Clinical classification of recurrent laryngeal nerve palsy.

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.

Role of Surgery in Patients with Stage IE Primary Thyroid MALT Lymphoma Staged by a Modified Classification System: The Tokyo Classification.

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.

Impact of Age on Prognosis in Papillary Thyroid Carcinoma: How Should Age be Incorporated into the Treatment Strategy?

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.

Response to neoadjuvant paclitaxel predicts survival in anaplastic thyroid carcinoma.

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.

Successful dose escalation of lenvatinib for thyroid cancer after disease progression.

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.

Preoperative inflammatory markers for predicting parathyroid carcinoma.

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.

Predictors of maximum efficacy of lenvatinib for real-world patients with differentiated thyroid carcinoma.

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.

Encapsulated Angioinvasive Follicular Thyroid Carcinoma: Prognostic Impact of the Extent of Vascular Invasion.

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.

Clinical course and outcome of differentiated thyroid cancer patients with pregnancy after diagnosis of distant metastasis.

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 131I 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.

Cutoff Age Between Pediatric and Adult Thyroid Differentiated Cancer: Is 18 Years Old Appropriate?

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.

Impact of lenvatinib on renal function: long-term analysis of differentiated thyroid cancer patients.

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 m2 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 m2 (n = 6), < 90 but ≥60 mL/min/1.73 m2 (n = 26), or < 60 but ≥45 mL/min/1.73 m2 (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.

Risk stratification in differentiated thyroid cancer with RAI-avid lung metastases.

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.

Outcomes for Minimally Invasive Follicular Thyroid Carcinoma in Relation to the Change in Age Stratification in the AJCC 8th Edition.

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.

Indications and Strategy for Active Surveillance of Adult Low-Risk Papillary Thyroid Microcarcinoma: Consensus Statements from the Japan Association of Endocrine Surgery Task Force on Management for Papillary Thyroid Microcarcinoma.

Background: The question of how to manage patients with low-risk papillary thyroid microcarcinoma (PTMC; T1aN0M0) has recently become an important clinical issue. Two Japanese centers have conducted prospective clinical trials of active surveillance (AS) for low-risk PTMC since the 1990s, reporting favorable outcomes. This policy has thus seen gradual adoption worldwide to avoid overtreatment. Not all PTMCs are suitable for AS, however, and many physicians still hesitate to apply the management policy in daily clinical practice. A task force on management for PTMC created by the Japan Association of Endocrine Surgery collected and analyzed bibliographic evidence and has produced the present consensus statements regarding indications and concrete strategies for AS to facilitate the management of adult patients diagnosed with low-risk PTMC. Summary: These statements provide indications for AS in adult patients with T1aN0M0 low-risk PTMC. PTMCs with clinical lymph node metastasis, distant metastasis, recurrent laryngeal nerve (RLN) paralysis due to carcinoma invasion, or protrusion into the tracheal lumen warrant immediate surgery. Tumors suspected of aggressive subtypes on cytology are recommended for immediate surgery. Immediate surgery is also recommended for tumors adherent to the trachea or located along the course of the RLN. Practical strategies include diagnosis, decision-making, follow-up, and monitoring related to the implementation of AS. The rate of low-risk PTMC progression is lower in older patients. However, we recommend continuing AS as long as circumstances permit. Future tasks in optimizing management for low-risk PTMC are also described, including molecular markers and patient-reported outcomes. Conclusions: An appropriate multidisciplinary team is necessary to accurately evaluate primary tumors and lymph nodes at the beginning of and during AS, and to adequately reach a shared-decision with individual patients. If appropriately applied, AS of low-risk PTMC is a safe management strategy offering favorable outcomes and preserves quality of life at low cost.

Distant Metastasis in Pediatric and Adolescent Differentiated Thyroid Cancer: Clinical Outcomes and Risk Factor Analyses.

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.

Urinalysis by combination of the dipstick test and urine protein-creatinine ratio (UPCR) assessment can prevent unnecessary lenvatinib interruption in patients with thyroid cancer.

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.

Inflammatory biomarkers and dynamics of neutrophil-to-lymphocyte ratio in anaplastic thyroid carcinoma.

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.

Rapid disease progression after discontinuation of lenvatinib in thyroid cancer.

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.

Risk Stratification of Pediatric Patients with Differentiated Thyroid Cancer: Is Total Thyroidectomy Necessary for Patients at Any Risk?

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.