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BACKGROUND:: Although clinical differences in lung cancer between men and women have been noted, few studies have examined the sex dissimilarity using gene expression analysis. OBJECTIVE:: The purpose of this study was to determine the different molecular carcinogenic mechanisms involved in lung cancers in Japanese men and women. METHODS:: Patients who received surgery for stage I lung adenocarcinoma were included. RNA was extracted from cancerous and normal tissue, and gene expression was then examined with oligonucleotide microarray analysis. A quantitative polymerase chain reaction assay was performed. RESULTS:: In a microarray analysis of tissue from 13 men and 6 women, 12 genes were under-expressed and 24 genes were overexpressed in lung adenocarcinoma in women compared with men. Genes related to cell cycle were present in underexpressed genes, and genes related to apoptosis, ubiquitination, and metabolism were observed in overexpressed genes. Of interest among the selected genes were WAP four-disulfide core domain 2 (WFDC2) and major histocompatibility complex, class II, DM alpha (HLA-DMA); these genes were classified into 2 groups by hierarchical clustering analysis. Expression of WFDC2 in nonsmokers was significantly higher than that in smokers (P = 0.023). However, there was no significant difference in HLA-DMA expression between smokers and nonsmokers. CONCLUSION:: Thirty-six genes that characterize lung adenocarcinoma by sex were selected. This information may contribute to the development of novel diagnostic techniques and treatment modalities that consider sex differences in lung adenocarcinoma. [ABSTRACT FROM AUTHOR]

Abstract Background Anaplastic thyroid cancer (ATC) is one of the most aggressive human malignancies and appears to arise mainly from transformation of pre-existing differentiated thyroid cancer (DTC). However, the carcinogenic mechanism of anaplastic transformation remains unclear. Previously, we investigated specific genes related to ATC based on gene expression profiling using cDNA microarray analysis. One of these genes, transcription elongation factor A (SII)-like 4 (TCEAL4), encodes a member of the transcription elongation factor A (SII)-like gene family. The detailed function of TCEAL4 has not been described nor has any association between this gene and human cancers been reported previously. Methods To investigate the role of TCEAL4 in ATC carcinogenesis, we examined expression levels of TCEAL4 in ACLs as well as in other types of thyroid cancers and normal human tissue. Results Expression of TCEAL4 was down-regulated in all 11 ACLs as compared to either normal thyroid tissues or papillary and follicular thyroid cancerous tissues. TCEAL4 was expressed ubiquitously in all normal human tissues tested. Conclusion To our knowledge, this is the first report of altered TCEAL4 expression in human cancers. We suggest that loss of TCEAL4 expression might be associated with development of ATC from DTC. Further functional studies are required.

Background: Papillary thyroid microcarcinoma (PTMC) management has evolved, with active surveillance (AS) gaining prominence as a management option. However, a key concern for both clinicians and patients is the potential for patient loss to follow-up during AS., Aims: This study aimed to determine adherence and loss-to-follow-up rates in low-risk PTMC patients undergoing AS versus surgical intervention, in order to gain insights into clinical pathways and safety profiles., Materials and Methods: This cohort study analyzed the 2016 data from a single registered institution of Japan's public National Cancer Registry., Results: We identified and retrospectively analyzed the cases of 327 patients diagnosed with low-risk PTMC; 227 patients chose to undergo AS while the other 100 underwent PTMC surgery. Main outcomes were the adherence rate and loss-to-follow-up rate of each group, factors influencing discontinuation, and safety considerations. The rate of AS adoption was substantial in the complete series of 327 low-risk PTMC patients (69.4%). There was a significantly higher loss-to-follow-up rate at 5 years in the AS group (28.6%) compared to the Surgery group (17.8%) (HR 1.62, 95% CI: 1.01-2.61; p = 0.046). Both univariate and multivariate analyses confirmed the significantly higher loss-to-follow-up rate in the AS group as well as in older patients. No deaths due to PTMC progression were observed in the cases lost to follow-up., Conclusion: Despite concerns about loss to follow-up, active surveillance remains a safe option for low-risk PTMCs. Consistent follow-up strategies are crucial, and further research is needed to enhance patient counseling and care for the management of patients with PTMC., (© 2024 The Author(s). Cancer Medicine published by John Wiley & Sons Ltd.)

Background: The application of intraoperative neurophysiological monitoring (IONM) has been accepted to avoid injury of a recurrent laryngeal nerve (RLN). Loss of the neuromonitoring signal indicates nerve injury and is subdivided into segmental type and global type nerve paralysis. This study aimed to determine the course of vocal cord function recovery after definitive loss of signal (LOS) types., Methods: This retrospective study included 1,442 patients (with 2,752 nerves at risk) who had thyroidectomies between January 2018 and December 2021. Preoperative and postoperative vocal cord functions were evaluated by laryngoscopic examination., Results: LOS occurred in 168 of 1,442 (11.7%) patients and 171 of 2,748 (6.2%) nerves at risk during surgery. Of LOS nerves of benign tumors, 74.2% showed global type. In cancer cases, segmental paralysis was more common, accounting for 51.3% of LOS nerves. Of nerves with segmental LOS in cancer patients, 55.3% needed partial layer resection for RLN invasion. Intraoperative recovery was seen in 9 of 62 nerves (14.5%) with segmental LOS and 32 of 109 (29.4%) nerves with global type LOS. The vocal cord palsy rate on postoperative days (PODs) 2-3 was lower after global type nerve paralysis (63.6%) than after segmental loss (84.9%). At 6 months postoperatively, the rate of vocal cord paralysis in benign tumors was not significantly different between segmental type and global type (P=0.586). However, cancer patients with segmental LOS significantly more often had vocal cord dysfunction than those with global LOS at 6 months postoperatively (rate of nerve palsy: segmental 40.0% vs . global 3.4%) (P<0.001)., Conclusions: The intraoperative recovery rate and early nerve recovery rate are significantly higher for patients with global LOS than for patients with segmental LOS. Cancer patients with segmental LOS significantly more often had vocal cord dysfunction than those with global LOS at 6 months postoperatively., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://gs.amegroups.com/article/view/10.21037/gs-23-149/coif). The authors have no conflicts of interest to declare., (2023 Gland Surgery. All rights reserved.)

Background: Age has been recognized as one of the strong prognostic indicators for thyroid cancer. However, treatment strategies for papillary thyroid cancer (PTC) are usually determined only by the extent of disease progression, without considering the patient's age. The aim of this study was to investigate how the surgical strategy for PTC should take into account patient age., Methods: To exclude the effect of treatment strategy, 837 patients treated with uniform treatment strategies (hemithyroidectomy without radioiodine therapy) between 1986 and 1995 were the subjects of this study. Using a Cox proportional hazard model, clinical risk factors related to disease-specific survival (DSS), disease-free survival (DFS), and distant metastasis-free survival (DMFS) were analyzed. A receiver-operating characteristic (ROC) curve analysis was performed to identify the optimal cutoff points., Results: Significant risk factors related to DSS and DMFS were age, extrathyroidal extension (ETE), and numbers of metastatic lymph nodes (NMLNs), but age was not significantly related to DFS. The 20-year DSS and DMFS rates were fair in patients without ETE regardless of age or NMLNs. However, in patients with ETE, DSS and DMFS rates were significantly worse in elderly patients than in young patients. ROC curve analysis showed that the optimal cutoff age was 48 years for discriminating DSS in patients with ETE., Conclusion: Regardless of age, PTC patients without ETE are candidates for a treatment strategy not using RAI, and more aggressive treatment may be recommended for elderly PTC patients with ETE., (© 2022. The Author(s) under exclusive licence to Société Internationale de Chirurgie.)

Purposes: To establish the appropriate staging system and assess the role of curative thyroidectomy alone (Surgery) vs. involved-site radiation therapy after open biopsy (OB-ISRT) in stage IE mucosa-associated lymphoid tissue (MALT) lymphoma., Methods: We examined the Tokyo Classification as a modified classification. This retrospective cohort study included 256 patients with thyroid MALT lymphoma; 137 underwent standard therapy (i.e., OB-ISRT) and were enrolled for the Tokyo classification. Sixty stage IE patients with the same diagnosis were examined to compare Surgery with OB-ISRT., Results: Overall survival ( p = 0.0092) and relapse-free survival (0.00113) were significantly better in stage IE vs. stage IIE under the Tokyo classification. No OB-ISRT and Surgery patients died, but three OB-ISRT patients relapsed. The incidence of permanent complications was 28% in OB-ISRT (mainly dry mouth) and 0% in Surgery ( p = 0.027). The number of painkiller prescription days was significantly greater in OB-ISRT ( p < 0.001). During follow-up, the rate of the new appearance/change of the low-density area in the thyroid gland was significantly higher in OB-ISRT ( p = 0.031)., Conclusions: The Tokyo classification allows an appropriate discrimination between stages IE and IIE MALT lymphoma. Surgery can provide a good prognosis in stage IE cases; it also avoids complications, shortens painful periods during treatment, and simplifies ultrasound follow-up.

The clinical utilities of paclitaxel in anaplastic thyroid carcinoma (ATC) have been reported. The current study investigated the outcomes in ATC patients treated by paclitaxel as neoadjuvant setting. Furthermore, the prognostic factor for overall survival (OS) and predictive marker for response to paclitaxel were investigated. Records of ATC patients treated by paclitaxel as neoadjuvant setting in our hospital were reviewed. The median OS for the patients with (n = 43) and without (n = 23) resection were 14.7 (95% CI, 11.0-21.7) and 4.2 (95% CI, 3.0-5.4) months, respectively (p < 0.001). Univariate analysis identified the factors of stage (p = 0.028), prognostic index (PI) ≥2 (p < 0.001), response to paclitaxel (p = 0.007), resection (p < 0.001), and radiotherapy (p < 0.001) to be associated with OS, and multivariate analysis revealed that the factors of PI ≥2 [hazard ratio (HR), 2.406 (95% CI, 1.096-5.281), p = 0.029], response to paclitaxel [HR, 0.423 (95% CI, 0.193-0.930), p = 0.032], resection [HR, 0.316 (95% CI, 0.129-0.773), p = 0.012], and radiotherapy [HR, 0.229 (95% CI, 0.100-0.526), p < 0.001] were independent prognostic factors of OS. There were no significant predictive factors for response to paclitaxel in baseline characteristics. PI ≥2, response to paclitaxel, resection, and radiotherapy were independent prognostic factors in ATC patients treated with paclitaxel as neoadjuvant setting. It is important to investigate predictor for response to paclitaxel for improving resectability and prognosis in ATC., (© 2022 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Background and Objectives: Tyrosine kinase inhibitors (TKIs) have provided excellent clinical benefits to patients with advanced differentiated thyroid cancer (DTC): however, the tumor status for which maximum efficacy can be obtained remains controversial. We conducted this study to identify effective clinical predictors, focusing on disease progression., Methods: Using the data of 42 DTC patients treated with lenvatinib, we investigated the clinical factors related to overall survival (OS) and progression-free survival (PFS), and conducted analyses by the scoring of the factors., Results: The 3 year OS and median PFS were 51% and 13.8 months, respectively. Univariate analysis identified performance status (PS), tumor-related symptoms, and tumor diameter as the only factors affecting both these outcomes. Giving 1-point for each of these three factors, a higher score was significantly related to shorter OS and PFS. Patients with two or fewer points (n = 34) had better median OS (NR vs 3.9 months, p < 0.001) and PFS (15.7 vs 2.1 months, p < 0.001) than patients with three points (n = 8). Patients with all three factors had a significantly worse prognosis than patients with two or fewer factors., Conclusion: DTC patients with all three indicators are unlikely to have longer survival. Therefore, it is important to commence TKIs before disease progression., (© 2022. The Author(s) under exclusive licence to Springer Nature Singapore Pte Ltd.)

Purpose: Lenvatinib is started at a standard dose, continuing with dose reduction and interruption, balancing between efficacy and adverse events (AEs). Because few drugs are available for thyroid cancer, efforts for continuing treatment with one agent, such as "dose escalation (DE)", are made. The dose is increased, aiming to regain the anti-tumor effect after dose reduction. The effects of lenvatinib DE in differentiated thyroid carcinoma (DTC) patients are reported., Patients and Methods: The efficacy of lenvatinib DE in DTC patients using the serum thyroglobulin (Tg) level and management of AEs was investigated., Results: A total of 70 DE episodes in 33 patients were investigated. The median increased dose was 2.0 (1.0-14.0) mg, increased from 8.6 (2-16) mg to 10.1 (6-24) mg. The serum Tg level decreased in 53 DE episodes. Though the serum Tg level in 17 DE episodes was not decreased, the Tg rate of increase was decreased in 7 of these DE episodes using the Tg-doubling rate. Overall, clinical benefit was seen in 60 (86%) DE episodes. AEs that could not be controlled after DEs were seen in only 16% of cases. No intolerable AEs were observed in patients who received more drug holidays at the time of DEs compared to two times before the DEs., Conclusion: DE may become one of the standard treatment strategies after disease progression if AEs are well managed. Drug holidays may be a key for successfully controlling AEs with DE. DE can be useful for controlling progressive disease with increasing Tg levels., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Objective: Parathyroid carcinoma is a rare tumor among parathyroid tumors. Aspiration cytology and needle biopsy are generally not recommended for diagnostic purposes because they cause dissemination. Therefore, it is commonly diagnosed by postoperative histopathological examination. In this study, we investigated whether preoperative inflammatory markers can be used as predictors of cancer in patients with primary hyperparathyroidism., Design: This was a retrospective study., Methods: Thirty-six cases of parathyroid carcinoma and 50 cases of parathyroid adenoma (PA) operated with the diagnosis of primary hyperparathyroidism and confirmed histopathologically at Ito Hospital were included in this study. Preoperative clinical characteristics and inflammatory markers (neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio, and lymphocyte-to-monocyte ratio (LMR)) were compared and their values in preoperative prediction were evaluated and analyzed., Results: Preoperative intact-parathyroid hormone (P = 0.0003), serum calcium (P = 0.0048), and tumor diameter (P = 0.0002) were significantly higher in parathyroid carcinoma than in PA. LMR showed a significant decrease in parathyroid carcinoma (P = 0.0062). In multivariate analysis, LMR and tumor length diameter were independent predictors. In the receiver operating characteristics analysis, the cut-off values for LMR and tumor length diameter were 4.85 and 28.0 mm, respectively, for parathyroid cancer prediction. When the two extracted factors were stratified by the number of factors held, the predictive ability improved as the number of factors increased., Conclusion: In the preoperative evaluation, a combination of tumor length diameter of more than 28 mm and LMR of less than 4.85 was considered to have a high probability of cancer.

Purpose: There is no sufficient data about the clinical course and outcome in thyroid cancer patients who become pregnant after diagnosis of distant metastasis (DM). The current study was conducted to collect information regarding the clinical and reproductive characteristics, and outcomes in thyroid cancer patients who became pregnant after being diagnosed with DM., Methods: Records of 125 differentiated thyroid cancer (DTC) patients with age ≤45 years at DM diagnosis who had visited Ito Hospital from January 2005 to June 2021 were retrospectively reviewed. Among those 125 patients, 28 who became pregnant after DM diagnosis were classified as pregnancy group, and the remained 97 patients were classified as comparator group., Results: In pregnancy group, the median age at malignancy diagnosis, DM diagnosis, and first pregnancy after DM diagnosis was 25 years (range, 4-41 years), 27 years (range, 11-41 years), and 32 years (range, 25-45 years), respectively. Fifty-five pregnancies and 40 live births were reported. Other pregnancy outcomes were miscarriage (n = 14) and induced abortion (n = 1). The 10-year progression-free survival (PFS) rates of pregnant and comparator group were 92.1% and 74.4%, respectively (p = 0.018). The multivariate analysis showed that multiple 131 I treatment was independent negative prognostic factor for PFS (p = 0.046)., Conclusions: DTC patients with age ≤45 years at DM diagnosis had good survival even though they became pregnant. Our results add to the information required for counseling thyroid cancer patients who have concerns about their fertility in the future., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Several studies have shown that music can reduce unpleasant emotions. Based on the results of this research, several systems have been proposed to suggest songs that match the emotions of the audience. As a part of the system, we aim to develop a method that can infer the emotional value of a song from its Japanese lyrics with higher accuracy, by applying the technology of inferring the emotions expressed in sentences. In addition to matching with a basic emotion dictionary, we use a Web search engine to evaluate the sentiment of words that are not included in the dictionary. As a further improvement, as a pre-processing of the input to the system, the system corrects the omissions of the following verbs or particles and inverted sentences, which are frequently used in Japanese lyrics, into normal sentences. We quantitatively evaluate the degree to which these processes improve the emotion estimation system. The results show that the preprocessing could improve the accuracy by about 4%. Japanese lyrics contain many informal sentences such as inversions. We pre-processed these sentences into formal sentences and investigated the effect of the pre-processing on the emotional inference of the lyrics. The results show that the preprocessing may improve the accuracy of emotion estimation.

Background: Previous studies have reported an association between four or more foci of vascular invasion (VI) and thyroid cancer prognosis, while the current study aimed to investigate the association between extent of VI and outcome of encapsulated angioinvasive follicular thyroid carcinoma (FTC)., Methods: The records of 303 patients with encapsulated angioinvasive FTC confirmed by surgical specimens at Ito Hospital from January 2005 to December 2014 were retrospectively reviewed. Thirteen patients had distant metastasis at diagnosis and were classified as M1., Results: Among the 290 patients with M0 encapsulated angioinvasive FTC, the 10-year disease-free survival (DFS) rate was 85.6%. Those with a VI of 1 (n = 131) or ≥ 2 (n = 159) had a 10-year DFS rate of 94.9% and 77.9% (p < 0.001), respectively, and those with a VI of 1-3 (n = 211) or ≥ 4 (n = 79) had a 10-year DFS rate of 86.3% and 83.3% (p = 0.311), respectively. Multivariate analysis identified age ≥ 55 years (p = 0.031) and VI ≥ 2 (p = 0.002) as independent negative prognostic factors for DFS. Patients with M0 encapsulated angioinvasive FTC aged ≥ 55 years and VI ≥ 2 had significantly poorer prognosis and a 10-year DFS rate of 66.4% (p < 0.001)., Conclusions: Patients with encapsulated angioinvasive FTC who had two or more foci of VI, especially patients aged ≥ 55 years, should be carefully followed-up., (© 2022. Society of Surgical Oncology.)

Background: The characteristics of pediatric differentiated thyroid cancer (DTC) are substantially different from those of adult DTC. This study investigated whether the cutoff age of 18 years, as recommended by the American Thyroid Association (ATA) management guidelines for pediatric DTC, is appropriate based on clinical characteristics and outcomes. Methods: The medical records of 288 patients aged <21 years with DTC, who underwent initial surgery between 1979 and 2014, were retrospectively reviewed. Disease-free survival (DFS) rates and distant metastasis-free survival (DMFS) rates were calculated using the Kaplan-Meier method. As per the International Incidence of Childhood Cancer Report and the ATA management guidelines, cutoff ages of 14 and 18 years were analyzed in this study. Results: The age distributions of the subjects were as follows: 53 patients were aged <15 years (18.4%), 118 patients were aged 15-18 years (41%), and 117 patients were aged 19-20 years (40.6%). The DMFS rates were significantly different between the two cutoff ages. The DMFS was also significantly different between patients aged >15 years and patients aged 15-18 years; however, no significant difference was observed between patients aged 15-18 and 19-20 years. Multivariate analyses showed that clinically apparent lymph node metastasis (cN1) and gross extrathyroidal extension were significant factors related to DFS and DMFS. Although age as a continuous variant was not a significant factor related to either DFS or DMFS, when the cutoff age was set as 14 years rather than 18 years, differences in patient characteristics related to DMFS and DFS stood out. Conclusions: This study found that age was not significantly related to clinical outcome. However, in the younger patient group, more patients had factors that related to DFS and DMFS. Due to the indolent biological behavior of DTC, age at presentation or thyroidectomy does not always represent the age at occurrence, but patients aged <15 years had distinct clinical manifestations. Age <15 years rather than <19 years may therefore be a more suitable cutoff age in pediatric DTC.

Most anaplastic thyroid carcinomas (ATCs) arise from papillary thyroid carcinoma (PTC). This process is also called anaplastic transformation, and the morphological harbingers of this phenomenon in nodal recurrence have not been assessed systematically. For this reason, the current study focused on features of 10 PTCs with regional lymph node recurrence that was accompanied with disease progression due to anaplastic transformation in at least one of the nodal recurrences. The findings of additional 19 PTCs which recurred without anaplastic transformation after ≥ 10 years of follow-up served as the control group. There were no clinicopathological differences between the two groups at initial surgery including age, gender, tumor size, lymph node metastasis, distant metastasis, extrathyroidal extension, histologic subtype, and treatment. The median time from the initial thyroid surgery to anaplastic transformation in the nodal recurrence was 106 months (range 6 to 437 months). Mutational analyses showed recurrent PTCs with anaplastic transformation had a high prevalence of BRAF V600E mutation (8/9) and TERT promoter mutation (9/9), both of which were detected in primary tumors. PIK3CA H1047R mutation was detected in one case. No case had RAS mutation. Nineteen recurrent PTCs without anaplastic transformation harbored BRAF V600E mutation and seventeen of these had TERT promoter mutation. Unlike primary tumors with subsequent nodal anaplastic transformation, TERT promoter mutation was only present in the metastatic nodal recurrence from 4 patients without transformation. No patients had neither high-grade features (necrosis and increased mitotic activity) nor solid/insular growth or hobnail cell features in their primary tumors. In the group of patients with transformation, 3 had solid/insular growth in the lymph node metastasis at the time of primary tumor resection (one displaying nuclear features of PTC and solid growth with increased mitotic activity, one with insular component consistent with poorly differentiated carcinoma component, and one displaying nuclear features of PTC and solid growth), and additional 2 patients had solid/insular growth with no high-grade features or poorly differentiated carcinoma component at the time of subsequent nodal recurrence prior to anaplastic transformation. Hobnail cell features were exclusively seen in subsequent metastatic lymph nodes prior to anaplastic transformation. The control group lacked solid/insular growth and hobnail cell features in the metastatic nodal disease. Aberrant p53 expression and loss of TTF-1 featured tumor components with anaplastic transformation. This series identified a subset of recurrent PTCs with TERT promoter mutation was prone to undergo anaplastic transformation, and that solid/insular growth and hobnail cell features were morphological predictors of anaplastic transformation in the nodal recurrence., (© 2021. The Author(s).)

Background: Because lenvatinib is well known to induce proteinuria by blocking the vascular endothelial growth factor (VEGF) pathway, renal function is a concern with long-term administration of lenvatinib. The long-term effects of lenvatinib on renal function in patients with advanced differentiated thyroid carcinoma (DTC) were analyzed., Method: This study involved 40 DTC patients who continued lenvatinib therapy for ≥6 months. Estimated glomerular filtration rate (eGFR) was calculated as an indicator of renal function. The temporal course of eGFR, effects of baseline eGFR on eGFR changes, and factors affecting renal impairment were investigated., Results: The overall cohort showed sustainable decreases in eGFR, with decreased values of 11.4, 18.3, and 21.0 mL/min/1.73 m 2 at 24, 36, and 48 months after starting treatment, respectively. No differences in eGFR decrease every 6 months were seen for three groups classified by baseline eGFR ≥90 mL/min/1.73 m 2 (n = 6), < 90 but ≥60 mL/min/1.73 m 2 (n = 26), or < 60 but ≥45 mL/min/1.73 m 2 (n = 8). Grade 3 proteinuria was associated with declines in eGFR (p = 0.0283). Long observation period was also associated with decreases in eGFR (p = 0.0115), indicating that eGFR may decrease in a time-dependent manner., Conclusion: Lenvatinib can induce declines in eGFR, particularly with treatment duration > 2 years, regardless of baseline eGFR. Proteinuria is a risk factor for declines in eGFR. Patients who start lenvatinib with better renal function show a renal reserve capacity, prolonging clinical outcomes. Decision-making protocols must balance the benefits of lenvatinib continuation with acceptable risks of harm., (© 2021. The Author(s).)

Objective: Radioactive iodine (RAI) therapy is effective for differentiated thyroid cancer (DTC) patients with lung metastasis. However, some patients have a poor prognosis despite the RAI accumulation. The utility of inflammatory biomarkers, including neutrophil-to-lymphocyte ratio (NLR), has been reported as a prognostic factor for many carcinomas. This study aimed to investigate the risk factors related to DTC patient survival with RAI-avid lung metastasis and to attempt risk stratification., Design and Methods: This retrospective study included 123 patients with RAI-accumulating lung metastatic DTC. The cause-specific survival (CSS) rate from the time of detection of lung metastasis was tested using the Kaplan-Meier log-rank test, and the multivariate analysis was calculated using the Cox proportional hazards model. NLR was retrospectively calculated using the blood sample collected before initial RAI treatment. The NLR cutoff value was 2.6 on the ROC curve., Results: Age ≥ 55 years at the time of operative treatment, follicular carcinoma, lung metastasis tumor ≥ 10 mm in diameter, age ≥ 55 years at the time of detection of lung metastasis, age ≥ 55 years at the time of RAI treatment, and NLR ≥ 2.6 at the initial RAI treatment were predictive of decreased CSS. Multivariate analysis identified that the independent prognostic factors were lung metastatic tumor ≥ 10 mm in diameter and NLR ≥ 2.6. Patients in the high-risk group with both factors had significantly lower CSS rates than those in the low- and intermediate-risk groups with one or none of these factors., Conclusions: The high-risk group patients had significantly poorer survival, and these patients could be considered as future candidates for tyrosine kinase inhibitor therapy.

Background: Completion total thyroidectomy with radioactive iodine (RAI) therapy is not uniformly recommended for minimally invasive follicular thyroid carcinomas (MI-FTCs) without distant metastasis, but may be considered for cases with a risk factor of recurrence, such as age ≥ 45 years., Objective: The present study aimed to investigate the outcomes for patients with MI-FTC using a stratification age of 55 years., Methods: The records of 478 patients with MI-FTC confirmed by surgical specimens at Ito Hospital from January 2005 to December 2014 were retrospectively reviewed. Twenty patients had distant metastasis at diagnosis and were subsequently classified as M1., Results: Among the 478 patients with MI-FTC, univariate analysis identified that age ≥ 55 years (p = 0.002) and M1 (p < 0.001) were related to cause-specific survival. In 458 patients with M0 MI-FTC, male sex (p = 0.041), age ≥ 55 years (p = 0.001), and tumor size > 40 mm (p < 0.001) were related to poor disease-free survival (DFS) in univariate analysis. Multivariate analysis showed that age ≥ 55 years (p = 0.005) and tumor size > 40 mm (p = 0.005) were independent prognostic factors for DFS. The 10-year DFS rates of patients aged < 45 years, 45 years ≤ age < 55 years, and ≥ 55 years were 97.0%, 95.5%, and 86.4%, respectively., Conclusions: The change in the recommended age for completion total thyroidectomy with RAI, from 45 to 55 years, seemed reasonable.

Context: The specific characteristics of pediatric and adolescent differentiated thyroid cancer (DTC) is the more frequent occurrence of distant metastasis (DM) compared with adult DTC., Objective: To investigate the clinical outcomes of DM in this population and analyze risk factors related to DM., Design, Setting, and Participants: Medical records of 171 patients with DTC < 19 years old, who underwent initial surgery between 1979 and 2014 were retrospectively reviewed., Main Outcome Measure: Clinical responses to radioiodine (RAI) therapy evaluated by the American Thyroid Association (ATA) guidelines for adult DTC and Response Evaluation Criteria in Solid Tumors (RECIST) criteria. Risk factors related to distant-metastasis-free survival (DMFS)., Results: DM was observed in 29 patients, and all were lung metastases. The pattern of lung metastasis was classified into 3 categories: macronodular, micronodular, and no apparent nodule (detected only by RAI scintigraphy). Patients with excellent responses according to the ATA guideline criteria or complete remission of the RECIST criteria were most frequently observed in those with no apparent nodule. Significant factors related to DMFS were sex, clinical lymph node metastasis (LNM), extrathyroidal extension, and number of LNM. Subjects were divided into 3 groups according to the number of risk factors: low risk (no risk factors); intermediate risk (1 risk factor); and high risk (≥2 risk factors). Twenty-year DMFS rates in the low-, intermediate-, and high-risk groups were 99.0%, 71.7%, and 28.6%, respectively., Conclusion: To achieve the full efficacy of RAI therapy, early diagnosis of DM before apparent metastases appear is desirable. The selective approach would be preferable for pediatric and adolescent DTC., (© Endocrine Society 2020. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Purpose: Studies have shown that inflammatory biomarkers, such as neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and lymphocyte-to-monocyte ratio (LMR), are associated with prognosis or treatment efficacy in various cancers. The present study investigated the association between the inflammatory biomarkers and dynamics of NLR, and prognosis or disease progression in anaplastic thyroid carcinoma (ATC)., Methods: This study included 55 patients with ATC who had available complete blood count (CBC) data. Overall survival based on inflammatory biomarker value, and the dynamics of NLR among patients with ATC were investigated. Change in NLR was obtained by subtracting the baseline value from the max value obtained during follow-up period, and we subclassified 51 ATC patients who had follow-up CBC data into the increased group (change of NLR > 5.5) and non-increased group (change of NLR ≤ 5.5)., Results: There were no significant differences in OS according to baseline NLR, PLR, and LMR values. Among the 51 patients with ATC who had follow-up CBC data, the median OS was 7.7 [95% confidence interval (CI): 5.2-12.1] months in the increased group (n = 27), versus 23.5 [95% CI: 13.9-not available] months in the non-increased (n = 24) group (p < 0.001)., Conclusions: The present study found no association between baseline inflammatory biomarkers and OS among patients with ATC. However, ATC patients whose NLR increased compared with individual baseline during follow-up period had worse prognosis than non-increased patients.

Radioactive iodine (RAI) therapy has been the mainstay of treatment for papillary thyroid carcinoma (PTC) patients with distant metastasis (DM). Although tyrosine kinase inhibitors (TKIs) were introduced for the treatment of RAI refractory metastatic thyroid carcinoma several years ago, clinical outcomes for PTC patients with DM treated using RAI therapy remain unclear. We retrospectively examined 64 PTC patients (9 men, 55 women) with DM at diagnosis treated using RAI therapy without administration of any kind of chemotherapy or TKIs. Median age of patients was 58 years. Site of DM was the lungs (n = 59), bone (n = 3), and pleural dissemination (n = 2). No patients showed multiple-organ metastases at diagnosis. By the end of the study period, 21 patients had died of PTC. Cause-specific survival rates at 10, 15, and 20 years after initial surgery were 68.2%, 63.6% and 61.1%, respectively. Uni- and multivariate analyses identified age ≥55 years (HR 3.1, p = 0.023), site of DM other than the lungs (HR 13.4, p < 0.0001), and DM with no RAI avidity (HR 5.1, p = 0.0098) as factors independently associated with disease-related death. When analyses were restricted to patients with lung metastasis (n = 59), surgical non-curability was another independent risk factor (HR 5.2, p = 0.0047) in addition to age and RAI avidity. According to risk stratification analysis based on these risk factors, patients with site of DM other than the lungs or with lung metastasis showing ≥2 risk factors among age ≥55 years, DM with no RAI avidity, and surgical non-curability are expected to show higher mortality rates.

Background: Proteinuria induced by lenvatinib is a class effect that occurs secondary to VEGFR suppression. Withholding of lenvatinib is required in cases with severe proteinuria. Urine protein-creatinine ratio (UPCR, g/gCre) has recently attracted attention as an alternative to 24-h urine collection for assessing proteinuria. The aim of this study was to examine the correlation between the results of proteinuria assessed by the dipstick test and UPCR, and to investigate the influence of proteinuria grading with UPCR on lenvatinib dose adjustment compared to that with only the dipstick test., Method: Three hundred and ten urine samples from 63 patients with advanced thyroid cancer under treatment with lenvatinib, which were tested by both the dipstick test and UPCR were analyzed. Lenvatinib was withheld when there was evidence of CTCAE grade 3 proteinuria, and restarted when it resolved. The frequency of proteinuria, correlation between the results of the dipstick test and UPCR test, and the effect of dose withholding in cases with results of 3 + in the dipstick test were calculated., Results: Proteinuria was seen in 56 (88.9%) patients. Of the 154 dipstick 3 + samples, only 56 (36.4%) were judged as more than 3.5 g/gCre by UPCR (grade 3 proteinuria), although none of the 1 + and only 3.7% of 2 + samples were judged as grade 3 proteinuria. We were able to prevent unnecessary lenvatinib interruption due to proteinuria in 63.6% of dipstick 3 + samples by assessment of UPCR., Conclusions: Urinalysis by combination of the dipstick test and UPCR assessment might be a better strategy for preventing unnecessary interruption of lenvatinib.

Purpose: Among patients with various cancers receiving anticancer drugs, sarcopenia is associated with poor survival and treatment outcomes. We conducted an observational study using skeletal muscle index (SMI) evaluation to investigate the association between sarcopenia and treatment outcomes of tyrosine kinase inhibitors (TKIs) in metastatic thyroid cancer patients., Methods: We included 54 patients (19 men, 35 women; age, 66.5 ± 10.9 years) with differentiated thyroid carcinoma (DTC) or medullary thyroid carcinoma (MTC). The records of patients with metastatic DTC and MTC treated with TKIs were retrospectively reviewed. Patients were divided into sarcopenia and non-sarcopenia groups based on SMI. The SMI cutoff values for sarcopenia were 42 and 38 (cm 2 /m 2 ) for males and females, respectively. Thirty-three patients had sarcopenia before TKI treatment., Results: The sarcopenia group had more females and a lower body mass index. The median progression-free survival (PFS) durations were 13.6 (95% confidence interval (CI): 6.1-29.9) and 41.9 (95% CI: 25.2-not estimable) months in the sarcopenia and non-sarcopenia groups (p= 0.017), respectively. Univariate analysis showed that sarcopenia was significantly associated with PFS (p= 0.037). Sex, age, and performance status did not affect PFS. Multivariate analysis showed that sarcopenia was the only independent prognostic factor for PFS (hazard ratio: 2.488, 95% CI: 1.058-5.846, p= 0.037)., Conclusions: Sarcopenia could be a predictive factor of TKI treatment outcomes in patients with metastatic thyroid cancer as well as intervention target to improve prognosis. Further prospective investigations are needed to confirm these preliminary data.

Background: In the recent American Thyroid Association (ATA) guidelines for adult differentiated thyroid carcinoma (DTC) patients, risk stratification is clearly defined and lobectomy is acceptable for low-risk DTC. However, risk stratification for children with DTC in the ATA pediatric guidelines is rather unclear, and total thyroidectomy is recommended for all patients with any risk. The aim of this study was to attempt risk stratification based on our experience and to consider the appropriate extent of thyroidectomy, especially for low-risk DTC in the pediatric population. Patients and Methods: The subjects were 153 patients with DTC ≤18 years old, including 58 patients ≤15 years old and 136 female patients, who underwent initial curative surgery in our hospital between 1979 and 2014. Underlying pathology was papillary thyroid carcinoma in 130 patients and follicular thyroid carcinoma in 23. Risk factors related to disease-free survival (DFS) were analyzed and risk stratification was performed. Results: No patient died of the disease and 34 patients (22.2%) developed recurrences. At initial surgery, 30 patients (19.6%) had lymph node metastases diagnosed before initial surgery (cN1) and 9 (5.9%) had gross extrathyroidal extension (ETE). Significant factors related to DFS on multivariate analysis were cN1, ETE, and number of metastatic lymph nodes (NMLNs) ≥10, including microscopic MLNs. According to these factors, subjects were divided into three categories: low risk (no risk factors, n  = 89); intermediate risk (1 risk factor, n  = 37); and high risk (≥2 risk factors, n  = 27). Ten-year DFS rates in the low-, intermediate-, and high-risk groups were 96%, 83%, and 48%, respectively. Only 12% of low-risk patients underwent total thyroidectomy. Because NMLNs become obvious only after surgery, another analysis after excluding "NMLNs" as a factor showed that cN and ETE were significant factors related to poor DFS. According to these two factors, risk stratification was attempted in the same manner. Ten-year DFS rates in the low- (no risk factor, n  = 117), intermediate- (one risk factor, n  = 29), and high-risk (two risk factors, n  = 7) groups were 92%, 59%, and 43%, respectively. Only 12% of low-risk patients underwent total thyroidectomy. Conclusions: For low-risk pediatric patients, lobectomy may be sufficient as the initial surgical procedure.

Some thyroid cancer patients experience a rapid disease progression after the discontinuation of tyrosine kinase inhibitors (TKIs), which is called flare phenomenon. The incidence of the flare phenomenon of epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) ranged from 4% to 11.1% and the median time to occurrence of the flare phenomenon ranged from 7 to 12 days in previous reports. In this study, we investigate the timing and incidence of the flare phenomenon in thyroid cancer patients treated with lenvatinib.The records of patients treated with lenvatinib were retrospectively reviewed. The primary outcomes were the incidence rate and timing of the flare phenomenon after the discontinuation of lenvatinib. The flare phenomenon was defined as death, hospitalization attributable to tumor progression, or unexpected event (e.g., pleural drainage) within 1 month of lenvatinib cessation. We excluded patients with progression of underlying diseases other than thyroid cancer or infection, those in whom the disease progressed, or those who died without achieving a clinical response (stable disease, partial response, or complete response).In total, 8 (14.3%) of the 56 patients experienced the flare phenomenon. The median time from lenvatinib cessation to the flare phenomenon was 9 (range, 4-30) days. Three patients in the flare group died within 1 month of lenvatinib cessation without an imaging evaluation. The remaining 5 patients had dyspnea and pleural effusion, and pleural drainage was performed in 3 of the 5 patients. Lenvatinib was resumed in 4 of the 8 patients in the flare group. Median overall survival (OS) was 15.1 months in the flare group and 41.9 months in the non-flare group. The OS tended to be poor in the flare group than in the non-flare group; however, this difference was not statistically significant (P = .051).In lenvatinib treatment for thyroid cancer, the incidence and timing of the flare phenomenon were similar to those observed with other TKIs. OS tended to be poor in the flare group than in the non-flare group. Further studies are needed to determine the mechanism of the flare phenomenon and establish measures and treatment policies.

Background: The ultimate clinical goal of advanced cancer treatment is improvement of survival. Tyrosine kinase inhibitors (TKIs) were recently approved for radioiodine-refractory differentiated thyroid carcinoma (RR-DTC) that is resistant to conventional therapies since they have significant potential to improve survival in patients who previously had no more treatment strategies available. However, eligible patients are limited in clinical practice, making it difficult to accurately determine the efficacy of TKIs. Patients and Methods: We retrospectively analyzed the efficacy of lenvatinib at a single institution, enrolling 42 RR-DTC patients. Results: The best overall response was partial remission in 26 (62%) patients, stable disease in 10 (24%) patients, and progressive disease (PD) in 6 (14%) patients. The results indicated three-year overall survival (OS) and progression-free survival rates of 51.0% and 32.4%, respectively. Twenty-three (55%) patients had backgrounds that did not match the inclusion criteria of the Study of (E7080) Lenvatinib in Differentiated Cancer of the Thyroid (SELECT) trial. Furthermore, PD-experienced patients individually decided whether to continue lenvatinib, and 17 (41%) made the decision themselves; these patients had a three-year OS of 43.0% and postprogression survival (PPS) of 13.3 [95% confidence interval 6.1-not reached] months. Conclusions: Our real-world investigation revealed that patients have wide-ranging background characteristics, and the decision regarding continuation of therapy after PD is based on the patient's general condition. Our management protocol resulted in good PPS. Furthermore, our results indicated equivalent efficacy of lenvatinib as in the SELECT trial. In conclusion, lenvatinib proved effective for RR-DTC patients in a real-world setting.

Differentiated thyroid cancer (DTC) is associated with a good long-term prognosis, but bone metastases can adversely affect patients' quality of life and survival. Stereotactic radiotherapy (SRT) can deliver high-dose irradiation to target lesions and it has been reported to be useful for various cancers. However, few studies have examined the efficacy of SRT for thyroid cancer. In the present study, the aim was to investigate the efficacy of SRT using the CyberKnife for bone metastases from DTC. From September 2013 to April 2018, SRT with the CyberKnife system was used to treat 60 bone metastases from DTC in 13 patients. The patients' medical records were retrospectively reviewed to obtain information about the adverse events associated with SRT. Of the 60 lesions, 40 could be evaluated by follow-up CT for therapeutic effectiveness, and the RECIST criteria were used to assess the response. The cancers were papillary cancer in 3 patients, follicular cancer in 9 and poorly differentiated cancer in 1. SRT was delivered in 1-10 fractions, with a median dose of 27 Gy (range, 8-48 Gy). Adverse events were infrequent and mild. The median follow-up of the 40 lesions was 11 (range, 2-56) months. The responses were partial response in 2 lesions, stable disease in 37 lesions and progressive disease in 1 lesion, with a 1-year local control rate of 97.1%. The present study showed that SRT using the CyberKnife system was a feasible and effective treatment for bone metastases of DTC., (© The Author(s) 2019. Published by Oxford University Press on behalf of The Japan Radiation Research Society and Japanese Society for Radiation Oncology.)