Lymphovascular invasion and risk of recurrence in papillary thyroid carcinoma.

BACKGROUND: Lymphovascular invasion (LVI) is an established adverse prognostic factor in many cancers, however, there are few studies assessing its significance in papillary thyroid carcinoma (PTC). We aimed to determine if LVI is an independent prognostic factor in PTC. METHODS: We conducted a single institution retrospective analysis of 610 patients with PTC treated between 1987 and 2016. LVI was defined as the presence or absence of cancer cells in blood vessels and/or lymphatics on histopathology. Multivariate Cox regression analysis was used to evaluate the association between LVI and recurrence-free survival (RFS). RESULTS: The study cohort included 481 (78.9%) females and 129 (21.1%) males, with a median age of 47.6 years and median follow-up of 3.4 years. LVI was present in 56 (9.2%) patients and was associated with nodal metastases (P < 0.001), extrathyroidal extension (P < 0.001), extranodal extension (P < 0.001), multifocality (P = 0.018) and microscopic positive margins (P < 0.001). On univariate analysis, LVI was associated with reduced RFS (hazard ratio (HR) 2.3; 95% confidence interval (CI) 1.3-4.3; P = 0.007). However, after adjusting for nodal stage (pN0, pN1a, pN1b) there was no association between LVI and RFS (HR 1.3; 95% CI 0.7-2.5; P = 0.398). Similar results were obtained in full multivariate models adjusting for additional prognostic factors (HR 1.2; 95% CI 0.6-2.4; P = 0.627). CONCLUSION: LVI is strongly associated with other adverse prognostic factors in PTC, particularly the presence and extent of nodal metastases. However, after adjusting for these, LVI is not an independent predictor of recurrence.

The extent of extrathyroidal extension is a key determinant of prognosis in T4a papillary thyroid cancer.

BACKGROUND AND OBJECTIVES: In papillary thyroid cancer (PTC), the adverse prognostic impact of extrathyroidal extension (macro-ETE) invading the subcutaneous soft tissues, larynx, trachea, esophagus, or recurrent laryngeal nerve (T4a disease) is well established. We investigated whether the extent of macro-ETE, defined as "limited" with single structure involvement (lim-ETE) and "extensive" with multiple structures involved (ext-ETE), influences prognosis in T4a PTC. METHODS: A retrospective analysis of 610 patients with PTC identified 39 with T4a disease, including 26 with lim-ETE and 13 with ext-ETE. Univariate Cox regression was used to assess the relationship between the extent of macro-ETE and recurrence-free survival (RFS). RESULTS: Ext-ETE was associated with a five times increased risk of recurrence compared to lim-ETE (HR 5.0, P < .030), with or without adjustment for radioactive iodine administration and after adjustment for margin status (HR 4.7; P = .041). A low-risk subset of T4a disease comprising of patients aged less than 55 years with lim-ETE and clear margins accounted for one-third of the cohort and demonstrated an excellent 5-year RFS of 92%. CONCLUSIONS: The extent of macro-ETE appears to be an important determinant of prognosis in T4a PTC. A low-risk subset of T4a disease exists with an excellent prognosis.

Microscopic positive margins strongly predict reduced disease-free survival in pT4a papillary thyroid cancer.

BACKGROUND: Although microscopic positive margins appear to have no independent prognostic impact in papillary thyroid cancer (PTC), this may not be the case in pT4a tumors. METHODS: Retrospective analysis of 610 patients with PTC, 39 with pT4a tumors, to determine if microscopic positive margins impact disease-free survival (DFS) in pT4a PTC. RESULTS: On univariate analysis, microscopic positive margins were not associated with reduced DFS in patients with no extrathyroidal extension (ETE) (hazard ratio [HR], 1.7; P = 0.32), microscopic ETE (HR, 1.6; P = 0.36), or macroscopic ETE limited to strap muscles (HR, 1.2; P = 0.87). In contrast, microscopic positive margins were associated with reduced DFS in T4a disease (HR, 4.1; P = 0.04). Disease recurrence was nodal, distant, or biochemical, and did not occur directly at the site of positive margins. CONCLUSION: Although microscopic positive margins do not influence DFS in the majority of patients with PTC, they are associated with a fourfold increased risk of recurrence in pT4a disease.

Effect of seawalls on tsunami evacuation departure in the 2011 Great East Japan Earthquake.

OBJECTIVE: To quantitatively evaluate the effect of seawalls on tsunami evacuation departure. METHODS: A mixed-effect Cox proportional-hazards regression model was applied to evacuation behavioural data obtained from a probability survey of survivors of the 2011 Great East Japan Earthquake and Tsunami in Iwate and Miyagi prefectures. FINDINGS: Presence of a seawall higher than the forecast tsunami height at any given time reduces the likelihood of prompt evacuation by 30%. Findings suggest the existence of a false sense of security among residents deriving from the presence of seawalls. CONCLUSION: Prompt evacuation is a key factor affecting survival. The effect of seawalls on evacuation decisions is an important policy consideration. More work is needed in disaster preparedness education and in the way tsunami warnings are given, taking into consideration the risk of forecast error. Priority should be given to promoting prompt evacuation and educating residents as to the uncertainty of tsunami forecasting, to ensure that residents do not ignore evacuation warnings due to false impressions of the safety provided by seawalls.

The Prognostic Impact of Tumor Size in Papillary Thyroid Carcinoma is Modified by Age.

BACKGROUND: Although the importance of tumor size in papillary thyroid cancer (PTC) is well established, there is no research investigating whether age modifies the impact of tumor size, and there is conflicting evidence regarding optimal size thresholds for prognostic discrimination. We aimed to verify that tumor size is an independent prognostic factor in PTC, investigate the impact of patient age, and identify optimal size cutoffs for risk stratification using objective measures of model performance. METHODS: A retrospective analysis of 574 patients with PTC, using multivariate Cox regression models to test the impact of tumor size on recurrence-free survival (RFS). Subgroup analyses were performed in patients aged <55 and ≥55 years. Exploratory analyses to identify optimal size cutoffs for prognostic discrimination were performed using the proportion of variation explained (PVE) and Harrell's C-index. RESULTS: Tumor size predicted RFS on multivariate analysis in the overall study cohort (hazard ratio [HR] 1.16; [95% confidence interval (CI)1.01-1.34]; p = 0.038). In subgroup analysis, there was no association between tumor size and RFS in patients aged <55 years (HR 1.11; [CI 0.89-1.38]; p = 0.362). In contrast, size was an independent predictor of RFS in patients aged ≥55 years (HR 1.52; [CI 1.11-2.07]; p = 0.009). In this subgroup, an optimal size threshold of >2 cm versus ≤2 cm (HR 5.24; [CI 2.30-11.92]; p < 0.001; PVE: 36%; C-index: 0.66) provided the greatest prognostic discrimination. There was no incremental improvement in prognostic value by further stratification of size. CONCLUSION: In our PTC cohort, the impact of tumor size on RFS was limited to patients aged ≥55 years. A single size threshold of 2 cm maximized prognostic discrimination with tumors >2 cm associated with a five times higher risk of recurrence than those ≤2 cm. These findings need to be validated in independent large cohorts and the potential management and staging implications further studied.

Microscopic positive margins in papillary thyroid cancer do not impact disease recurrence.

BACKGROUND: The prognostic significance of microscopic positive margins in papillary thyroid carcinoma (PTC) remains unclear. The aim of this study was to determine if microscopic positive margins are associated with increased risk of disease recurrence. METHODS: This is a retrospective analysis of 610 patients with PTC using multivariate Cox regression to evaluate the association between microscopic positive margins and disease-free survival. RESULTS: Microscopic positive margins were found in 67 (11%) patients and associated with extrathyroidal extension (P < 0.001), multifocality (P < 0.001), nodal metastases (P < 0.001), lymphovascular invasion (P < 0.001), age ≥55 years (P = 0.048), administration of radioactive iodine (RAI) therapy (P = 0.001) and a trend towards larger tumour size (18 versus 15 mm; P = 0.074). After a median follow-up of 3.4 years, there were 83 recurrences. Although involved margins were associated with increased risk of recurrence on univariate analysis (hazard ratio 2.6, 95% confidence interval 1.5-4.6; P = 0.001), there was no association after adjusting for age, nodal metastases, tumour size and extrathyroidal extension on multivariate analysis (hazard ratio 1.5, 95% confidence interval 0.8-2.9; P = 0.242). Similar results were obtained after adjusting for RAI and if margins were analysed as focal versus widely positive. In our study cohort, patients with involved margins generally had other indications for RAI. However, in the nine patients who did not receive RAI, there was no recurrence in the thyroid bed. CONCLUSION: Despite a strong association between microscopic positive margins and other adverse prognostic factors in PTC, there is no independent association with disease recurrence on multivariate analysis. Microscopic positive margins are rare (1.1%) in the absence of other indications for RAI.

An Analysis of The American Joint Committee on Cancer 8th Edition T Staging System for Papillary Thyroid Carcinoma.

Background: The American Joint Committee on Cancer (AJCC) removed microscopic extrathyroidal extension (ETE) from the 8th edition T staging for papillary thyroid cancer (PTC) based on increasing evidence that it is not an independent prognostic factor. Objectives: We compared the prognostic performance of AJCC 7th (pT7) and 8th (pT8) edition T stage systems, particularly in patients ≥55 years old without macroscopic ETE or distant metastases in whom T classification affects AJCC Tumor Node Metastasis (TNM) stage. Method: A retrospective analysis of disease-free survival (DFS) in 577 patients with PTC comparing pT8 vs pT7 using the Akaike information criterion (AIC), Harrell's C-index, and Proportion of Variation Explained (PVE). Results: Of 105 patients with AJCC7 T3 disease, 74 were down-staged. Overall, the prognostic performance of pT7 and pT8 was similar. However, in patients ≥55 years old without macroscopic ETE or distant metastases, pT8 was inferior to pT7 on the basis of higher AIC, lower C-index (0.67 vs 0.76), and lower PVE (30% vs 45%). In this subset, microscopic ETE was associated with multiple other adverse prognostic features and reduced DFS (hazard ratio, 2.8; 95% confidence interval, 1.5 to 5.2; P = 0.002), irrespective of tumor size. Discussion: In our cohort, pT8 was inferior to pT7 in patients ≥55 years old without macroscopic ETE or distant metastases in whom T classification affects TNM stage. Microscopic ETE was strongly associated with other adverse prognostic factors and reduced DFS in this patient subgroup and may be an effective surrogate for disease biology in PTC, irrespective of whether it is an independent prognostic factor.

Electron Transport Chain Is Biochemically Linked to Pilus Assembly Required for Polymicrobial Interactions and Biofilm Formation in the Gram-Positive Actinobacterium Actinomyces oris.

The Gram-positive actinobacteria Actinomyces spp. are key colonizers in the development of oral biofilms due to the inherent ability of Actinomyces to adhere to receptor polysaccharides on the surface of oral streptococci and host cells. This receptor-dependent bacterial interaction, or coaggregation, requires a unique sortase-catalyzed pilus consisting of the pilus shaft FimA and the coaggregation factor CafA forming the pilus tip. While the essential role of the sortase machine SrtC2 in pilus assembly, biofilm formation, and coaggregation has been established, little is known about trans-acting factors contributing to these processes. We report here a large-scale Tn5 transposon screen for mutants defective in Actinomyces oris coaggregation with Streptococcus oralis We obtained 33 independent clones, 13 of which completely failed to aggregate with S. oralis, and the remainder of which exhibited a range of phenotypes from severely to weakly defective coaggregation. The former had Tn5 insertions in fimA, cafA, or srtC2, as expected; the latter were mapped to genes coding for uncharacterized proteins and various nuo genes encoding the NADH dehydrogenase subunits. Electron microscopy and biochemical analyses of mutants with nonpolar deletions of nuo genes and ubiE, a menaquinone C-methyltransferase-encoding gene downstream of the nuo locus, confirmed the pilus and coaggregation defects. Both nuoA and ubiE mutants were defective in oxidation of MdbA, the major oxidoreductase required for oxidative folding of pilus proteins. Furthermore, supplementation of the ubiE mutant with exogenous menaquinone-4 rescued the cell growth and pilus defects. Altogether, we propose that the A. oris electron transport chain is biochemically linked to pilus assembly via oxidative protein folding.IMPORTANCE The Gram-positive actinobacterium A. oris expresses adhesive pili, or fimbriae, that are essential to biofilm formation and Actinomyces interactions with other bacteria, termed coaggregation. While the critical role of the conserved sortase machine in pilus assembly and the disulfide bond-forming catalyst MdbA in oxidative folding of pilins has been established, little is known about other trans-acting factors involved in these processes. Using a Tn5 transposon screen for mutants defective in coaggregation with Streptococcus oralis, we found that genetic disruption of the NADH dehydrogenase and menaquinone biosynthesis detrimentally alters pilus assembly. Further biochemical characterizations determined that menaquinone is important for reactivation of MdbA. This study supports the notion that the electron transport chain is biochemically linked to pilus assembly in A. oris via oxidative folding of pilin precursors.