Predictive Value of Somatic Mutations for the Development of Malignancy in Thyroid Nodules by Cytopathology

Objective: The purpose of our prospective longitudinal study was to evaluate the predictive efficacy of genetic testing for malignancies in fine-needle aspiration biopsy samples that are cytologically benign at the time of biopsy.Methods: A total of 779 aspirated cytological samples collected from thyroid nodules of 626 patients were included in a 3-year follow-up study. Consecutive patients with cytologically benign thyroid nodules by the Bethesda System for Reporting Thyroid Cytopathology were enrolled in the study. At enrollment, somatic 1-point nucleotide polymorphisms of BRAF and RAS family genes were tested by melting-point analysis, while RET/PTC and PAX8/PPAR-gamma rearrangements were examined by real-time polymerase chain reaction. The genetic test was considered to be positive if a somatic mutation was found. Malignant cytopathologic diagnoses were confirmed by histopathology.Results: In samples collected from 779 thyroid nodules, there were 39 BRAF, 33 RAS mutations, and 1 RET/PTC rearrangements found at the beginning of the study. No PAX8/PPAR-gamma rearrangement was identified. There were 52 malignant thyroid tumors removed during follow-up, out of which 24 contained a somatic mutation. The specificity of the presence of somatic mutations for malignancies was as high as 93.3%, and sensitivity was 46.2%. The negative predictive value of genetic testing reached 96.0%.Conclusion: Our results show that our set of genetic tests can predict the appearance of malignancy in benign thyroid nodules (at the beginning of follow-up) with high specificity and strong negative predictive value.Abbreviations:BRAF = v-raf murine sarcoma viral oncogene homolog B1FLUS = follicular lesion of undetermined significanceFNAB = fine-needle aspiration biopsyFTC = follicular thyroid carcinomaHRAS = homologous to the oncogene from the Harvey rat sarcoma virusKRAS = homologous to the oncogene from the Kirsten rat sarcoma virusNRAS = first isolated from a human neuroblastoma/neuroblastomaRAS = viral oncogene homologPAX8 = paired box 8PCR = polymerase chain reactionPPAR-gamma = peroxisome proliferator-activated receptor gammaPTC = papillary thyroid carcinomaRAS = rat sarcomaRET = rearranged during transfection tyrosine-kinase proto-oncogeneSM = somatic mutationSNP = single-nucleotide polymorphism     

Tumor Size is an Independent Predictor of Mortality Risk in Differentiated Thyroid Cancer Patients with T4 Disease

Objective: The eighth edition of the American Joint Committee on Cancer (AJCC) guideline on the tumor-node-metastasis staging system has been applied in clinical practice for thyroid cancer since 2018. However, using these criteria, a few studies have shown no significant difference between stage III and IV diseases amongst the differentiated thyroid cancer (DTC) patients. Thus, we aimed to study the underlying reason behind this observation.Methods: Patients were selected from the Surveillance, Epidemiology, and End Results database between 2004 and 2015. The Cox proportional hazards regression model was used for the univariate and multivariate analyses to plot the Kaplan-Meier survival curves for overall survival (OS) and disease-specific survival (DSS).Results: A total of 1,431 patients had a median tumor size of 3.0 cm (range: 0.1 to 50 cm). When stratified by tumor size (≤2 cm, 2 to 4 cm, and >4 cm), lower survival rates were observed in patients with stage III (T4a) cancer and large tumor size than in those with stage IVA (T4b) cancer and small tumor size. Univariate and multivariate analyses showed that tumor size (≤4 cm versus >4 cm) is an independent prognostic factor for OS (P<.001) and DSS (P<.001) in DTC patients with T4a and T4b diseases.Conclusion: Tumor size is an independent prognostic factor for OS and DSS in DTC patients with T4 disease; tumor size-related modification of the T4 category can improve the AJCC staging system for DTC patient with stage III–IV diseases.Abbreviations: AJCC = American Joint Committee on Cancer; CI = confidence interval; DSS = disease-specific survival; DTC = differentiated thyroid cancer; FTC = follicular thyroid cancer; HR = hazard ratio; OS = overall survival; PTC = papillary thyroid cancer; SEER = Surveillance, Epidemiology, and End Results; TNM = tumor-node-metastasis     

Clinical Impact of Non-Invasive Follicular Thyroid Neoplasm with Papillary-Like Nuclear Features on the Risk of Malignancy in the Bethesda System for Reporting Thyroid Cytopathology: A Meta-Analysis of 14,153 Resected Thyroid Nodules

Objective: It is still controversial as to how the reclassification of noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) affects the risk of malignancy (ROM) in The Bethesda System for Reporting Thyroid Cytopathology (TBSRTC). This meta-analysis was aimed to investigate the impact of NIFTP on the ROM in each TBSRTC category.Methods: We accessed three electronic databases including PubMed, Web of Science, and Scopus to search for relevant data from January, 2016 to July, 2018. Relative risk and meta-analysis of proportions using the DerSimonian-Laird method, and each corresponding 95% confidence interval (CI) was pooled using a random-effect model.Results: A total of 14 studies consisting of 14,153 resected nodules were included for meta-analyses. Overall, there was a significant reduction in ROM in all TBSRTC categories following the NIFTP reclassification, except TBSRTC category I. The largest absolute and relative decrease in ROM was observed in TBSRTC category V (16%; 95% CI = 8 to 24) and category III (32%; 95% CI = 24 to 39), respectively. There was a positive correlation between the rate of NIFTP and resection rate (r = 0.83; P = .02). The decreases in ROM were more prominent in Western than in Asian cohorts.Conclusion: We confirmed the decrease in ROM due to the NIFTP reclassification for most of TBSRTC categories, which was more significant in Western than in Asian practice. The incidence of NIFTP was higher in institutions where surgical resection rates were high in patients with indeterminate cytology nodules.Abbreviations: AUS/FLUS = atypia of undetermined significance/follicular lesion of undetermined significance; CI = confidence interval; FNA = fine-needle aspiration; FN/SFN = follicular neoplasm/suspicious for follicular neoplasm; NIFTP = noninvasive follicular thyroid neoplasm with papillary-like nuclear features; NI-FVPTC = noninvasive follicular variant of papillary thyroid carcinoma; ROM = risk of malignancy; RR = relative risk; SM = suspicious for malignancy; TBSRTC = The Bethesda System for Reporting Thyroid Cytopathology     

Risk Factors and Outcomes for Postoperative Delirium after Major Surgery in Elderly Patients

Background

Early identification of patients at risk for delirium is important, since adequate well timed interventions could prevent occurrence of delirium and related detrimental outcomes. The aim of this study is to evaluate prognostic factors for delirium, including factors describing frailty, in elderly patients undergoing major surgery.

Methods

We included patients of 65 years and older, who underwent elective surgery from March 2013 to November 2014. Patients had surgery for Abdominal Aortic Aneurysm (AAA) or colorectal cancer. Delirium was scored prospectively using the Delirium Observation Screening Scale. Pre- and peri-operative predictors of delirium were analyzed using regression analysis. Outcomes after delirium included adverse events, length of hospital stay, discharge destination and mortality.

Results

We included 232 patients. 51 (22%) underwent surgery for AAA and 181 (78%) for colorectal cancer. Postoperative delirium occurred in 35 patients (15%).Predictors of postoperative delirium included: delirium in medical history (Odds Ratio 12 [95% Confidence Interval 2.7–50]), advancing age (Odds Ratio 2.0 [95% Confidence Interval 1.1–3.8]) per 10 years, and ASA-score ≥3 (Odds Ratio 2.6 [95% Confidence Interval 1.1–5.9]). Occurrence of delirium was related to an increase in adverse events, length of hospital stay and mortality.

Conclusion

Postoperative delirium is a frequent complication after major surgery in elderly patients and is related to an increase in adverse events, length of hospital stay, and mortality. A delirium in the medical history, advanced age, and ASA-score may assist in defining patients at increased risk for delirium. Further attention to prevention of delirium is essential in elderly patients undergoing major surgery.     

Polymorphisms in the TNFA and IL6 Genes Represent Risk Factors for Autoimmune Thyroid Disease

Background

Autoimmune thyroid disease (AITD) comprises diseases including Hashimoto''s thyroiditis and Graves'' disease, both characterized by reactivity to autoantigens causing, respectively, inflammatory destruction and autoimmune stimulation of the thyroid-stimulating hormone receptor. AITD is the most common thyroid disease and the leading form of autoimmune disease in women. Cytokines are key regulators of the immune and inflammatory responses; therefore, genetic variants at cytokine-encoding genes are potential risk factors for AITD.

Methods

Polymorphisms in the IL6-174 G/C (rs1800795), TNFA-308 G/A (rs1800629), IL1B-511 C/T (rs16944), and IFNGR1-56 T/C (rs2234711) genes were assessed in a case-control study comprising 420 Hashimoto''s thyroiditis patients, 111 Graves'' disease patients and 735 unrelated controls from Portugal. Genetic variants were discriminated by real-time PCR using TaqMan SNP genotyping assays.

Results

A significant association was found between the allele A in TNFA-308 G/A and Hashimoto''s thyroiditis, both in the dominant (OR = 1.82, CI = 1.37–2.43, p-value = 4.4×10⁻⁵) and log-additive (OR = 1.64, CI = 1.28–2.10, p-value = 8.2×10⁻⁵) models. The allele C in IL6-174 G/C is also associated with Hashimoto''s thyroiditis, however, only retained significance after multiple testing correction in the log-additive model (OR = 1.28, CI = 1.06–1.54, p-value = 8.9×10⁻³). The group with Graves'' disease also registered a higher frequency of the allele A in TNFA-308 G/A compared with controls both in the dominant (OR = 1.85, CI = 1.19–2.87, p-value = 7.0×10⁻³) and log-additive (OR = 1.69, CI = 1.17–2.44, p-value = 6.6×10⁻³) models. The risk for Hashimoto''s thyroiditis and Graves'' disease increases with the number of risk alleles (OR for two risk alleles is, respectively, 2.27 and 2.59).

Conclusions

This study reports significant associations of genetic variants in TNFA and IL6 with the risk for AITD, highlighting the relevance of polymorphisms in inflammation-related genes in the etiopathogenesis of AITD.     

Systematic Examination of Infant Size and Growth Metrics as Risk Factors for Overweight in Young Adulthood

Objective

To systematically examine infant size and growth, according to the 2006 WHO infant growth standards, as risk factors for overweight status in young adulthood in a historical cohort. Specifically, to assess: Whether accounting for length (weight-for-length) provides a different picture of risk than weight-for-age, intervals of rapid growth in both weight-for-age and weight-for-length metrics, and what particular target ages for infant size and intervals of rapid growth associate most strongly with overweight as a young adult.

Patients/Methods

Data analysis of 422 appropriate for gestational age white singleton infants enrolled in the Fels Longitudinal Study. Odds ratios (OR) for overweight and obesity in young adulthood (age 20–29) were calculated using logistic regression models for the metrics at each target age (0, 1, 3, 6, 9, 12, 18, 24 months) comparing ≥85^th v. <85^th percentile, as well as rapid growth (Δ≥0.67 Z-score) through target age intervals. Models accounted for both maternal and paternal BMI.

Results

Infants ≥85^th percentile of weight-for-age at each target age (except 3 months) had a greater odds of being overweight as a young adult. After accounting for length (weight-for-length) this association was limited to 12, and 18 months. Rapid weight-for-age growth was infrequently associated with overweight as a young adult. Rapid weight-for-length growth from 0 to 24 months, 1 to 6, 9, 12, 18, and 24 months and from 3 to 9, 12, 18, and 24 months was strongly associated with overweight status as a young adult.

Conclusions

The WHO weight-for-length metric associates differently with risk of being overweight as a young adult compared to weight-for-age. Intervals of rapid weight-for-length growth ranging from months (0–24), (1–12, 18, and 24) and (3–9, and 12) displayed the largest OR for being overweight as a young adult.     

Risk Factors for Central Lymph Node Metastasis in CN0 Papillary Thyroid Carcinoma: A Systematic Review and Meta-Analysis

Background

Central lymph node metastasis (CLNM) is common in papillary thyroid carcinoma (PTC). Prophylactic central lymph node dissection (PCLND) for patients with clinically negative central compartment lymph nodes (CN0) remains controversial. The phrase “clinically negative” is used to indicate that patients exhibited no clinical evidence of CLNM by ultrasonography (US) or computerized tomography (CT) preoperatively. In this study, we analyze the risk factors for CLNM in CN0 patients.

Methods

The PUBMED and SCIE databases were systematically searched for works published through January 31, 2015. All of the patients included in this study underwent thyroidectomy+PCLND. Revman 5.3 software was used to analyze the data.

Results

Twenty studies and 9084 patients were included in this meta-analysis. The following variables were associated with an increased risk of CLNM in CN0 patients: age < 45 years (OR = 1.59, 95% CI = 1.42–1.78, p<0.00001), male sex (OR = 1.95, 95% CI = 1.63–2.32, p<0.00001), multifocality (OR = 1.43, 95% CI = 1.22–1.67, p<0.00001), tumor size > 2 cm for PTC patients (OR = 2.98, 95% CI 2.08–4.28, p<0.00001) or tumor size > 0.5 cm for papillary thyroid microcarcinoma (PTMC) patients (OR = 2.30, 95% CI = 1.71–3.09, p<0.00001), location of the primary tumor in the central area and low pole (OR = 1.86, 95% CI = 1.48–2.33, p<0.00001), lymphovascular invasion (OR = 4.35, 95% CI = 2.24–8.46, p<0.0001), extrathyroidal extension (OR = 2.27, 95% CI = 1.76–2.94, p<0.00001), and capsular invasion (OR = 1.72, 95% CI = 1.39–2.41, p<0.00001). PTC (tumor size>1cm) exhibited a higher risk factor associated with CLNM than PTMC (tumor size<1cm) (OR = 2.83, 95% CI = 2.15–3.72, p<0.00001). Bilateral tumors (OR = 1.21, 95% CI = 0.92–1.58, p = 0.17) and lymphocytic thyroiditis (OR = 0.88, 95% CI = 0.71–1.09, p = 0.25) had no association with CLNM in CN0 patients.

Conclusions

Our systematic review identified several clinical features associated with CLNM in CN0 patients, including age, sex, multifocality, size, location, lymphovascular invasion, capsular invasion, and extrathyroidal extension. These factors should guide the application of PCLND in CN0 patients.     

Aberrant Levels of Hematopoietic/Neuronal Growth and Differentiation Factors in Euthyroid Women at Risk for Autoimmune Thyroid Disease

BackgroundSubjects at risk for major mood disorders have a higher risk to develop autoimmune thyroid disease (AITD) and vice-versa, implying a shared pathogenesis. In mood disorder patients, an abnormal profile of hematopoietic/neuronal growth factors is observed, suggesting that growth/differentiation abnormalities of these cell lineages may predispose to mood disorders. The first objective of our study was to investigate whether an aberrant profile of these hematopoietic/neuronal growth factors is also detectable in subjects at risk for AITD. A second objective was to study the inter relationship of these factors with previously determined and published growth factors/cytokines in the same subjects.MethodsWe studied 64 TPO-Ab-negative females with at least 1 first- or second-degree relative with AITD, 32 of whom did and 32 who did not seroconvert to TPO-Ab positivity in 5-year follow-up. Subjects were compared with 32 healthy controls (HCs). We measured serum levels of brain-derived neurotrophic factor (BDNF), Stem Cell Factor (SCF), Insulin-like Growth Factor-Binding Protein 2 (IGFBP-2), Epidermal Growth Factor (EGF) and IL-7 at baseline.ResultsBDNF was significantly lower (8.2 vs 18.9 ng/ml, P<0.001), while EGF (506.9 vs 307.6 pg/ml, P = 0.003) and IGFBP-2 (388.3 vs 188.5 ng/ml, P = 0.028) were significantly higher in relatives than in HCs. Relatives who seroconverted in the next 5 years had significantly higher levels of SCF than non-seroconverters (26.5 vs 16.7 pg/ml, P = 0.017). In a cluster analysis with the previously published growth factors/cytokines SCF clustered together with IL-1β, IL-6 and CCL-3, of which high levels also preceded seroconversion.ConclusionRelatives of AITD patients show aberrant serum levels of 4 hematopoietic/neuronal growth factors similar to the aberrancies found in mood disorder patients, suggesting that shared growth and differentiation defects in both the hematopoietic and neuronal system may underlie thyroid autoimmunity and mood disorders. A distinct pattern of four inter correlating immune factors in the relatives preceded TPO-Ab seroconversion in the next 5 years.     

Ecological,Social and Biological Risk Factors for Continued Trypanosoma cruzi Transmission by Triatoma dimidiata in Guatemala

Background

Chagas disease transmission by Triatoma dimidiata persists in Guatemala and elsewhere in Central America under undefined ecological, biological and social (eco-bio-social) conditions.

Methodology

Eco-bio-social risk factors associated with persistent domiciliary infestation were identified by a cross-sectional survey and qualitative participatory methods. Quantitative and qualitative data were generated regarding Trypanosoma cruzi reservoirs and triatomine hosts. Blood meal analysis and infection of insects, dogs and rodents were determined. Based on these data, multimodel inference was used to identify risk factors for domestic infestation with the greatest relative importance (>0.75).

Principal Findings

Blood meal analysis showed that 64% of 36 bugs fed on chickens, 50% on humans, 17% on dogs; 24% of 34 bugs fed on Rattus rattus and 21% on Mus musculus. Seroprevalence among 80 dogs was 37%. Eight (17%) of 46 M. musculus and three (43%) of seven R. rattus from households with infected triatomines were infected with T. cruzi Distinct Typing Unit I. Results from interviews and participatory meetings indicated that vector control personnel and some householders perceived chickens roosting and laying eggs in the house as bug infestation risk factors. House construction practices were seen as a risk factor for bug and rodent infestation, with rodents being perceived as a pest by study participants. Multimodel inference showed that house infestation risk factors of high relative importance are dog density, mouse presence, interior wall plaster condition, dirt floor, tile roofing and coffee tree presence.

Conclusions/Significance

Persistent house infestation is closely related to eco-bio-social factors that maintain productive T. dimidiata habitats associated with dogs, chickens and rodents. Triatomine, dog and rodent infections indicate active T. cruzi transmission. Integrated vector control methods should include actions that consider the role of peridomestic animals in transmission and community memberś level of knowledge, attitudes and practices associated with the disease and transmission process.     

Risk Factors for Nonremission and Progression-Free Survival after I-131 Therapy in Patients with Lung Metastasis from Differentiated Thyroid Cancer: A Single-Institute,Retrospective Analysis in Southern China

Objective: Prognostic factors related to progression-free survival (PFS) have not received much attention in the literature regarding iodine-131 (¹³¹I) therapy for patients with differentiated thyroid cancer and lung metastases. We sought to explore the factors associated with PFS and nonremission in a group of patients with differentiated thyroid cancer and pulmonary metastases at initial diagnosis and to investigate the impact of ¹³¹I therapy on pulmonary function and peripheral blood counts in the same cohort of patients.Methods: The medical records of 1,050 patients with differentiated thyroid cancer treated at the Zhujiang Hospital of Southern Medical University from January 2006 to January 2015 were retrospectively reviewed. Among them, 107 patients fulfilled the inclusion criteria.Results: Multivariate Cox regression analysis indicated that age ≥45 years and ¹³¹I nonavidity were independent risk factors for disease progression. Multivariate logistic regression analysis revealed that pulmonary nodule size ≥1 cm and ¹³¹I nonavidity were the strongest risk factors predicting nonremission. Varying cumulative ¹³¹I dosage had no association with posttreatment pulmonary function or peripheral blood cell counts.Conclusion: Similar to earlier studies, our results confirm that ¹³¹I nonavidity was associated with an increased risk of disease progression and greater odds of nonremission. In addition, patients with differentiated thyroid cancer and lung metastases with pulmonary nodules ≥1 cm had a reduced likelihood of achieving remission. Furthermore, special attention is needed when monitoring patients over 45 years at a higher risk of disease progression.Abbreviations:CI = confidence intervalDTC = differentiated thyroid cancer¹⁸F-FDG = fluoro-18 fluorodeoxyglucoseFEF = forced expiratory flowFTC = follicular thyroid cancerFVC = forced vital capacityGR = granulocytesHb = hemoglobinHR = hazard ratio¹³¹I = iodine-131LN = lymph nodeOR = odds ratioOS = overall survivalPET/CT = positive positron emission tomography/computed tomographyPFS = progression-free survivalPT = partial thyroidectomyPTC = papillary thyroid cancerRAI = radioactive iodineRBC = red blood cellTg = thyroglobulinTgAb = thyroglobulin antibodyTSH = thyroid-stimulating hormoneTT = total thyroidectomyWBC = white blood cellsWBS = whole body scan     

High Risk for Obstructive Sleep Apnea in Truck Drivers Estimated by the Berlin Questionnaire: Prevalence and Associated Factors

The health issues that attract our attention when analyzing the truck driver population are the high prevalence of sedentary habits, inadequate diet, obesity, and proportion of hypertensive. All these are either considered risk factors for or a consequence of Obstructive Sleep Apnea (OSA). The objective of this study was to investigate the risk for OSA among 10,101 truck drivers and to correlate it with potentially related factors, such as serum glucose and cholesterol levels, smoking habits, alcohol and drug consumption, and self-reported physical activity. The drivers were invited to participate in the campaign “Saúde na Boléia” (Health Behind the Wheel) promoted by a Brazilian company responsible for the maintenance of approximately 360 km of roads in the country. Drivers who spontaneously stopped at the campaign booths placed along the roads were invited to answer a questionnaire covering sociodemographic data such as age, alcohol, and drug consumption. All participants completed a Berlin Questionnaire and were classified as low- or high-risk subjects for OSA based on questions about snoring, tiredness during the day, and the presence of hypertension or obesity. Blood collection was accomplished at the same site by nurses and/or nursing students collaborating with the campaign for subsequent laboratory studies. Approximately 26% of the truck drivers were found to be at high-risk group for OSA. An adjusted multiple logistic model found the independent risk factors of smoking (OR = 1.16; p = 0.014) and drug use (OR = 1.32; p < 0.0001) were associated with high risk for OSA. The presence of self-reported occasional (OR = 0.62; p < 0.0001) and regular (OR = 0.53; p < 0.0001) physical activity was found to be an independent factor protective of OSA. Educational programs, including ones aimed at improving one's health habits, such as engagement in physical exercise, should be considered in the development of initiatives to reduce the risk for OSA among the truck driver population.