conflicting findings and thus it remains unclear which approach is superior. METHODS: This trial was conducted between September 2012 and February 2016. Patients were randomized to either LTA or PRA groups in a 1:1 ratio using web-based randomization. The primary outcome was operative time, and the secondary outcomes were blood loss, intraoperative hemodynamic stability, postoperative pain, recovery of bowel movement, and complication rates. This trial was registered with ClincalTrials.gov, number NCT01676025. RESULTS: A total of 83 patients were randomly assigned to the LTA group (n = 42) or the PRA group (n = 41). Median follow-up was 31.3 months. The mean operative times of LTA and PRA were comparable (59.7 ±â€Š18.6 vs 67.6 ±â€Š28.7 minutes, P = 0.139). Logistic regression analysis showed that male sex [odds ratio (OR) = 4.20] and pheochromocytoma (OR = 5.06) were associated with an operative time ≥60 minutes. There were no differences in the secondary outcomes between the groups. One patient in the PRA group required open conversion. CONCLUSION: Both LTA and PRA were performed safely with similar operative outcomes, and thus are comparable options for the treatment of benign adrenal gland tumor.

Comprehensive Analysis of the Transcriptional and Mutational Landscape of Follicular and Papillary Thyroid Cancers.

Follicular thyroid carcinoma (FTC) and benign follicular adenoma (FA) are indistinguishable by preoperative diagnosis due to their similar histological features. Here we report the first RNA sequencing study of these tumors, with data for 30 minimally invasive FTCs (miFTCs) and 25 FAs. We also compared 77 classical papillary thyroid carcinomas (cPTCs) and 48 follicular variant of PTCs (FVPTCs) to observe the differences in their molecular properties. Mutations in H/K/NRAS, DICER1, EIF1AX, IDH1, PTEN, SOS1, and SPOP were identified in miFTC or FA. We identified a low frequency of fusion genes in miFTC (only one, PAX8-PPARG), but a high frequency of that in PTC (17.60%). The frequencies of BRAFV600E and H/K/NRAS mutations were substantially different in miFTC and cPTC, and those of FVPTC were intermediate between miFTC and cPTC. Gene expression analysis demonstrated three molecular subtypes regardless of their histological features, including Non-BRAF-Non-RAS (NBNR), as well as BRAF-like and RAS-like. The novel molecular subtype, NBNR, was associated with DICER1, EIF1AX, IDH1, PTEN, SOS1, SPOP, and PAX8-PPARG. The transcriptome of miFTC or encapsulated FVPTC was indistinguishable from that of FA, providing a molecular explanation for the similarly indolent behavior of these tumors. We identified upregulation of genes that are related to mitochondrial biogenesis including ESRRA and PPARGC1A in oncocytic follicular thyroid neoplasm. Arm-level copy number variations were correlated to histological and molecular characteristics. These results expanded the current molecular understanding of thyroid cancer and may lead to new diagnostic and therapeutic approaches to the disease.

The application of subcapsular saline injection during bilateral axillo-breast approach robotic thyroidectomy: a preliminary report.

PURPOSE: Saving the parathyroid gland during robotic thyroidectomy is challenging. This study evaluated the application of a novel method, subcapsular saline injection (SCASI), to save the parathyroid gland during bilateral axillo-breast approach (BABA) robotic total thyroidectomy. METHODS: Of the 81 included patients operated on from 2014 to 2016, 31 and 50 underwent BABA robotic total thyroidectomy with and without SCASI, respectively. Serum concentrations of parathyroid hormone (PTH), calcium, and ionized calcium were measured at 1 day and 9 months postoperatively. Transient hypoparathyroidism was defined as PTH < 10.0 pg/mL after 1 day and permanent hypoparathyroidism as PTH < 15.0 pg/mL at 9 months. RESULTS: There were no significant clinicopathologic differences between the two groups. The rate of transient hypoparathyroidism was significantly lower in the SCASI group than in the non-SCASI group [16.1% (5/31) vs. 44% (22/50), p < 0.01]. However, the rates of permanent hypoparathyroidism [0% (0/31) vs. 4% (2/50), p = 0.699] did not differ significantly. CONCLUSIONS: SCASI is a feasible and safe method of saving the parathyroid gland during BABA robotic total thyroidectomy.

Comparison of Immunohistochemistry and Direct Sequencing Methods for Identification of the BRAFV600E Mutation in Papillary Thyroid Carcinoma.

BACKGROUND: BRAFV600E mutation is the most common somatic variant in papillary thyroid carcinoma (PTC) and is associated with aggressive prognostic factors. The conventional detection method for BRAF mutations is polymerase chain reaction followed by Sanger sequencing. Recently, an immunohistochemistry (IHC) method using a BRAFV600E-specific antibody (VE1) has been developed and widely adopted in the clinics; however, there is a lack of evidence regarding the comparability of the IHC and Sanger sequencing methods. METHODS: Our institution began using the BRAFV600E IHC test in January 2013. We retrospectively analyzed 697 samples that were tested using both the IHC and sequencing methods, and evaluated their concordance. RESULTS: BRAF mutation was detected in 90.0% (627/697) of samples using IHC and 83.4% (581/697) of samples using direct sequencing. The diagnostic parameters of IHC compared with Sanger sequencing were as follows: 100% sensitivity (581/581), 60.3% specificity (70/116), 92.7% positive predictive value (581/627), and 100% negative predictive value (70/70). No false negative results were recorded using IHC. The overall concordance rate between the two methods was 93.4% (651/697). Discordant results were found in 46 samples (6.6%), 29 of which were from cases with small tumors (< 6 mm), 8 were from cases with low tumor cellularity, and 9 were specimens yielding low-quality DNA. CONCLUSIONS: IHC using the VE1 antibody is a reliable and highly sensitive method for detecting the BRAFV600E mutation in classic PTC.

Prevention of total thyroidectomy in noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) based on combined interpretation of ultrasonographic and cytopathologic results.

OBJECTIVE: To explore the potential preoperative ultrasonography (US) and cytopathological features to avoid total thyroidectomy in NIFTP. CONTEXT: Recently, it has been proposed that that noninvasive follicular thyroid neoplasms with papillary-like nuclear features (NIFTP) be classified as tumours, rather than cancer. PATIENTS: A total of 142 surgically proven follicular variant papillary thyroid carcinomas (FVPTCs; 45 NIFTP, 97 non-NIFTP; mean size: 20.4±11.0 mm, range: 10.0-65.0 mm) from 142 patients were included in this study. MEASUREMENTS: Three preoperative features of thyroid nodules (each US finding, US and Bethesda category) were compared in NIFTP and non-NIFTP groups. The preoperative decision-making process to avoid total thyroidectomy in NIFTP was evaluated based on combination of those features. RESULTS: In each US finding, there was only significantly less macrocalcification in the NIFTP group than in the non-NIFTP group (8.8% [4/45] vs 32.0% [31/97], P = .006). In US category, all of the NIFTP nodules were a low or intermediate suspicion (100% [45/45]). In Bethesda category, 26.7% [12/45] of the NIFTP was diagnosed as either suspicious malignancy or malignant, which increased the risk of a total thyroidectomy. In our study, a total thyroidectomy might be avoided in all of the NIFTP cases if lobectomy was selected for the nodules classified as a low or intermediate suspicion in US, despite being classified as a suspicious malignancy or malignant by cytopathology. CONCLUSIONS: Combining the US and cytopathological results could sensitively reduce total thyroidectomy in cases of NIFTP.