Ansa Cervicalis External Branch Anastomosis to Restore High Tone Voice in Thyroid Surgery.

OBJECTIVES: Injury to the external branch of the superior laryngeal nerve (EBSLN) causes low-pitch voice and voice fatigue, particularly in female subjects, and available treatments are limited. Here, we assess a novel surgical procedure to restore a high-tone voice: ansa cervicalis to EBSLN anastomosis (A-E anastomosis). METHODS: Between November 2012 and April 2022, 13 patients (12 female) underwent unilateral EBSLN resection and A-E anastomosis, while 20 (16 female) underwent EBSLN resection during thyroid surgery. Patients (4494 women and 1025 men) with normal laryngoscopy scheduled for thyroid surgery served as normal controls. Phonatory function was examined using a Phonation Analyzer PA-1000 preoperatively and intermittently postoperatively. RESULTS: In patients who underwent A-E anastomosis, high-tone voice pitch decreased significantly postoperatively (673.9-471.5 Hz, p = 0.047), with restoration achieved within 5 months. The mean voice pitch in female patients who underwent A-E anastomosis, EBSLN resection, and controls were 580.4, 522.8, and 682.0 Hz, respectively, indicating a significant decrease in EBSLN resection patients than controls (p = 0.002). The (mean - 1SD) of high-tone voice pitch in female controls was 497 Hz; exceeding this may indicate recovery to a high-tone voice. Overall, 73% (8/11) of A-E anastomosis patients exceeded this value, which was marginally larger than the 43% (6/14) who underwent EBSLN resection. Data on male subjects are limited. There were no cases of adverse functional or cosmetic events. CONCLUSIONS: A-E anastomosis, a novel simple procedure, restored high-tone voice to some extent without any adverse events and thus warrants further investigation. LEVEL OF EVIDENCE: 3 Laryngoscope, 2024.

Active surveillance for adult low-risk papillary thyroid microcarcinoma-a review focused on the 30-year experience of Kuma Hospital.

Active surveillance (AS) for low-risk papillary thyroid microcarcinoma (PTMC), which was initiated at Kuma Hospital (Kobe, Japan) in 1993 and Cancer Institute Hospital (Tokyo) in 1995, is now gradually being adopted worldwide, and several prospective studies have described the favorable outcomes of PTMC patients who underwent AS. The most important factor predicting PTMC growth is young age, and PTMC enlargement in young patients may be affected by high serum levels of thyroid-stimulating hormone. This review notes that one patient showed lung metastasis after conversion surgery (CS) following AS, but there are no reports of patients dying of thyroid carcinoma during or after AS. Some PTMCs enlarge or show newly appeared metastatic nodes requiring CS, and findings on the postoperative prognosis and incidence of significant surgical complications (e.g., permanent vocal cord paralysis, hypoparathyroidism) do not differ significantly between patients who underwent CS after AS and those who underwent immediate surgery (IS). IS has been associated with significantly higher incidences of these complications compared to AS as the initial management. Several studies have examined the quality of life (QoL) of patients who underwent AS versus IS, and reported discrepant findings regarding various psychological conditions (including anxiety). Medical costs for AS and IS vary regionally, and in Japan, the 10-year total cost of IS was 4.1 times greater than that of AS in 2017. Taken together, the existing findings demonstrate that AS can be appropriate for the initial management of patients with PTMC.

Tumor volume-doubling rate is negatively associated with patient age in papillary thyroid microcarcinomas under active surveillance.

BACKGROUND: Active surveillance of low-risk papillary thyroid microcarcinomas has gained popularity worldwide as a management strategy. We previously reported that young age was associated with tumor enlargement by ≥3 mm. Here, we used the tumor volume-doubling rate to study the age-related tumor volume dynamics of papillary thyroid microcarcinomas under active surveillance. METHODS: Between 2005 and 2019, 2,896 patients diagnosed with low-risk papillary thyroid microcarcinomas underwent active surveillance. We excluded patients who underwent ultrasound examination fewer than 4 times, had coexisting Graves' disease, or were treated with levothyroxine at the time of diagnosis, and we enrolled 2,129 patients for this study. We divided them into 3 subsets based on the age at diagnosis: young (<40 years), middle-aged (40-59 years), and elderly (≥60 years). The tumor volume-doubling rate was calculated based on ultrasound-derived tumor sizes and the respective examination date for each patient. RESULTS: Overall, 140 patients (6.6%) had moderate or rapid growth (tumor volume-doubling rate ≥0.3/year), and the incidence significantly decreased with advanced age (P < .01): 11.3%, 7.1%, and 5.0% in the young, middle-aged, and elderly groups, respectively. Tumor regression (tumor volume-doubling rate <0/year) was detected in 1,200 patients (56.4%), and the incidence significantly increased with age (P < .01): 44.6%, 55.3%, and 60.0% in the young, middle-aged, and elderly groups, respectively. On multivariate analysis, both the ≥60 years and 40 to 59 years age groups were independent negative predictors of papillary thyroid microcarcinoma enlargement and positive predictors of tumor regression. CONCLUSION: Tumor volume-doubling rate analysis demonstrated that the incidence of tumor enlargement decreased and that of tumor regression increased with advancing age in patients with papillary thyroid microcarcinomas.

Recurrent laryngeal nerve's course running anteriorly to a thyroid tumor.

The thyroid gland's neurovascular relationship is commonly portrayed as the recurrent laryngeal nerve (RLN) coursing posteriorly to the thyroid gland. We report a rare case with the RLN running anteriorly to a thyroid tumor. A 56-year-old Japanese woman underwent a thyroidectomy for a benign thyroid tumor. Preoperatively, computed tomography confirmed that part of the tumor had extended into the mediastinum and was descending posteriorly up to the brachiocephalic artery. Intraoperatively, when the sternothyroid muscle was incised to expose the thyroid gland, a cord (nerve)-like structure was observed directly anterior to the thyroid tumor. Although the course of this cord-like structure was clearly different from the "traditional" course of the right RLN, the possibility that the structure was the RLN could not be excluded. The structure was traced back in order to preserve it; we saw that it entered the larynx at the lower margin of the cricothyroid muscle and approximately at the level of the cricothyroid junction through the back of the normal thyroid tissue. With intraoperative neuromonitoring, the structure was identified as the RLN. As a result, the course of the RLN run anterior to the tumor but then posterior to the 'normal thyroid' i.e. into it normal anatomical position. Had we assumed that the RLN was behind the thyroid tumor, we would have damaged the RLN. It would not be possible to diagnose this abnormal running course of the RLN reliably before surgery, but extra care should be taken in similar cases, that is, when a large thyroid tumor is descending posteriorly up to the brachiocephalic artery on the right side.

Outcomes of immediate surgery for low-risk papillary thyroid microcarcinoma in patients with or without risky features at surgery.

Active surveillance (AS) is an accepted management option for patients with low-risk papillary thyroid microcarcinoma (PTMC), although some patients undergo immediate surgery (IS). At surgery, patients may have risky features such as adhesion or invasion to the adjacent organs. The surgical outcomes of this subset of patients are unknown. Here, we investigated the surgical and oncological outcomes of these patients in comparison with others. Between 2005 and 2019, 4,635 patients were diagnosed with low-risk PTMC at our institute. Of these, 1,739 patients underwent IS. In total, 114 patients had risky features at surgery (risky feature group), while the remaining 1,625 did not (no-risky feature group). The median follow-up periods in the risky and no-risky feature groups were 8.5 and 7.6 years, respectively. The risky feature group had higher incidences of tracheal invasion (8.8%), recurrent laryngeal nerve invasion (RLN) (7.9%), and permanent vocal cord paralysis postoperatively (10.0%) and higher frequency of pathological lateral lymph node metastasis (6.1%) than the no-risky feature group (0%, 0%, and 0.2%, and 0%, respectively [p < 0.01]). However, unexpectedly, the former had a lower incidence of high Ki-67 labeling index (1.1%) and lower locoregional recurrence rate (0%) than the latter (8.3% and 0.7, respectively [p < 0.01], not calculable). None of the groups developed distant metastasis or died of the disease. The risky feature group required resection of the trachea and/or the RLN more often than the no-risky feature group. However, unexpectedly, the tumor growth activity in the risky feature group was low, and their oncological outcome was excellent.

Active Surveillance Outcomes of Patients with Low-Risk Papillary Thyroid Microcarcinoma According to Levothyroxine Treatment Status.

Background: During active surveillance (AS), serum thyrotropin (TSH) levels may affect papillary thyroid microcarcinoma (PTMC) progression. We investigated AS outcomes according to whether levothyroxine (LT4) treatment was administered. Patients and Methods: From 2005 to 2019, 2896 patients with low-risk PTMC underwent AS. Of these, 2509 patients were included: 2187 patients did not receive LT4 at diagnosis (group I), 1935 patients did not receive LT4 during AS (group IA), and 252 patients started LT4 during AS (group IB). The remaining 322 patients were administered LT4 before or at diagnosis (group II). The tumor volume doubling rate (TVDR) and tumor size based on ultrasound examination results and time-weighted detailed TSH scores were calculated. Disease progression was defined as tumor enlargement ≥3 mm and/or the appearance of novel lymph node metastasis. Results: At diagnosis, group II had more high-risk features, such as younger age and larger tumors, than group I. However, group II had a lower disease progression rate (2.9% at 10 years) than group I (6.1%) (p = 0.091). The disease progression rate of group IB (13.8% at 10 years) was significantly higher than that of groups IA (5.0%) and II (2.9%) (p < 0.01). The TVDR of group IB before LT4 administration was significantly higher than that of groups IA and II (0.095 per year, -0.0085 per year, and -0.057 per year, respectively; p < 0.01), suggesting that patients with progression signs during AS were selectively prescribed LT4. The time-weighted detailed TSH score of group IB significantly decreased after LT4 administration compared with those before administration (3.35 and 3.05, respectively; p < 0.01). The TVDR also decreased from 0.13 per year to 0.036 per year (p = 0.08). The proportions of patients with rapid or moderate growth decreased significantly after LT4 (from 26.8% to 12.5%, p < 0.01). A multivariable analysis revealed group IB status was independently associated with disease progression (odds ratio [OR] = 3.42 [CI 2.15-5.44], p < 0.01), whereas age ≥40 years and <60 years and age ≥60 years were independently negatively associated with this outcome (OR = 0.23 [CI 0.14-0.38, p < 0.01 and OR = 0.16 [CI 0.10-0.27], p < 0.01). Conclusion: LT4 treatment may be associated with decreased tumor growth during AS of PTMC, but further confirmatory research is needed.

Long-Term Outcomes of Active Surveillance and Immediate Surgery for Adult Patients with Low-Risk Papillary Thyroid Microcarcinoma: 30-Year Experience.

Background: It has been 30 years since the initiation of active surveillance (AS) for adult patients with low-risk papillary thyroid microcarcinoma (PTMC). This study compared the long-term oncological outcomes of patients who underwent AS or immediate surgery (IS). Methods: This is a retrospective review of extended follow-up data from patients enrolled in a single-center, prospective observational study in Japan. In total, 5646 patients diagnosed with low-risk PTMC at Kuma Hospital between 1993 and 2019 were enrolled in this study. Of these, 3222 patients underwent AS (AS group), whereas 2424 underwent IS (IS group). The patients were followed up regularly, at least once per year. Descriptive outcome data were presented according to the treatment group. Results: In the AS group, 124 patients (3.8%) had tumor enlargement of ≥3 mm, and the 10- and 20-year enlargement rates were 4.7% and 6.6%, respectively. Novel lymph node metastases occurred in 27 patients (0.8%), and the 10- and 20-year nodal metastasis occurrence rates were 1.0% and 1.6%, respectively. In the IS group, 13 patients (0.5%) experienced lymph node recurrence postoperatively, and the 10- and 20-year nodal recurrence rates were 0.4% and 0.7%, respectively. Eighteen (1.4%) of the 1327 patients who underwent hemithyroidectomy experienced recurrence in the residual thyroid. The rate of lymph node metastasis was significantly higher in the AS group than in the IS group (1.1% vs. 0.4% and 1.7% vs. 0.7% at 10 and 20 years, respectively; p = 0.009), but the differences were small. However, the proportion of patients who underwent one or more and two or more surgeries was significantly higher in the IS group than in the AS group (100% vs. 12.3% and 1.07% vs. 0.09%, p < 0.01). Distant metastatic recurrence was observed in one patient after AS and conversion surgery and another after IS; however, they were alive (18.4 and 18.8 years after diagnosis, respectively). None of the patients in this study died of thyroid carcinoma. Conclusions: Long-term oncological outcomes of patients with PTMC generally did not differ clinically significantly between those undergoing AS and IS. AS is a viable initial management option for patients with low-risk PTMC.

Active surveillance is an excellent management technique for identifying patients with progressive low-risk papillary thyroid microcarcinoma requiring surgical treatment.

Although the outcomes of active surveillance (AS) for low-risk papillary thyroid microcarcinoma (PTMC) are generally excellent, some patients undergo conversion surgery for various reasons, including disease progression. We studied the outcomes of PTMC patients who underwent AS, who underwent conversion surgery after AS, and who underwent immediate surgery. Between 2005 and 2019, 4,635 patients were diagnosed with low-risk cT1aN0M0 PTMC at Kuma Hospital: 2,896 opted for AS (AS group) and 1,739 underwent immediate surgery (Surgery group). In the AS group, 242 patients underwent conversion surgery (Conversion group): 72 owing to disease progression (Conversion-prog group) and 170 for other reasons (Conversion-non-prog group). Of the 1,739 patients in the Surgery group, 1,625 had no high-risk features (Surgery-low-risk group). Locoregional recurrence (LRR) occurred in 9, 1, 1, and 0 patient in the Surgery-low-risk group, the Conversion-prog group, the AS group, and the Conversion-non-prog group, respectively. The LRR rate of the AS group was significantly lower than that of the Surgery-low-risk group (0.1% vs. 0.7% at 10 years, p = 0.006). Additionally, the LRR rate of the Conversion group (0.6% at 10 years, p = 0.741) and that of the Conversion-prog group (3.3% at 10 years, p = 0.103) did not significantly differ from the LRR of the Surgery-low-risk group. As the postoperative prognosis of patients with progressive PTMC who underwent conversion surgery did not significantly differ from that of patients who underwent immediate surgery, we think that AS may have resulted in efficient identification of the small proportion of patients with progressive PTMC that require surgical treatment.

Comparison of Postoperative Unfavorable Events in Patients with Low-Risk Papillary Thyroid Carcinoma: Immediate Surgery Versus Conversion Surgery Following Active Surveillance.

Background: Active surveillance (AS) for low-risk papillary thyroid microcarcinoma (PTMC) was initiated at Kuma Hospital in 1993 and has gradually spread worldwide. We previously demonstrated that AS is associated with a much lower incidence of unfavorable events than immediate surgery (IS). However, conversion surgery (CS) raises concerns about increased surgical complications due to advanced disease. In this study, we conducted a comparative analysis of unfavorable events after IS and CS. Methods: Between 2005 and 2019, 4635 patients clinically diagnosed with low-risk PTMC at Kuma Hospital were enrolled. Of these, 2896 underwent AS (AS group), and the remaining 1739 underwent IS (IS group). To date, 242 patients (0.8%) in the AS group have undergone CS for various reasons (CS group). Results: The incidence of unfavorable events, such as levothyroxine administration after surgery, postoperative hematoma, transient/persistent hypoparathyroidism, and transient/persistent vocal cord paralysis, did not differ between the CS and IS groups. None of the patients in the CS group had permanent vocal cord paralysis; however, this occurred in 15 patients (0.9%) in the IS group and was caused by accidental injury in 4 patients and carcinoma invasion in 11 patients. The incidence of surgery, levothyroxine administration, postoperative hematoma, transient/permanent hypoparathyroidism, and vocal cord paralysis was significantly higher (p < 0.001) in the IS group than in the AS group. There were no differences in the incidence of lymph node recurrence and overall mortality between the AS and IS groups. None of the patients in the AS and IS groups showed distant metastasis or died from thyroid carcinoma. Conclusions: There were no differences in the incidence of unfavorable events between the CS group and the IS group. Although none of the CS and AS groups had permanent vocal cord paralysis, accidental injury of the recurrent laryngeal nerve occurred in four patients (0.2%) in the IS group. The IS group had a significantly higher incidence of unfavorable events than the AS group. The prognoses of patients in both the AS and IS groups were excellent. Therefore, we recommend AS as the first-line management for low-risk PTMC.

Thyroid-Stimulating Hormone, Age, and Tumor Size are Risk Factors for Progression During Active Surveillance of Low-Risk Papillary Thyroid Microcarcinoma in Adults.

BACKGROUND: Active surveillance (AS) of low-risk papillary thyroid microcarcinoma (PTMC) was initiated at Kuma Hospital in 1993 and is gradually spreading worldwide. We assessed the effect of thyroid-stimulating hormone (TSH) levels on PTMC enlargement in patients on AS. METHODS: We enrolled 2705 patients with cytologically diagnosed PTMC who had undergone AS between January 2005 and July 2019. Patients with Graves disease were excluded. The median AS period was 5.5 years (range 1.0-15.7 years). Tumor enlargement was defined as a size increase ≥3 mm. Chi-square test, Kaplan-Meier method, log-rank test, Cox proportional hazard, and logistic regression were used to compare variables. RESULTS: Ninety-two patients (3.4%) experienced tumor enlargement; the 5-, 10-, and 15-year enlargement rates were 3.0%, 5.5%, and 6.2%, respectively. Young age (<40 years, p < 0.001), large tumor size (≥9 mm, p = 0.017), and high detailed TSH score (≥3, higher than the lower normal limit, p = 0.011) were significant factors relating to tumor enlargement in the multivariate analysis. In a subset of patients aged <40 years, a low detailed TSH score (<3) was an independent factor against tumor enlargement (p = 0.039). Only 22 patients (0.8%) experienced novel lymph node metastasis; the 5-, 10-, and 15-year node metastasis rates were very low, at 0.9%, 1.1%, and 1.1%, respectively. CONCLUSIONS: Young patients with PTMC are more likely to experience tumor growth. Mild TSH suppression to achieve a low normal range may prevent carcinoma enlargement; however, prospective studies are needed to draw more reliable conclusions.

Clinical significance of the neutrophil-to-lymphocyte ratio in oligometastatic breast cancer.

PURPOSE: This study investigated the clinical impact of pretreatment neutrophil-to-lymphocyte ratio (NLR) on survival in patients with oligometastatic breast cancer. PATIENTS AND METHODS: We collected data from 397 patients who underwent primary breast surgery from 2004 to 2015 and developed recurrence during the follow-up. We reviewed the images and clinical information and defined OMD according to the European Society for Medical Oncology advanced breast cancer guidelines. The NLR was calculated using pretreatment data of primary breast cancer. The cutoff value of the NLR was determined by receiver operating characteristic curve with Youden Index. RESULTS: Among 397 patients, 131 had OMD at recurrence. The low-NLR group included patients of significantly older age at primary cancer than those in the high-NLR group. A low NLR indicated a better overall survival (p = 0.023) after adjusting for relevant factors, including estrogen receptor status, surgical resection of metastatic disease, metastatic organ number, disease-free interval, and liver metastasis than did the high-NLR group. We developed prognostic models for OMD using six independent prognostic factors, including the NLR. The number of factors was associated with overall survival; patients with all six favorable factors showed a good overall survival of 90.9% at 8 years and those with four or more factors showed 70.4%. CONCLUSIONS: The NLR was an independent prognostic factor for overall survival in OMD. The number of favorable prognostic factors was associated with overall survival. A prognostic model, including the NLR, will help identify patients with a favorable prognosis.

Lipoadenoma of the parathyroid: characteristics of a rare cause of hyperparathyroidism.

Parathyroid Lipoadenoma (PLA) contains abundant mature adipose tissue and is a rare cause of hyperparathyroidism. This study aimed to investigate the clinical features of PLA in nine patients with primary hyperparathyroidism, including two men and seven women, with ages ranging from 45-84 years (median 60 years). PLA accounted for 0.5% of all parathyroid tumors during the study period. One patient presented with anorexia due to hypercalcemia; however, the other eight patients were asymptomatic. The median preoperative serum intact-parathyroid hormone (iPTH) and calcium levels were 143 pg/mL (range, 102-378) and 10.8 mg/dL (range, 10.3-11.3), respectively. PLA was difficult to identify using ultrasonography (US) as it appears as a moderately hyperechoic nodule and is difficult to distinguish from the surrounding adipose tissues. Only 33% of the lesions (three out of nine lesions) were accurately identified. However, they could be distinctly differentiated from the surrounding tissue using computed tomography (CT). All PLAs were also detected using the sesta-methoxyisobutylisonitrile single-photon emission-computed tomography (SPECT). All the patients were treated by a single gland extirpation. The median size and weight of the PLA were 14 mm (range, 10-22) and 567 mg (range, 200-1,533), respectively. In conclusion, the clinical manifestations of PLA are similar to those of ordinal parathyroid adenomas, except for their unique US and CT images. PLA should be considered as a potential etiologic factor in cases of hyperparathyroidism when the lesions are demonstrated as hyperechoic nodules or unidentified by US but detected by CT or SPECT imaging.

Gauze blotting technique: a novel method to identify parathyroid glands during thyroid surgery without tissue damage.

Hypoparathyroidism is a major complication of thyroid surgery. To avoid this complication, visual identification of the parathyroid glands is essential. However, its effectiveness depends heavily on the surgeon's expertise. Here, we describe a novel method, the gauze blotting technique, to immunochemically identify the parathyroid glands during thyroid surgery. Twenty-three patients who underwent thyroid lobectomy were enrolled in this study; 16 and 7 had benign and malignant thyroid diseases, respectively. After visually identifying candidate nodules for the parathyroid gland, a piece of dry gauze (5 mm × 10 mm) was applied to each tissue until it was moistened by exudates from the tissue. Pieces of gauze were also applied to the thyroid gland and adipose tissue located away from the candidate nodules. The gauze was immersed in saline, and the intact PTH (i-PTH) level of the supernatant was measured. The median PTH level for the parathyroid glands was 1,060 pg/mL, which was significantly higher than that for the thyroid gland (34 pg/mL) and adipose tissue (28 pg/mL) (p < 0.001). The cut-off value to distinguish the parathyroid gland from other tissues was 68 pg/mL with a positive predictive value, negative predictive value, sensitivity, and specificity of 84.6%, 88.8%, 86.8%, and 86.7%, respectively. A value ≥250 pg/mL yielded a 100% positive predictive value. Our novel gauze blotting technique can identify the parathyroid glands without damaging tissues during thyroid surgery.

Prognostic significance of patient age in papillary thyroid carcinoma with no high-risk features.

Older age is recognized as a predictor of poor prognosis in papillary thyroid carcinoma (PTC) patients. However, young age is associated with disease progression of PTC measuring 1 cm or smaller in patients on active surveillance. In this study, we investigated the relationship between patient age and prognosis of PTC belonging to very low-, low-, and intermediate-risk groups based on the guidelines published by the Japan Association of Endocrine Surgery in 2018. We enrolled 4,870 PTC patients with no high-risk features and assigned each to one of three categories: very low risk (N = 1,161), low risk (N = 1,746), and intermediate risk (N = 1,963). In very low-risk patients, the local recurrence-free survival (RFS) rate of young patients (<55 years) was significantly worse (p = 0.0437) than that of older patients (≥55 years). In low-risk patients, although age did not affect local recurrence, older patients were more likely to show distant recurrence on univariate (p = 0.0005) and multivariate analyses (p = 0.0017). In the intermediate-risk series, the local RFS rate of older patients tended to be poor (p = 0.0538), and older age was significantly associated with distant RFS (univariate, p = 0.0356; multivariate, p = 0.0439) and carcinoma death (univariate, p < 0.0001; multivariate, not done because of no other suitable factors). The prognostic significance of patient age depends on risk classification: younger age significantly predicts local recurrence in very low-risk PTC, while older age predicts worse prognosis in low- and intermediate-risk patients. These findings indicate that young age is related to rapid growth in early-phase PTC.

Metastatic papillary thyroid carcinoma presenting with elevated serum levels of carbohydrate antigen 19-9 (CA19-9): a case report.

BACKGROUND: The major sites of distant metastases of papillary thyroid carcinoma (PTC) are the lung and bone; metastasis to the liver is rare. Although the postoperative serum thyroglobulin (Tg) level after total thyroidectomy is a good prognostic indicator for PTC when anti-thyroglobulin antibody (TgAb) is negative, the presence of TgAb interferes with the Tg assay, making serum Tg levels unreliable. Here we report a case of liver metastasis of PTC that presented with elevated serum levels of carbohydrate antigen 19-9 (CA19-9), which is usually a serum marker of pancreatic and gastrointestinal neoplasias. CASE PRESENTATION: A 69-year-old man was diagnosed with PTC and underwent total thyroidectomy 16 years ago. The patient's serum Tg levels increased progressively during follow-up and his serum TgAb was negative. Positron emission tomography (PET) and computed tomography (CT) revealed metastases of the lung, cervical spine, mediastinum and liver. The liver lesion was a solitary tumor measuring 4.0 cm in the greatest dimension. His serum CA19-9 level was very high (326 U/mL), and intrahepatic cholangiocarcinoma was suspected from the results of various examinations including gastrointestinal endoscopic imaging and CT. Laparoscopic partial liver resection for segment 4 was performed. The histopathological diagnosis was a metastatic liver tumor from PTC. The immunohistological examination revealed that the liver tumor was positive for CA19-9 and Tg. The primary PTC, recovered from paraffin-embedded specimen, was also positive for CA19-9. After the surgery, his serum CA19-9 level as well as serum Tg level markedly decreased. CONCLUSIONS: We presented the first reported case of liver metastasis of a PTC presenting with elevated serum levels of CA19-9 after total thyroidectomy. This case suggests that the serum CA19-9 levels may serve as a surrogate marker for PTC in place of the serum Tg level in patients with positive serum TgAb if the PTC and/or the metastatic lesions are positive for CA19-9 staining.

Observational management of papillary microcarcinoma appearing in the remnant thyroid after hemithyroidectomy.

Active surveillance for papillary thyroid microcarcinomas (PTMCs) initiated in Japan is becoming adopted worldwide as a management option. However, it remains unclear how to manage newly appearing PTMCs in the remnant thyroid after hemithyroidectomy. We investigated the outcomes of similar observational management (OM) for PTMCs appearing in the remnant thyroid after hemithyroidectomy for papillary thyroid carcinoma (PTC) and benign thyroid nodules. Eighty-three patients were newly diagnosed with PTMC in the remnant thyroid between January 1998 and March 2017. Of these, 42 patients underwent OM with >3 times ultrasound examinations. Their initial diagnoses were PTC (initially malignant group) in 37 patients and benign nodule (initially benign group) in 5 patients. We calculated the tumor volume doubling rate (TV-DR) during OM for each PTMC. The TV-DR (/year) was <-0.1, -0.1-0.1, 0.1-0.5, and >0.5 in 12, 19, 5, and 6 patients, respectively. The TV-DRs in both groups did not statistically differ, but six patients (16%) in the initially malignant group showed moderate growth (TV-DR >0.5/year). They underwent conversion surgery and none of them had further recurrence. The remaining 36 patients retained OM without disease progression. The TV-DR in the initially malignant group was not significantly associated with patients' backgrounds or their initial clinicopathological features. None of the patients in this study showed distant metastases/recurrences or died of thyroid carcinoma. Although a portion of PTMCs appearing after hemithyroidectomy for thyroid malignancy are moderately progressive, OM may be acceptable as a management option for PTMCs appearing in the remnant thyroid after hemithyroidectomy.

Evaluation of the diagnostic utility of the aminotransferase/lactate dehydrogenase ratio for the suspension of tissue specimens during thyroid surgery for the identification of parathyroid tissue.

Identification of the parathyroid glands during surgery is crucial for preventing postoperative hypoparathyroidism. Kikumori et al. reported that the aspartate aminotransferase (AST)/lactate dehydrogenase (LDH) ratio for the saline suspension of a suspicious tissue can differentiate parathyroid tissue from other tissues. The aim of this study was to evaluate the utility of this method and investigate the appropriate time for measurement. We obtained 465 tissue specimens during thyroidectomy of 102 patients with papillary thyroid carcinoma (PTC), and 422 specimens (129 parathyroid, 92 PTC, and 201 other tissues) with measurable AST and LDH were analyzed. Small pieces of the tissues were immersed in saline and sent for measurement of AST and LDH. The assay was performed immediately after thyroidectomy for 245 specimens (the same-day group) and during the next morning for the remaining 177 specimens (the next-day group). The accuracy of diagnosing parathyroid tissue was significantly better in the same-day group than in the next-day group. A cut-off value of 0.18 gave the best diagnostic precision, with an area under the receiver operating characteristic curve of 0.95 and 88.7% sensitivity and specificity in the same-day group. When the cut-off value was set to 0.20, the specificity for excluding carcinomatous tissues was 100%. When measured on the day of the surgery, the AST/LDH ratio for the saline suspension of the surgical specimens is useful for discriminating parathyroid tissues from other tissues. This method can be utilized at most hospitals where intraoperative frozen sections or rapid parathyroid hormone assays are not available.

Prognostic significance of vascular invasion and cell-proliferation activity in widely invasive follicular carcinoma of the thyroid.

Widely invasive follicular thyroid carcinoma (wi-FTC) is regarded as having an aggressive character and a dire prognosis, but it has not been known whether all wi-FTCs have a dire prognosis. Herein we retrospectively analyzed the cases of 133 patients with wi-FTCs to determine the prognostic significance of vascular invasion and cell-proliferation activity based on the Ki-67 labeling index (LI). Of the 119 patients without distant metastasis (M0), 11 (9.2%) showed recurrence during the postoperative follow-up. In a univariate analysis, the recurrence-free survival (RFS) rates of the M0 patients with vascular invasion and those with a Ki-67 LI ≥5% were significantly poorer (p = 0.0013 and p = 0.0268, respectively) than those of the patients without vascular invasion or with a Ki-67 LI <5%. Other clinicopathological factors such as patient age, gender, tumor size, and oxyphilic tumor were not significantly related to the patients' RFS. In a multivariate analysis, positive vascular invasion independently affected the RFS (p = 0.0133), but Ki-67 >5% did not (p = 0.1348). To date, only five patients have died of their thyroid carcinoma; four cases were M1. In conclusion, although M0 wi-FTC generally has a favorable prognosis, cases with positive vascular invasion or a high Ki-67 LI are likely to recur, and careful postoperative follow-up is necessary.

Ultradeep targeted sequencing of circulating tumor DNA in plasma of early and advanced breast cancer.

We present a study to evaluate the feasibility and clinical utility of amplicon-based Oncomine Pan-Cancer cell-free assay to detect circulating tumor DNA (ctDNA) in patients with early or advanced breast cancer. In this study, 109 early and metastatic breast cancer patients were recruited before the initiation of treatment. ctDNA mutation profiles were assessed through unique molecular tagging (UMT) and ultradeep next generation sequencing (NGS). For patients with mutations, DNA from corresponding white blood cells (WBC) was sequenced to exclude variants of clonal-hematopoietic (CH) origin. UMT targeted sequencing from plasma of 109 patients achieved a median total coverage of 55 498X and a median molecular coverage of 4187X. Among 53 ctDNA positive samples, 38% were mutation positive by WBC sequencing, indicating potentially false-positive results contributed by CH origin. Prevalence of CH-related mutations was associated with age (P = 7.51 × 10-4 ). After exclusion of CH mutations, ctDNA detection rates were 37% for local or locally advanced breast cancer (stage I-III) and 81% for metastatic or recurrent breast cancer. The ctDNA detection rate correlated with disease stage (P = 2.60 × 10-4 ), nodal spread (P = 6.49 × 10-3 ) and the status of distant metastases (P = 5.00 × 10-4 ). ctDNA variants were detected mostly in TP53, PIK3CA and AKT1 genes, with variants showing therapeutic relevance. This pilot study endorses the use of targeted NGS for non-invasive molecular profiling of breast cancer. Paired sequencing of plasma ctDNA and WBC should be implemented to improve accurate interpretation of liquid biopsy.