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Objectives: To investigate the relevance of clinical and sonographic features as indicators of metastasis in indeterminate lymph node (LN), to determine possible indications for fine-needle aspiration (FNA).Methods: Consecutive patients who underwent US-guided FNA for sonographic indeterminate LNs from differentiated thyroid carcinoma between January 2014 and December 2018 were retrospectively reviewed. Indeterminate LNs were defined as LNs which had neither an echogenic hilum nor hilar vascularity in the absence of any suspicious finding in accordance with the Korean Society of Thyroid Radiology (KSThR) guidelines. Univariate and multivariate logistic regression analyses were performed to identify significant risk factors related to malignancy of indeterminate LNs.Results: Of the 236 LNs in 212 patients enrolled in this study, 67 LNs (28.3%) were metastatic. The multivariate logistic regression analysis showed that the long diameter of LNs has a negative association with metastasis in indeterminate LNs and the sonographic features of extrathyroidal extension (ETE) and nonparallel orientation of the primary tumor are associated with metastasis in indeterminate LNs. The sensitivity and positive predictive value were increased when FNA was performed for LNs with primary tumors showing ETE or nonparallel orientation than when FNA was performed for LNs larger than 5 mm (59.7% and 40.4% vs. 11.94% and 15.69%).Conclusions: The size of LNs has a negative association with metastasis in indeterminate LNs. Performing FNA for indeterminate LNs in patients whose primary tumor shows ETE or a nonparallel orientation can improve the diagnostic performance and decrease the rate of unnecessary FNA.Key Points: • The size of lymph nodes was negatively related to the risk of metastasis in indeterminate lymph nodes. • Extrathyroidal extension and a nonparallel orientation of the primary tumor were suggested as sonographic features predicting metastasis in indeterminate lymph nodes. • The routine practice of FNA for large indeterminate lymph nodes detected during preoperative evaluation of thyroid cancer should be discouraged. [ABSTRACT FROM AUTHOR]

Background: Some papillary thyroid microcarcinomas (PTMCs) may progress with tumor enlargement or development of new lymph node (LN) metastasis during active surveillance (AS). This study evaluated the relevant predictors of disease progression, especially new cervical LN metastasis. Methods: This was a long-term follow-up study conducted using a previous multicenter cohort of AS in Korea. After excluding 54 (14.2%) patients with a short follow-up duration, 326 PTMC patients were evaluated for tumor kinetics, including changes in tumor volume (TV) and TV doubling time (TVDT). Results: During a median follow-up duration of 4.9 years, 17 (5.2%, 95% confidence intervals [CI] 2.7–7.6%) patients showed a maximal diameter increase of ≥3 mm after a median of 4.0 years follow-up, while 9 (2.8%, CI 1.0–4.5%) developed new LN metastasis after a median of 2.2 years follow-up. New cervical LN metastasis occurred exclusively of a maximal diameter increase of ≥3 mm. The prevalence of new development of LN metastasis was higher in patients with TVDT <5 years (7.4%) than in those with TV ≥50% (3.2%). Furthermore, only TVDT <5 years was significantly associated with LN metastasis (p = 0.002). In univariate and multivariate analyses, TVDT <5 years was an independent risk factor for disease progression with respect to new development of LN metastasis (hazard ratio [HR] = 6.51, CI 1.73–24.50; p = 0.002) and tumor enlargement (HR = 20.89, CI 5.78–75.48; p < 0.001). Finally, 86 (22.6%) patients underwent delayed surgery, and the most common reason was patient anxiety. Conclusions: TVDT <5 years is a predictor of disease progression during AS in terms of new LN metastasis development as well as tumor enlargement. Determination of TVDT in the early phase of AS could help in predicting disease progression, tailoring follow-up intensity of AS and in determining if early surgical intervention is needed. [ABSTRACT FROM AUTHOR]

Previous randomized trials, performed decades ago, showed no survival benefit of intensive screening for distant metastasis in breast cancer. However, recent improvements in targeted therapies and diagnostic accuracy of imaging have again raised the question of the clinical benefit of screening for distant metastasis. Therefore, we investigated the association between the use of modern imaging and survival of patients with breast cancer who eventually developed distant metastasis. We retrospectively reviewed data of 398 patients who developed distant metastasis after their initial curative treatment between January 2000 and December 2015. Patients in the less-intensive surveillance group (LSG) had significantly longer relapse-free survival than did patients in the intensive surveillance group (ISG) (8.7 vs. 22.8 months; p = 0.002). While the ISG showed worse overall survival than the LSG did (50.2 vs. 59.9 months; p = 0.015), the difference was insignificant after adjusting for other prognostic factors. Among the 225 asymptomatic patients whose metastases were detected on imaging, the intensity of screening did not affect overall survival. A small subgroup of patients showed poor survival outcomes when they underwent intensive screening. Patients with HR-/HER2 + tumors and patients who developed lung metastasis in the LSG had better overall survival than those in the ISG did. Highly intensive screening for distant metastasis in disease-free patients with breast cancer was not associated with significant survival benefits, despite the recent improvements in therapeutic options and diagnostic techniques. [ABSTRACT FROM AUTHOR]

Objective: Evidence for American Thyroid Association (ATA) risk stratification stems largely from studies involving patients undergoing total thyroidectomy. We aimed to assess the risk of recurrence according to the present ATA risk stratification system in patients who underwent lobectomy. Design: Retrospective cohort study. Patients: Patients who underwent thyroid lobectomy for 1‐4 cm‐sized papillary thyroid carcinoma (n = 571). Measurements: Disease‐free survival (DFS) was compared according to the ATA risk stratification, and specific lymph node (LN) characteristics were evaluated to modify the ATA criteria with a higher predictability for recurrence. Results: Based on the ATA risk stratification, 439 patients (61.1%) were classified into intermediate‐ or high‐risk group, and consideration for completion thyroidectomy is suggested by ATA guidelines for these patients. However, no significant differences were found in DFS among the low‐, intermediate‐ and high‐risk groups (P =.9). In contrast, when patients were stratified according solely to the LN criteria from the ATA risk stratification, only 127 patients (22.2%) had intermediate risk (intermediate‐N1a) and exhibited significantly poorer DFS than those with N0 disease (P =.035). Modifying the intermediate‐N1a criteria by adding the extranodal extension (ENE) status and omitting the clinical nodal disease enabled the subclassification of 19 patients (3%) with a high risk for recurrence. Conclusions: The present study suggests that risk stratification based solely on LN metastases is more reasonable for predicting structural persistence/recurrence following lobectomy than that based on the overall ATA criteria. Considering the ENE status can assist in selecting patients with a high risk of recurrence to minimize further treatments. [ABSTRACT FROM AUTHOR]

Background: Estimating the growth rate of lung metastases for the treatment of patients with metastases of differentiated thyroid carcinoma (DTC) is important. This study aimed to evaluate survival outcomes according to different criteria for estimating the growth rate of lung metastases. Methods: Patients with macronodular (≥1 cm) lung metastases of DTC who underwent total thyroidectomy and high-dose radioactive iodine therapy between 1995 and 2013 were enrolled. The time to progressive disease (PD) by the Response Evaluation Criteria in Solid Tumors (RECIST), average tumor volume doubling time of the two dominant target lung lesions (midDT), and thyroglobulin doubling time (TgDT) were measured in each patient, and their association with disease-specific survival (DSS) was evaluated. Results: Forty-four patients with target lung metastatic nodules with an initial maximal diameter of 1.3 cm (median) were followed-up for a median of 6.8 years after the diagnosis of lung metastases. Based on RECIST, 12 patients (27.3%) showed fast tumor progression, with time to PD <1 year. When assessed by midDT, nine patients (20.5%) had midDT ≤1 year, showing rapid tumor progression. Seven of 33 patients (21.2%) who were negative for thyroglobulin antibody had midDT <1 year. Growth rates assessed by all three criteria were significantly associated with DSS. However, midDT had the highest predictive value for DSS, with a proportion of variation explained of 33.6%. Five-year DSS was 29.6% in patients with midDT ≤1 year, 50.0% in patients with time to PD <1 year, and 42.9% in patients with TgDT <1 year. Conclusions: Among the different criteria for estimating the growth rate of metastases in patients with lung metastases of DTC, midDT was the most powerful for predicting DSS, in comparison with RECIST and TgDT. Performing at least three serial chest computed tomography scans during the first year from the diagnosis of lung metastases can facilitate early detection of patients with rapid tumor progression and provide objective guidance for initiation of systemic therapy. [ABSTRACT FROM AUTHOR]

Background: Active surveillance has been introduced as a management option for low-risk papillary thyroid microcarcinoma (PTMC) due to its mostly indolent course. Methods: This was a multicenter study of 370 PTMC patients who underwent active surveillance more than one year. The changes in volume and maximum diameter between initial and last ultrasonography were evaluated to identify the natural course of PTMC during active surveillance. Results: Patients' age at diagnosis was 51 ± 12 years, and 110 (30%) patients were <45 years of age. The initial maximum diameter and volume of PTMCs were 5.9 ± 1.7 mm and 81.0 ± 77.7 mm3, respectively. During the median 32.5 months of follow-up, 86 (23.2%) patients were found to have an increase in tumor volume, and 13 (3.5%) patients showed an increase in the maximal diameter of the tumor. The cumulative incidence of volume increase gradually rose with time (6.9%, 17.3%, 28.2%, and 36.2% after two, three, four, and five years, respectively). The risk of volume increase in patients <45 years of age was twice as high as in older patients (p = 0.002). There was no significant difference in tumor size change according to sex, levothyroxine treatment, or presence of Hashimoto's thyroiditis. During the period, 58 (15.7%) patients underwent delayed thyroid surgery due to anxiety (37.9%), tumor size increase (32.8%), or appearance of cervical lymph node metastasis (8.6%). Lymph node metastasis was found in 29.3% of patients on pathological examination. Conclusions: A significant number of PTMCs grow during active surveillance, and tumor volume change is a more sensitive means of evaluating tumor growth. Active surveillance can be carefully applied for selected patients. Although it is not contraindicated, it should be applied more cautiously for younger patients. [ABSTRACT FROM AUTHOR]

Background: Regional lymph node metastases (LNM) have prognostic significance in differentiated thyroid cancer (DTC). However, there was no distinction between N1a and N1b in the final staging classification in the eighth edition of the tumor-node-metastasis (TNM) staging system. This study aimed to evaluate the prognostic implication of N1b classification for predicting disease-specific survival (DSS) in DTC patients with stage I/II disease. Methods: A total of 3089 patients with stage I/II DTC who underwent thyroid surgery between 1996 and 2005 were included. DSS was evaluated according to N classification and number of LNM. A modification of the TNM was assessed that classified N1b cases in patients aged ≥55 years as stage IIB and the remaining cases as stage IIA. Results: The mean patient age was 45.6 years, and the median follow-up period was 10.0 years. In patients aged ≥55 years, patients with N1b had significantly poorer DSS compared to those with N0 (hazard ratio [HR] = 11.0; p < 0.001) and N1a (HR = 4.2; p = 0.013). The large-volume LNM group had significantly poorer DSS compared to the N0 (HR = 10.1; p < 0.001) and small-volume LNM (HR = 3.9; p = 0.019) groups. When patients were reclassified using the modified TNM staging system, DSS was significantly poorer in stage IIB patients than in stage IIA patients (HR = 2.9; p = 0.030). Conclusions: N1b classification has a significant prognostic implication in patients with stage I/II DTC, especially in older patients. Modified TNM staging employing N1b classification could be more useful for the prediction of DSS. [ABSTRACT FROM AUTHOR]

Objective Previous studies did not focus on the differences in the extent of cervical lymph node ( LN) dissection according to coexistent Hashimoto's thyroiditis ( HT) in patients with papillary thyroid carcinoma ( PTC) and its clinical impact. We aimed to determine whether extensive cervical LN dissection is responsible for favourable clinical outcomes in PTC patients with HT and whether the coexistence of HT itself has an independent protective effect regardless of LN status. Design Retrospective cohort study. Patients 1369 patients with PTC who underwent total thyroidectomy with central compartment neck dissection. Measurements Metastatic LN ratio, defined as number of metastatic LNs divided by number of removed LNs, was used to evaluate the extent of LN dissection as well as the status of LN metastasis. Disease-free survival and dynamic risk stratification were compared for clinical outcomes. Results Presence of HT did not lower the risk of cervical LN metastasis (61.6% in patients with HT vs 65.1% in patients without HT, P = .292). Patients with HT had significantly larger numbers of removed LNs than patients without HT (11 vs 8, respectively, P < .001). Accordingly, metastatic LN ratio was smaller in patients with HT ( P = .002), which was independently associated with structural persistent/recurrent disease (hazard ratio [ HR] 2.33, 95% confidence interval [ CI] 1.30-4.16, P = .004). HT itself was negatively associated with structural persistent/recurrent disease after adjustment for other clinicopathological factors ( HR 0.39, 95% CI 0.18-0.87, P = .020). Conclusions Coexistence of HT itself is an independent factor associated with favourable outcome in PTC patients, regardless of the extent of LN dissection. [ABSTRACT FROM AUTHOR]

Background: The clinical course of patients with lung metastases of differentiated thyroid carcinoma (DTC) vary, and cancer-specific survival (CSS) can be associated with tumor burden. This study evaluated the growth kinetics of lung metastases from DTC using serial chest computed tomography for Response Evaluation Criteria in Solid Tumors assessment and its prognostic implications. Methods: Forty-four patients with macronodular lung metastases (≥1 cm) of DTC were included. The time intervals to disease progression of lung metastases were measured and compared to CSS rates. Results: On the basis of the time to progression, 15 (34%), 17 (39%), and 12 (27%) patients were classified into the slow (≥3 years), moderate (1-3 years), and rapid groups (<1 year), respectively. The growth kinetics of lung metastases exhibited a linear pattern in the three groups. The doubling time of tumor burden was 1.8 years ( R2 = 0.973, p = 0.013) in the rapid group, and the estimated doubling time of the tumor burden in the moderate and slow groups was 5.9 years and 19.3 years, respectively. No independent variable predicted the growth kinetics of lung metastases. In multivariate analysis, disease progression within the first year was an independent predictor of CSS (hazard ratio = 8.6; p = 0.003). Conclusions: This is the first study to demonstrate objectively that tumor growth kinetics within the first year are an independent predictor of CSS in patients with macronodular lung metastases. Performing chest computed tomography at least twice a year in the early phase of the disease in patients with macronodular lung metastases may be helpful for identifying high-risk patients who are eligible for treatment with tyrosine kinase inhibitors. [ABSTRACT FROM AUTHOR]

Background: The association between the CpG island methylator phenotype (CIMP) and clinical outcomes in metastatic colorectal cancer remains unclear. We investigated the prognostic impact of CIMP in patients with metastatic colorectal cancer treated with systemic chemotherapy.Methods: Eight CIMP-specific promoters (CACNA1G, IGF2, NEUROG1, RUNX3, SOCS1, CDKN2A, CRABP1, and MLH1) were examined. The CIMP status was determined by the number of methylated promoters as high (⩾5), low (1-4), and negative (0).Results: A total of 153 patients were included (men/women, 103/50; median age, 61 years; range, 22-80 years). The CIMP status was negative/low/high in 77/ 69/7 patients, respectively. Overall survival (OS) was significantly different among the three CIMP groups, with median values of 35.7, 22.2, and 9.77 months for the negative, low, and high groups, respectively (P<0.001). For patients treated with fluoropyrimidine and oxaliplatin first-line chemotherapy (N=128), OS and progression-free survival (PFS) were significantly different among the three CIMP groups; the median OS was 37.9, 23.8, and 6.77 months for the negative, low, and high groups, respectively (P<0.001), while the median PFS was 9.97, 7.87, and 1.83 months, respectively (P=0.002). Response rates were marginally different among the three CIMP groups (53.4% vs 45.1% vs 16.7%, respectively; P=0.107). For patients treated with fluoropyrimidine and irinotecan second-line chemotherapy (N=86), only OS showed a difference according to the CIMP status, with median values of 20.4, 13.4, and 2.90 months for the negative, low, and high groups, respectively (P<0.001).Conclusions: The CIMP status is a negative prognostic factor for patients with metastatic colorectal cancer treated with chemotherapy. [ABSTRACT FROM AUTHOR]

Background: Recent large trials have shown the survival benefits of 10-year use of tamoxifen by reducing late recurrence compared with 5-year therapy in estrogen receptor(ER)-positive breast cancer. We tried to identify clinical factors associated with the late recurrence.Methods: We reviewed our database of ER-positive patients who had received operations between 1996 and 2006 in two institutions. We selected 444 who had completed 5-year tamoxifen and were disease-free up to 10 years after the operation. Patients who had received aromatase inhibitors with any regimens were excluded. As a late recurrence group, 139 patients were identified who had completed 5-year tamoxifen, but had recurrence afterwards. Among them, 61 had local/contralateral breast recurrence and 78 had distant metastasis. The median follow-up was 9.7 years. Clinicopathological factors at the time of initial operation, such as age, menopausal status, progesterone receptor expression, HER2 status, tumor grade and Ki-67, were compared between the disease-free group and the late recurrence group.Results: In a univariate analysis, tumor size (>2 cm), lymph node metastasis and high histologic grade were significantly associated with late recurrences (p < 0.05). In a multivariate analysis, only axillary lymph node metastasis was significant (p < 0.001). Late distant metastasis was significantly associated with tumor size and axillary lymph node metastasis (p = 0.038, p < 0.001,respectively). Late local/contralateral breast recurrence was associated with axillary lymph node metastasis (p = 0.042).Conclusions: Our data showed axillary lymph node metastasis at initial operation was the only risk factor of late recurrence after completion of tamoxifen for 5 years. Our results can be helpful in making decisions to use extended tamoxifen beyond 5 years. [ABSTRACT FROM AUTHOR]

Background: Although patients with minimally invasive follicular thyroid carcinoma (MIFTC) generally have an excellent prognosis, distant metastasis occurs in some patients. Risk factors for distant metastasis have been reported, none has been found to be conclusive. This study evaluated risk factors for distant metastasis, including protein markers, in patients with MIFTC. Methods: A review of patient records identified 259 patients who underwent surgery at Asan Medical Center from 1996 to 2010 and were subsequently diagnosed with MIFTC. After review of pathological slides, 120 patients with paraffin blocks suited for tissue microarrays (TMA) were included in this study. Immunohistochemical stain of TMA slides was performed by protein markers; β-catenin, C-MET, CK19, estrogen receptor (ER) α, ER β, HBME-1, MMP2, PPAR γ and progesterone receptor. Results: 120 patients included 28 males (23.3%) and 92 females (76.7%), of mean age 41.5±10.8 years (range, 13–74 years). Eight patients (6.7%) had distant metastases during follow-up. Univariate analysis showed that age (≥45 years), male sex, and extensive vascular invasion (≥4 foci) were associated with distant metastasis. Multivariate regression analysis showed that extensive vascular invasion was the only independent risk factor for distant metastasis (p = 0.012). Although no protein markers on TMA analysis were directly related to distant metastasis of MIFTC, CK19 expression was more frequent in patients with than without extensive vascular invasion (p = 0.036). Conclusion: Extensive vascular invasion was the only independent risk factor for distant metastasis of MIFTC. No proteins markers were directly related to distant metastasis, but CK19 was associated with extensive vascular invasion. [ABSTRACT FROM AUTHOR]

Objectives: Early detection and diagnosis of metastasis to the thyroid gland is important. This study aims to evaluate the clinical value of core-needle biopsy (CNB) by comparing the results of CNB and fine-needle aspiration (FNA) in patients with clinically suspected metastasis to the thyroid gland.Study Design: Case series with chart review.Setting: Tertiary referral practice.Subjects: Fifty-two thyroid nodules from 52 patients with clinically suspected metastasis to the thyroid gland (mean age, 62.8 years).Methods: Of these 52 patients, FNA was initially used in 41 patients and CNB in 20 patients (11 patients as the initial approach and 9 patients after inconclusive FNA results). Ultrasound features of metastasis to the thyroid gland were evaluated. The diagnostic performance, repeated diagnostic examination rate, and diagnostic surgery rate were evaluated for FNA and CNB.Results: Among these 52 patients, 46 were diagnosed with thyroid metastases and 6 were diagnosed with primary thyroid cancer. Common ultrasound features were an ovoid to round shape (58.7%), ill-defined margin (56.5%), hypoechogenicity (65.2%), and no calcifications (87.0%). Core-needle biopsy achieved a significantly higher sensitivity than FNA (100.0% vs 58.6%, P = .008) without any false-negative results. Both the repeated diagnostic examination rate and the diagnostic surgery rate were significantly lower in CNB than in FNA (5.0% vs 46.3%, P = .001, and 5.0% vs 34.1%, P = .013, respectively).Conclusions: In cases of known rare primary malignancy, nontypical ultrasound features of primary thyroid malignancy, and need for an additional immunohistochemical analysis, CNB may be primarily considered. [ABSTRACT FROM AUTHOR]

Introduction: Neutrophil to lymphocyte ratio (NLR) and standard uptake value (SUV) by 18F-FDG PET represent host immunity and tumor metabolic activity, respectively. We investigated NLR and maximum SUV (SUVmax) as prognostic markers in metastatic pancreatic cancer (MPC) patients who receive palliative chemotherapy. Methods: We reviewed 396 MPC patients receiving palliative chemotherapy. NLR was obtained before and after the first cycle of chemotherapy. In 118 patients with PET prior to chemotherapy, SUVmax was collected. Cut-off values were determined by ROC curve. Results: In multivariate analysis of all patients, NLR and change in NLR after the first cycle of chemotherapy (ΔNLR) were independent prognostic factors for overall survival (OS). We scored the risk considering NLR and ΔNLR and identified 4 risk groups with different prognosis (risk score 0 vs 1 vs 2 vs 3: OS 9.7 vs 7.9 vs 5.7 vs 2.6 months, HR 1 vs 1.329 vs 2.137 vs 7.915, respectively; P<0.001). In PET cohort, NLR and SUVmax were independently prognostic for OS. Prognostication model using both NLR and SUVmax could define 4 risk groups with different OS (risk score 0 vs 1 vs 2 vs 3: OS 11.8 vs 9.8 vs 7.2 vs 4.6 months, HR 1 vs 1.536 vs 2.958 vs 5.336, respectively; P<0.001). Conclusions: NLR and SUVmax as simple parameters of host immunity and metabolic activity of tumor cell, respectively, are independent prognostic factors for OS in MPC patients undergoing palliative chemotherapy. [ABSTRACT FROM AUTHOR]

Objective The follicular variant of papillary thyroid carcinoma (FVPTC) has multiple histological subtypes. Clinical outcomes of FVPTC are variable depending on the subtypes. This study evaluated the association of pre-operative ultrasonographic (US) findings and clinico-pathological features of FVPTC. Patients This retrospective study enrolled patients with FVPTC (n = 70), size-matched classical variant of papillary thyroid carcinoma (CPTC, n = 328), follicular carcinoma (n = 85) and follicular adenoma (FA, n = 120). We denned the histological subtypes of FVPTC as innltrative (I-FVPTC; n = 19) or encapsulated (E-FVPTC; n = 51) according to the presence of a fibrous capsule. Pre-operative US was reviewed using a US scoring system and classified into low US score (n = 42) and high US score (n = 28). Results The median US score for FVPTC was lower than CPTC (2 vs 7, P < 0-001), but higher than FA (2 vs 0, P < 0-001). The median US score for I-FVPTC was significantly higher than E-FVPTC (4 vs 2, P = 0-009). I-FVPTC was more likely to be diagnosed as a malignancy or suspicious for malignancy on cytology than E-FVPTC (P = 0-002). The cumulative risks of cervical lymph node (LN) or distant metastasis according to tumour size were significantly higher in I-FVPTC than E-FVPTC (all P < 0-001). The cumulative risks for cervical LN metastasis or capsular invasion according to tumour size were significantly higher in FVPTC with high US score than FVPTC with low US score (P = 0-005, P < 0-001, respectively). Conclusions Pre-operative US findings of thyroid nodules were associated with not only histological subtypes, but also the clinical behaviour in FVPTC. [ABSTRACT FROM AUTHOR]

Objective A larger primary tumour size, greater numbers of cervical lymph node ( LN) metastasis are associated with a higher risk of distant metastases in papillary thyroid carcinoma ( PTC). However, the impact of the location of cervical LN metastasis on distant metastasis is controversial. The aim of this study was to evaluate the risk of distant metastases according to the tumour size and LN status in PTC patients, with special consideration of the LN metastasis pattern. Patients This retrospective cohort study reviewed 1700 classical PTC patients who underwent initial thyroid surgery at Asan Medical Center between 2000 and 2004. Results The cumulative risk of distant metastases was increased with the increase in tumour size and was significantly different according to the location of involved LNs by the tumour node metastasis (TNM) staging. The cumulative risk in pN1b group showed the steepest increasing pattern with the increase in tumour size compared with pN1a and pN0/Nx group. When we analysed the cumulative risk of distant metastases according to the number of involved LNs, patients with more than 20 involved LNs also had the steepest increase in the risk of distant metastases with the increase in tumour size. However, only the location of involved LNs, not the number of involved LNs, was associated with distant metastases in multivariate analysis. Conclusions We confirm that the location of involved LNs categories based on the TNM staging system is more useful than the number of involved LNs categories for estimating the risk of distant metastasis in PTC. Differentiating N1a disease from N1b disease is important for the follow-up and management of patients with PTC. [ABSTRACT FROM AUTHOR]

Background: Known factors related to distant metastases in follicular thyroid carcinoma (FTC) included age, primary tumor size, and invasiveness. Distant metastasis is a main cause of death in FTC patients. Several studies showed that the presence of RAS mutations is also associated with poor clinical outcomes. We analyzed RAS mutations in FTC with distant metastases, FTC without a distant metastasis, follicular adenoma (FA), and nodular hyperplasia (NH). Furthermore, we elucidated the relationship between RAS mutations and clinical outcomes in FTC patients. Methods: We selected patients who underwent a thyroidectomy for FTC with distant metastases ( n=28), size matched FTC specimens without a distant metastasis ( n=28), FA ( n=17), and NH ( n=12). NRAS, HRAS, and KRAS mutations were assessed using direct sequencing. Results: Among 85 patients, 39 patients (46%) had RAS mutations. The NRAS codon 61 mutation ( n=21; 25%) was the most common point mutation. HRAS codon 61, KRAS codon 12/13, and KRAS codon 61 mutations were found in 7, 6, and 4 patients, respectively. A NRAS codon 12/13 mutation was found in only 1 patient, and a HRAS codon 12/13 mutation was not found. RAS mutations were significantly more common in the FTC than FA or NH groups. Especially, the NRAS codon 61 mutation was associated with distant metastasis in patients with FTC. Conclusions: The presence of a RAS mutation, especially a NRAS codon 61 mutation, was significantly associated with the distant metastasis. The NRAS codon 61 mutation status might be a potential prognostic factor in FTC patients. [ABSTRACT FROM AUTHOR]

The activation of metastatic reprogramming is vital for cancer metastasis, but little is known about its mechanism. This study investigated the potential role of death-associated protein kinase 1 (DAPK1) in thyroid cancer progression. We generated knockdown (KD) DAPK1 using siRNA or shRNA in 8505C and KTC-1 cell lines, which we transiently or stably overexpressed in MDA-T32 and BCPAP cell lines. DAPK1 KD in 8505C and KTC-1 cells significantly increased cell proliferation and colony formation compared with controls. We observed significant inhibition of cancer cell invasion in cells overexpressing DAPK1, but the opposite effect in KD cells. Tumorsphere formation significantly increased after inhibition of DAPK1 expression in 8505C cells and was significantly suppressed in DAPK1-overexpressing MDA-T32 and BCPAP cells. DAPK1 overexpression inhibited mRNA and protein levels of stem markers (OCT4, Sox2, KLF4, and Nanog). Furthermore, the expression of these markers increased after KD of DAPK1 in 8505C cells. Mechanistic studies suggest that DAPK1 may modulate the expression of stem cell markers through the inhibition of β-catenin pathways. These findings were consistent with the public data and our thyroid tissue analysis, which showed higher DAPK1 expression was associated with advanced-stage papillary thyroid cancer with a higher stemness index and lower disease-free survival. [ABSTRACT FROM AUTHOR]

Background: Measurement of the serum thyroglobulin (Tg) level with TSH stimulation (sTg) is the cornerstone of monitoring for the recurrence or persistence of differentiated thyroid cancer (DTC) in patients who have undergone surgery and remnant ablation. However, there have been several reports that an undetectable sTg could not predict the absence of future recurrence. The aim of this study was to evaluate the long-term outcome of DTC patients who achieved biochemical remission (BR, defined as sTg<1 ng/mL) after initial treatment, and to determine the role of repeated sTg measurement in detecting a clinical recurrence. Methods: This is a retrospective observational cohort study in a tertiary referral hospital. There were 1010 DTC patients who achieved BR at 12 months after the initial treatment (surgery and ablation), and they were eligible for analysis. Among them, 787 patients had values of repeated sTg. Results: Thirteen out of 1010 (1.3%) patients had clinical recurrences during a median 84 months of follow-up. All of the clinical recurrences were limited to the cervical lymph nodes without clinical evidence of distant metastasis. Among 787 patients with available repeated sTg, 10 had clinical recurrences (5 out of 750 patients with repeated sTg<1 ng/mL and 5 out of 37 patients with repeated sTg≥1 ng/mL). Patients with repeated sTg ≥1 ng/mL had a much greater chance of disease recurrence (log-rank statistics=43.7, df=1, p<0.001). Conclusions: About 1% of DTC patients who had sTg<1 ng/mL 12 months after initial treatment had a clinical recurrence. All of clinical recurrences were loco-regional recurrences. Although repeated sTg measurement can be helpful to predict recurrence, we could not recommend it for surveillance in patients with BR due to its very low yield. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate the efficacy and safety of S-1 in combination with oxaliplatin in a biweekly schedule as first-line treatment in metastatic colorectal cancer and the association between genetic polymorphisms and treatment outcomes. Methods: Eligibility included age 18-75 years, at least one measurable lesion, no prior chemotherapy except adjuvant chemotherapy, and Eastern Cooperative Oncology Group Performance Status (PS) 0-2. S-1 40 mg/m b.i.d. on days 1-7 with 85 mg/m of oxaliplatin on day 1 was repeated every 2 weeks. Genomic DNA from whole blood was analyzed for 15 single-nucleotide polymorphisms (SNPs) among 8 genes. Results: Fifty-two patients (median age 63 years, range 37-74) were enrolled: 37 men and 15 women; 44 with a PS of 0 and 8 with a PS of 1; and 41 with initially metastatic cancer and 11 with relapsed disease. Among 51 evaluable patients, objective response rate was 47.1% [95% confidence interval (CI) 32.9-61.2]. Median follow-up duration was 17.1 months (range 3.9-28.2 months). Median progression-free survival (PFS) was 6.4 months (95% CI 4.8-8.1), and median overall survival had not been reached yet. Reported grade 3 toxicities were neutropenia (7.7%), thrombocytopenia (5.8%), sensory neuropathy (7.7%) and diarrhea (1.9%). There was no grade 4 toxicity or neutropenic fever. Patients with A/G or G/G genotype in GSTP1 Ile105Val SNP had longer PFS than patients with A/A (median 8.3 vs. 6.1 months, P = 0.04). Conclusions: Biweekly S-1 with oxaliplatin is effective and has improved tolerability and convenience compared to other fluoropyrimidine with oxaliplatin combinations. GSTP1 Ile105Val SNP is associated with treatment outcomes. [ABSTRACT FROM AUTHOR]

Metastasis to the thyroid is uncommon, but the number of cases seems to have increased in recent years. This increase may be related to more frequent use of fine-needle aspiration biopsy (FNAB) in any suspected case.A retrospective review of patients with thyroid metastasis diagnosed by FNAB at the Asan Medical Centre.Twenty-two patients who were seen at the Asan Medical Centre between 1997 and 2003. Median age was 55 years with range between 34 and 74 years.Fourteen patients presented with a palpable thyroid nodule. Eight patients had an impalpable thyroid nodule that was found incidentally during the various imaging studies. The breast (five patients) was the most common primary site followed by the kidney (three), colon (three) and lung (three). FNAB confirmed metastatic disease in 19 patients and raised suspicion in three patients. The suspicion of metastasis to the thyroid was confirmed by Tru-cut needle core biopsy in one patient and surgery in two patients. Thyroid metastases were found during the initial work-up for primary tumour in eight patients. In the remaining 14 patients, the interval from diagnosis of primary tumour to the detection of thyroid metastasis varied from 8 months to 15 years, with a median of 54 months. Fifteen patients had metastatic disease elsewhere at the time of presentation. Ten patients received chemotherapy. Radiotherapy was used in two patients. Seven patients are still alive, with one patient disease free for 16 months following resection of the thyroid metastasis.Thyroid metastases are uncommon but can be detected more frequently with routine use of FNAB. Breast cancer is the most common tumour that metastasizes to the thyroid. They usually occur when there are metastases elsewhere, sometimes many years after the diagnosis of the original primary tumour and show poor prognosis in general. [ABSTRACT FROM AUTHOR]

Simple Summary: Arbitrary upfront dose reduction (UDR) of palliative chemotherapy has often been performed according to the judgement of the physician of older adults with metastatic solid cancer in current practice. UDR might decrease treatment efficacy in older adults but may be helpful for palliation, so selecting older adults who benefit from UDR and the identification of predictors of UDR are required. The authors investigated the prevalence and predictors of UDR through variables of geriatric assessment (GA). Chemotherapy compliance between the UDR and standard dose patient groups was also compared. The results of this study demonstrated that approximately 60% of older adults with metastatic solid cancer received UDR. Poor performance status (PS) and living without a spouse were predictive factors of UDR of first-line palliative chemotherapy, and patients with UDR better-tolerated chemotherapy compared with patients with standard doses. Old age alone does not reflect an intolerability to chemotherapy. However, upfront dose reduction (UDR) of the first cycle of first-line palliative chemotherapy has sometimes been chosen by physicians for older adults with metastatic cancer due to concerns regarding adverse events. The development of predictive factors for UDR of palliative chemotherapy would be helpful for treatment planning among older adults. This was a secondary analysis of a study on predicting adverse events of first-line palliative chemotherapy in 296 patients (≥70 years) with solid cancer. We assessed the prevalence of UDR of the first cycle of first-line chemotherapy and the association of UDR with the variables of geriatric assessment (GA) and chemotherapy compliance. Among the 296 patients, 177 (59.8%) patients were treated with UDR. The mean percentage of UDR for the total patient group was 19.2% (range: 4–47%) of the standard dose. In a multivariate analysis, poor performance status (PS) and living without a spouse were independent predictive factors of UDR of first-line palliative chemotherapy in older adults. Patients with UDR showed fewer grade 3–5 adverse events versus the standard dose group. Study completion as planned was significantly higher in the UDR group versus the standard dose group. Older adults with UDR better tolerated chemotherapy than patients with a standard dose. [ABSTRACT FROM AUTHOR]

This study compared the tumor immune microenvironments (TIMEs) of primary gastric cancer (PGC) and paired metastatic gastric cancer (MGC). CD4+ and CD8+ T-cell density and PD-L1 expression were evaluated by multiplex immunohistochemistry, DNA mismatch repair (MMR) by immunohistochemistry, and immune-related genes by RNA sequencing. Twenty-three patients who underwent surgical treatment for PGC and MGC were enrolled in this study. CD8+ T-cell, PD-L1+ cell, and PD-L1+CK+ cell densities were significantly lower in MGC than PGC. PD-L1 positivity using a combined positive score (≥ 1%) and deficient MMR were observed in 52.2% and 8.7% of PGC samples, respectively, whereas both occurred in only 4.3% of MGC samples. The most frequent TIME types were inflamed (34.8%) and adaptive immune resistance (34.8%) in PGC, and immune desert (65.2%) and immunological ignorance (73.9%) in MGC. In transcriptome analysis, the expression of the T-cell inflamed gene set and co-stimulatory gene module was down-regulated in MGC compared to PGC. The total CD8+ T-cell density was an independent prognostic marker in both PGC and MGC (univariate P = 0.002, multivariate P = 0.006). Our result suggest that the TIME of metastatic tumors was less immunologically active compared to that of primary tumors in gastric cancer patients. [ABSTRACT FROM AUTHOR]

Metastatic breast cancer refractory to anthracycline and taxanes often shows rapid progression. The development of effective and tolerable combination regimens for these patients is needed. This phase II trial investigated the efficacy of pemetrexed plus vinorelbine in patients with metastatic breast cancer. This randomized, open-label, phase II trial was conducted in 17 centers in Korea. Patients with advanced breast cancer who had previously been treated with anthracyclines and taxanes were randomly assigned in a 1:1 ratio to receive either vinorelbine or pemetrexed plus vinorelbine. Randomization was stratified by prior capecitabine treatment and hormone receptor status. The primary endpoint was investigator-assessed progression-free survival (PFS). Secondary endpoints included the objective response rate, overall survival, safety, and quality of life. Between March 2017 and August 2019, a total of 125 patients were enrolled. After a median follow-up duration of 14.1 months, 118 progression events and 88 death events had occurred. Sixty-two patients were assigned to the pemetrexed plus vinorelbine arm, and 63 were assigned to the vinorelbine arm. Pemetrexed plus vinorelbine significantly prolonged PFS compared to vinorelbine (5.7 vs. 1.5 months, p < 0.001). The combination arm had higher disease control rate (76.8% vs. 45.9%, p = 0.001) and a tendency toward longer overall survival (16.8 vs. 10.5 months, p = 0.102). Anemia was more frequent in the pemetrexed plus vinorelbine arm per cycle compared with vinorelbine (7.9% vs. 1.9%, p < 0.001), but there was no difference in the incidence of grade 3–4 neutropenia per cycle between the pemetrexed plus vinorelbine arm and the vinorelbine single arm (14.7% vs. 19.5%, p = 0.066). This phase II study showed that pemetrexed plus vinorelbine led to a longer PFS than vinorelbine. Adverse events of pemetrexed plus vinorelbine were generally manageable. • This phase II trial revealed the efficacy and safety of pemetrexed plus vinorelbine. • Pemetrexed plus vinorelbine prolonged progression free survival. • Pemetrexed plus vinorelbine was associated with higher disease control rate. • Pemetrexed plus vinorelbine had a tendency of longer overall survival. • Toxicity of pemetrexed plus vinorelbine was generally manageable. [ABSTRACT FROM AUTHOR]

Abstract Background We investigated the efficacy and safety of fulvestrant plus goserelin (F + G) versus anastrozole plus goserelin (A + G) in comparison with goserelin (G) alone in premenopausal women with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-), tamoxifen-pretreated metastatic breast cancer (MBC). Patients and methods In this multicentre, open-label, randomised phase II study, premenopausal women aged ≥18 years with HR+, HER2–, tamoxifen-pretreated MBC were randomly assigned (1:1:1) to F + G, A + G or G alone. The primary end-point was time to progression (TTP). Secondary end-points included overall survival, overall response rate, clinical benefit rate and toxicity. Results Of 138 eligible patients, 44 were randomly assigned to receive F + G, 47 to A + G and 47 to G alone. The median follow-up duration was 32.2 months (interquartile range: 23.69–40.86) and the median age was 43.0 years (range 23.0–55.0). The median TTP was 16.3 months (95% confidence interval [CI] 7.5–25.1) for F + G, 14.5 months (95% CI 11.0–18.0) for A + G and 13.5 months (95% CI 10.3–16.8) for G alone. Compared with G alone, the hazard ratios were 0.608 for F + G (95% CI, 0.370–0.998; p = 0.049) and 0.982 for A + G (95% CI, 0.624–1.546; p = 0.937). In terms of visceral metastasis, a stratification factor, there were no TTP differences according to treatment arm. Grade III or IV toxicities were rarely observed. Of the common adverse events, grade I arthralgia and joint stiffness were more frequently observed in the F + G than in the A + G or G-alone groups (p < 0.05, respectively). Conclusions F + G provides a promising new option for the treatment of premenopausal women with HR+, HER2-, tamoxifen-pretreated MBC. Trial registration ClinicalTrials.gov number NCT01266213 and Korean Cancer Study Group (KCSG) Breast cancer protocol number BR10-04. Highlights • In premenopausal women with hormone receptor-positive metastatic breast cancer, hormone treatment similar to that used in postmenopausal women is the standard treatment option after tamoxifen treatment failure. • In this study, fulvestrant plus goserelin (G) has better clinical outcome than G alone in premenopausal women, especially those younger than 40 years. • Aromatase inhibitor with G is not superior to G alone in tamoxifen-pretreated premenopausal women. [ABSTRACT FROM AUTHOR]

Objectives: Based on the tumor-node-metastasis staging system, eighth edition (TNM-8), N1b is no longer used as a variable to determine final stage in papillary thyroid carcinoma (PTC). We aimed to evaluate the predictability of a simple modification of the TNM staging with N1b classification in a large multicenter thyroid cancer cohort.Materials and Methods: This study included 7717 patients with PTC who underwent thyroid surgery between 1996 and 2005 from six tertiary hospitals. We classified patients with stage II into stage IIA and IIB with modified-TNM: older patients with N1b disease were classified as stage IIB, while remaining patients were classified as stage IIA.Results: The mean age was 46.2 years, and 24% were aged ≥55 years. In older patients, the 10-year disease-specific survival (DSS) rate of N1b disease (86.3%) was approximately 10% lower than that of N1a disease, and patients with N1b had significantly poorer DSS than those with N1a (HR = 3.3, p < 0.001). When the modified-TNM was applied, DSS curves between stage groups significantly differed (p < 0.001), and the relative risk of DSS in stage IIB patients was 2.3 times higher than in stage IIA patients (p < 0.001). The proportion of variation explained value of the modified-TNM was 4.9% and that of the TNM-8 was 4.7%.Conclusion: This multicenter study reveals that the presence of lateral lymph node metastasis affects disease mortality in PTC, especially in older patients. The sub-classification of stage II in older patients improves DSS predictability. This simple modification of TNM-8 provides better prognostic information for patients with PTC. [ABSTRACT FROM AUTHOR]

Abstract: The purpose of this study was to evaluate the diagnostic accuracies of ultrasound (US) and 18-F-FDG positron emission tomography (PET) or PET/computed tomography (CT) for detecting recurrent papillary thyroid carcinoma (PTC) after total thyroidectomy. Our study enrolled 76 postoperative patients who underwent both neck US and PET because of the suspicion of recurrence. The results of US and PET were correlated with the histopathology, the radioactive iodine whole body scan (WBS) or the clinical follow-up results. Among them, 53 patients had recurrent disease (local recurrence, 42; distant metastasis, 3; elevated Tg level, 8) and 23 showed no evidence of disease. From the analysis, US showed higher diagnostic accuracy, sensitivity and specificity compared with those of PET (71.1%, 71.7% and 69.6% vs. 55.3%, 56.6%, and 52.2%). PET added diagnostic information in a limited number of patients with negative results on neck US (3 with neck recurrence and 2 with distant metastasis). (E-mail: jeonghlee@hanmir.com) [ABSTRACT FROM AUTHOR]

The purpose of this study was to evaluate the diagnostic accuracies of ultrasound (US) and 18-F-FDG positron emission tomography (PET) or PET/computed tomography (CT) for detecting recurrent papillary thyroid carcinoma (PTC) after total thyroidectomy. Our study enrolled 76 postoperative patients who underwent both neck US and PET because of the suspicion of recurrence. The results of US and PET were correlated with the histopathology, the radioactive iodine whole body scan (WBS) or the clinical follow-up results. Among them, 53 patients had recurrent disease (local recurrence, 42; distant metastasis, 3; elevated Tg level, 8) and 23 showed no evidence of disease. From the analysis, US showed higher diagnostic accuracy, sensitivity and specificity compared with those of PET (71.1%, 71.7% and 69.6% vs. 55.3%, 56.6%, and 52.2%). PET added diagnostic information in a limited number of patients with negative results on neck US (3 with neck recurrence and 2 with distant metastasis). [ABSTRACT FROM AUTHOR]