Active Surveillance Versus Immediate Surgery for Low-Risk Papillary Thyroid Microcarcinoma Patients in South Korea: A Cost-Minimization Analysis from the MAeSTro Study.

Background: Active surveillance (AS) has been established as an alternative to immediate surgery for low-risk papillary thyroid microcarcinoma (PTMC). Nonetheless, it remains difficult to decide between AS and immediate surgery, since limited objective evidence exists regarding risks and benefits. The aim of study is to compare the cumulative costs of AS and immediate surgery. Methods: To estimate cumulative costs, a hypothetical model is simulated based on the Multicenter Prospective Cohort Study of Active Surveillance on Papillary Thyroid Micro-Carcinoma (MAeSTro) study, a multicenter prospective cohort study of AS for PTMC. Direct and indirect costs are estimated from diagnosis to the treatment decision and follow-up for 10 years and a longer period. In the case of the scenarios, AS, AS to surgery due to changing their mind, and lobectomy (analyzed regardless of levothyroxine [LT4] treatment, as well as subdivided into lobectomy/LT4[-] and lobectomy/LT4[+]) are considered. A sensitivity analysis is performed using different discount rates to address uncertainties in future time costs. To compare the cumulative costs, we referred to previous research conducted in Hong Kong, the United States, and Japan. Results: The initial cost of AS is estimated to be 5.6 times lower than that of lobectomy (regardless of LT4 use), while the 10-year cumulative costs of AS ($2545) and lobectomy regardless of LT4 ($3045) are similar under a discount rate of 3%. However, in the long-term follow-up period, immediate surgery is going to be estimated more economical than AS. The costs of the two management approaches are similar in Hong Kong, but substantially different in the United States and Japan, implying that it could be affected by each country's national health insurance coverage and the thyroid ultrasound interval during follow-up. Conclusion: Considering both direct and indirect costs, the cumulative costs of AS and immediate surgery in low-risk PTMC patients are similar during 10 years, and surgery could be more economical for patients with a life expectancy in long-term follow-up. However, careful interpretation is needed for long-term follow-up and the country's health care system and environment. Nevertheless, considering the representative protocols and objective costs in South Korea, it is expected to be a key to suggest the appropriate treatment for PTMC patients.

Reinforced-hydrogel encapsulated hMSCs towards brain injury treatment by trans-septal approach.

Encapsulated stem cells in various biomaterials have become a potentially promising cell transplantation strategy in the treatment of various neurologic disorders. However, there is no ideal cell delivery material and method for clinical application in brain diseases. Here we show silk fibroin (SF)-based hydrogel encapsulated engineered human mesenchymal stem cells (hMSCs) to overproduce brain-derived neurotrophic factor (BDNF) (BDNF-hMSC) is an effective approach to treat brain injury through trans-septal cell transplantation in the rat model. In this study, we observed SF induced sustained BDNF production by BDNF-hMSC both in 2D (9.367 ± 1.969 ng/ml) and 3D (7.319 ± 0.1025 ng/ml) culture conditions for 3 days. Through immunohistochemistry using α-tubulin, BDNF-hMSCs showed a significant increased average neurite length of co-cultured neuro 2a (N2a) cells, suggested that BDNF-hMSCs induced neurogenesis in vitro. Encapsulated BDNF-hMSC, pre-labeled with the red fluorescent dye PKH-26, exhibited intense fluorescence up to 14 days trans-septal transplantation, indicated excellent viability of the transplanted cells. Compared to the vehicle-treated, encapsulated BDNF- hMSC demonstrated significantly increased BDNF level both in the sham-operated and injured hippocampus (Hip) through immunoblot analysis after 7 days implantation. Transplantation of the encapsulated BDNF-hMSC promoted neurological functional recovery via significantly reduced neuronal death in the Hip 7 days post-injury. Using magnetic resonance imaging (MRI) analysis, we demonstrated that encapsulated BDNF-hMSC reduced lesion area significantly at 14 and 21 days in the damaged brain following trans-septal implantation. This stem cell transplantation approach represents a critical set up towards brain injury treatment for clinical application.

Endoscope-assisted transoral accessory parotid mass excision: Multicenter prospective observational study.

OBJECTIVE: Transoral surgery is gaining favor because it has the advantage of leaving no scar after surgery. The aim of this study was to evaluate the technical feasibility and safety of endoscope-assisted transoral accessory parotid mass excision. STUDY DESIGN: Multicenter, prospective, observational study. METHODS: This study was designed as a 7-year, prospective, multicenter evaluation of endoscope-assisted transoral accessory parotid mass excision. Clinical outcomes and complications related to the procedures were evaluated in patients. RESULTS: Twenty patients underwent endoscope-assisted transoral accessory parotid mass excisions, and 22 patients underwent conventional parotidectomy approach excisions. There was no significant difference with respect to overall demographic characteristics between the groups. However, the operation times were shorter in the transoral approach group (P = 0.001), and cosmetic satisfaction was much better in the transoral group (P < 0.001). CONCLUSION: Endoscope-assisted transoral accessory parotid mass excision is a potentially safe and effective procedure with excellent outcomes. LEVEL OF EVIDENCE: 2 Laryngoscope, 130:1218-1226, 2020.

PLAG1, SOX10, and Myb Expression in Benign and Malignant Salivary Gland Neoplasms.

BACKGROUND: Recent findings in molecular pathology suggest that genetic translocation and/oroverexpression of oncoproteins is important in salivary gland tumorigenesis and diagnosis. Weinvestigated PLAG1, SOX10, and Myb protein expression in various salivary gland neoplasm tissues. METHODS: A total of 113 cases of surgically resected salivary gland neoplasms at the NationalCancer Center from January 2007 to March 2017 were identified. Immunohistochemical stainingof PLAG1, SOX10, and Myb in tissue samples was performed using tissue microarrays. RESULTS: Among the 113 cases, 82 (72.6%) were benign and 31 (27.4%) were malignant. PLAG1 showednuclear staining and normal parotid gland was not stained. Among 48 cases of pleomorphicadenoma, 29 (60.4%) were positive for PLAG1. All other benign and malignant salivary glandneoplasms were PLAG1-negative. SOX10 showed nuclear staining. In normal salivary gland tissuesSOX10 was expressed in cells of acinus and intercalated ducts. In benign tumors, SOX10 expressionwas observed in all pleomorphic adenoma (48/48), and basal cell adenoma (3/3), but not inother benign tumors. SOX10 positivity was observed in nine of 31 (29.0%) malignant tumors.Myb showed nuclear staining but was not detected in normal parotid glands. Four of 31 (12.9%)malignant tumors showed Myb positivity: three adenoid cystic carcinomas (AdCC) and onemyoepithelial carcinoma with focal AdCC-like histology. CONCLUSIONS: PLAG1 expression is specificto pleomorphic adenoma. SOX10 expression is helpful to rule out excretory duct origin tumor,but its diagnostic value is relatively low. Myb is useful for diagnosing AdCC when histology isunclear in the surgical specimen.

Effect of wound massage on neck discomfort and voice changes after thyroidectomy.

BACKGROUND: Neck discomfort and voice change are common complications after thyroidectomy. These symptoms might be due to damaged laryngeal nerves, intrinsic structures, or extralaryngeal muscles. They can also occur without injury to any structure as with wound adhesion after thyroidectomy. The objective of this study was to determine causes of neck discomfort and voice change after thyroidectomy and to evaluate the effect of wound massage on symptom relief. METHODS: Forty-five female patients who underwent total thyroidectomy were included (21 in the experimental group and 24 in the control group). Wound massage was used as an intervention to release surgical adhesion. After wound massage education, participants in the experimental group received wound massage from 4 to 12 weeks after thyroidectomy. Analysis was performed for both groups. RESULTS: No laryngeal pathology was found after thyroidectomy. The experimental group had significantly better recovery from surgical adhesion and subjective visual analog scale, voice impairment score, and swallowing impairment score (all P < .01) compared with the control group. Voice analysis results associated with laryngeal movement (speaking fundamental frequency, voice range profile maximum, voice range profile range) also indicated significant recovery (P < .01) in the experimental group. These results indicate that local adhesion after thyroidectomy might affect general movement of the larynx and that wound massage could help patients recover normal general movement of the larynx. CONCLUSION: Neck discomfort and voice change after thyroidectomy are related to local wound adhesion, possibly associated with impairment of laryngeal vertical movement. Release of wound adhesion could help patients recover from neck discomfort and voice changes after thyroidectomy.

Tracheobronchial foreign body removal in infants who had very small airways: A prospective clinical trial.

BACKGROUND AND AIMS: Tracheobronchial foreign body aspiration is a life-threatening emergency. Using a rigid bronchoscope with optical forceps is the most effective method for foreign body removal. However, occasionally for some infants these instruments could not be used, as they may be too large for their small airways. Here, they present the apnea technique with only an optical forceps for foreign body removal in infants with very small airways. METHODS: Foreign bodies were removed using only an optical forceps for infants who had very small diameter airways. After general anesthesia, the suspension laryngoscope was set just above the vocal cord, and the inserted ventilation tube was pulled out, followed by a new one being inserted through the suspension laryngoscope and placed at the trachea. With the oxygen saturation at 100%, we pulled out the ventilation tube and inserted the optical forceps with an endoscope. After that, the foreign body was removed by the optical forceps. RESULTS: The foreign body removal using only an optical forceps is technically feasible for an infant. The mean operation time was 40.33 ± 8.06 min, and the hospital stay was 2.25 ± 0.62 days. When we pulled out the ventilation tube, the O2 saturation mean time (apnea time) was 106.25 ± 14.30 sec. In 12 infants, the foreign body was removed completely without a need for a second procedure. CONCLUSIONS: The apnea technique for the removal of foreign body from the airway, using only an optical forceps with an endoscope, is useful in infants who had very small airways.

Genome-wide association and expression quantitative trait loci studies identify multiple susceptibility loci for thyroid cancer.

Thyroid cancer is the most common cancer in Korea. Several susceptibility loci of differentiated thyroid cancer (DTC) were identified by previous genome-wide association studies (GWASs) in Europeans only. Here we conducted a GWAS and a replication study in Koreans using a total of 1,085 DTC cases and 8,884 controls, and validated these results using expression quantitative trait loci (eQTL) analysis and clinical phenotypes. The most robust associations were observed in the NRG1 gene (rs6996585, P=1.08 × 10-10) and this SNP was also associated with NRG1 expression in thyroid tissues. In addition, we confirmed three previously reported loci (FOXE1, NKX2-1 and DIRC3) and identified seven novel susceptibility loci (VAV3, PCNXL2, INSR, MRSB3, FHIT, SEPT11 and SLC24A6) associated with DTC. Furthermore, we identified specific variants of DTC that have different effects according to cancer type or ethnicity. Our findings provide deeper insight into the genetic contribution to thyroid cancer in different populations.

Midazolam induces cellular apoptosis in human cancer cells and inhibits tumor growth in xenograft mice.

Midazolam is a widely used anesthetic of the benzodiazepine class that has shown cytotoxicity and apoptosisinducing activity in neuronal cells and lymphocytes. This study aims to evaluate the effect of midazolam on growth of K562 human leukemia cells and HT29 colon cancer cells. The in vivo effect of midazolam was investigated in BALB/c-nu mice bearing K562 and HT29 cells human tumor xenografts. The results show that midazolam decreased the viability of K562 and HT29 cells by inducing apoptosis and S phase cell-cycle arrest in a concentration-dependent manner. Midazolam activated caspase-9, capspase-3 and PARP indicating induction of the mitochondrial intrinsic pathway of apoptosis. Midazolam lowered mitochondrial membrane potential and increased apoptotic DNA fragmentation. Midazolam showed reactive oxygen species (ROS) scavenging activity through inhibition of NADPH oxidase 2 (Nox2) enzyme activity in K562 cells. Midazolam caused inhibition of pERK1/2 signaling which led to inhibition of the anti-apoptotic proteins Bcl-XL and XIAP and phosphorylation activation of the pro-apoptotic protein Bid. Midazolam inhibited growth of HT29 tumors in xenograft mice. Collectively our results demonstrate that midazolam caused growth inhibition of cancer cells via activation of the mitochondrial intrinsic pathway of apoptosis and inhibited HT29 tumor growth in xenograft mice. The mechanism underlying these effects of midazolam might be suppression of ROS production leading to modulation of apoptosis and growth regulatory proteins. These findings present possible clinical implications of midazolam as an anesthetic to relieve pain during in vivo anticancer drug delivery and to enhance anticancer efficacy through its ROS-scavenging and pro-apoptotic properties.

Preoperative serum thyroglobulin as a useful predictive marker to differentiate follicular thyroid cancer from benign nodules in indeterminate nodules.

Indeterminate cytology results increase the number of repetitive procedure and unnecessary surgery. This study was designed to find useful and simple predictive tools to differentiate malignant thyroid nodules from indeterminate nodules. We retrospectively enrolled 164 patients who had undergone thyroid surgery as a result of indeterminate cytology in the National Cancer Center. We reviewed patients' age at diagnosis, sex, preoperative biochemical markers such as thyroglobulin (Tg), anti-Tg antibody, free T4 and TSH level, and sonographical and pathological findings, which were subjected to statistical analysis. We found several clinical and sonographical predictive factors that showed significant differences. Young age, male, preoperative high Tg level, and hypoechoic nodule on sonography all increased cancer probability significantly in multivariate analysis. With a cut-off value of 187.5 ng/mL Tg, sensitivity and specificity were 54.8% and 90.1%, respectively (AUC 0.748, P < 0.001). In the case of nodule size > 1.7 cm, elevated serum Tg predicts the risk of malignancy; especially Tg > 70 ng/mL (odds ratio 3.245, 95% confidence interval 1.115-9.450, P = 0.038). Preoperative Tg levels had very high specificity in predicting thyroid cancer in case of suspicious follicular neoplasm. Therefore, Tg levels may be a useful marker for differentiating thyroid cancer from benign thyroid nodules in the cytological diagnosis of indeterminate nodules.

Outcomes of postoperative simultaneous modulated accelerated radiotherapy for head-and-neck squamous cell carcinoma.

PURPOSE: To evaluate the treatment efficacy and toxicity of postoperative simultaneous modulated accelerated radiotherapy (SMART) for patients with head-and-neck squamous cell carcinoma (HNSCC). METHODS AND MATERIALS: Between February 2003 and September 2008, 51 patients with histologically confirmed HNSCC received postoperative intensity-modulated radiotherapy (N=33) or helical tomotherapy (N=18) using SMART after curative surgical resection. The sites included were the oral cavity (OC), oropharynx (OP), larynx, and hypopharynx in 23, 20, 5, and 3 patients, respectively. RESULTS: The median follow-up duration of all patients and surviving patients were 32 (range, 5-78 months) and 39 months (range, 9-77 months), respectively. The 3-year overall survival, cause-specific survival, disease-free survival, locoregional recurrence-free survival (LRRFS), and distant metastasis-free survival (DMFS) in all patients were 71%, 77%, 75%, 85%, and 82%, respectively. Although no significant difference in 3-year LRRFS were found between OC (82%) and OP (82%) carcinomas, the 3-year DMFS was worse in cases of OC (66%) carcinoma compared with OP carcinoma (95%; p=0.0414). Acute Grade 3 dermatitis, mucositis, and esophagitis occurred in 10%, 10%, and 2% of patients, respectively. At the last follow-up, Grade 3 xerostomia was documented in 10% of the patients. Young age (≤40 years) (p<0.001) and OC carcinoma primary (p=0.0142) were poor risk factors on univariate analysis for DMFS. CONCLUSION: Postoperative SMART was observed to be effective and safe in patients with HNSCC.

The effect of external beam radiotherapy volume on locoregional control in patients with locoregionally advanced or recurrent nonanaplastic thyroid cancer.

PURPOSE: We evaluated outcomes of patients treated with external beam radiotherapy (EBRT) for locoregionally advanced or recurrent nonanaplastic thyroid cancer and analyzed the effect of EBRT volume on locoregional control. METHODS: This study included 23 patients with locoregionally advanced or recurrent nonanaplastic thyroid cancer who were treated with EBRT. Two different EBRT target volumes were executed as follows: 1) limited field (LF, n = 11) included the primary (involved lobe) or recurrent tumor bed and the positive nodal area; 2) elective field (EF, n = 12) included the primary (involved lobe) or recurrent tumor bed and the regional nodal areas in the cervical neck and upper mediastinum. Clinical parameters, such as gender, age, histologic type, recurrence, stage, thyroglobulin level, postoperative residuum, radioiodine treatment, and EBRT volume were analyzed to identify prognostic factors associated with locoregional control. RESULTS: There were no significant differences in the clinical parameter distributions between the LF and EF groups. In the LF group, six (55%) patients developed locoregional recurrence and three (27%) developed distant metastasis. In the EF group, one (8%) patient developed locoregional recurrence and one (8%) developed a distant metastasis. There was a significant difference in locoregional control rate at 5 years in the LF and EF groups (40% vs. 89%, p = 0.041). There were no significant differences in incidences of acute and late toxicities between two groups (p >0.05). CONCLUSIONS: EBRT with EF provided significantly better locoregional control than that of LF; however, further larger scaled studies are warranted.

SMART (simultaneous modulated accelerated radiotherapy) for locally advanced nasopharyngeal carcinomas.

BACKGROUND: Concurrent chemoradiotherapy is commonly used for locally advanced nasopharyngeal carcinoma (NPC). We retrospectively analyzed the clinical outcomes of simultaneous modulated accelerated radiotherapy (SMART) with concurrent chemotherapy. METHODS: Between January 2003 and May 2005, 24 patients with stage IIB to IVB NPC underwent SMART encompassing 3 targets: gross tumor volume (GTV), high-risk subclinical disease (CTV1), and low-risk subclinical disease (CTV2). Daily fractions of 2.4, 2.15, and 1.9 Gy were delivered to GTV, CTV1, and CTV2 to a total dose of 64.8, 58.05, and 51.3 Gy in 27 fractions over 5.5 weeks, respectively. Fifteen patients received concurrent cisplatin (DDP group), and 9 received 5-fluorouracil plus cisplatin (FP group). RESULTS: With a median follow-up of 26 months (range, 17-45 months), 3-year overall and local-, regional-, and distant-progression-free survivals were 96% and 93%, 87%, and 88%, respectively. Grade 3 acute mucositis and pharyngitis were observed in 16 (67%) and 14 (59%) patients, respectively. Severe acute mucositis (100% vs 47%) and pharyngitis (100% vs 34%) were more frequently observed in the FP group than the DDP group (p < .01). CONCLUSIONS: Despite short follow-up with a small number of patients, our preliminary results demonstrated encouraging local-regional control and survival at the cost of modest increase in treatment related toxicities. The total dose and fractionation scheme of SMART used in our study is feasible with no life-threatening or fatal complications. However, the administration of fluorouracil in addition to cisplatin during SMART was associated with increased acute and late toxicities, and it should be administered with caution.

Fractionated irradiation leads to restoration of drug sensitivity in MDR cells that correlates with down-regulation of P-gp and DNA-dependent protein kinase activity.

We showed that the drug sensitivity of multidrug-resistant (MDR) cells could be enhanced by fractionated irradiation. The molecular changes associated with fractionated radiation-induced chemosensitization were characterized. Irradiated cells of the multidrug-resistant CEM/MDR sublines (CEM/MDR/IR1, 2 and 3) showed a loss of P-glycoprotein (P-gp) and concurrent reduction of Ku DNA binding and DNA-PK activities with decreased level of Ku70/80 and increased level of DNA-PKcs, and these changes were followed by an increased susceptibility to anticancer drugs. These irradiated MDR cells also exhibited the reduction of other chemoresistance-related proteins, including BCL2, NF-kappaB, EGFR, MDM2 and Ku70/80, and the suppression of HIF-1alpha expression induced by hypoxia. In contrast, fractionated irradiation increased the levels of these proteins and induced drug resistance in the parental drug-sensitive CEM cells. These results suggest that the chemoresistance-related proteins are differentially modulated in drug-sensitive and MDR cells by fractionated irradiation, and the optimized treatment with fractionated radiation could lead to new chemoradiotherapeutic strategies to treat multidrug-resistant tumors.