Calcitonin-negative medullary thyroid carcinoma: the 'triple-negative' phenotype.

Calcitonin-negative medullary thyroid carcinoma is a rare, poorly understood primary neuroendocrine carcinoma of the thyroid characterised by classic medullary thyroid carcinoma morphology without raised serum calcitonin. A 24-year-old woman presented with a slow-growing, right-sided neck swelling. She underwent an ultrasound scan, cytopathological and histopathological examination, and tests for alternative diagnoses. The ultrasound showed a heterogeneous, hyperechoic nodule in the right thyroid lobe. Serum calcitonin was normal. Cytopathology and histopathology showed typical medullary thyroid carcinoma morphology but without calcitonin upon immunostaining and mRNA in situ hybridisation. A 'triple-negative' calcitonin-negative medullary thyroid carcinoma was diagnosed. A completion thyroidectomy with bilateral central lymph node dissection was performed. The patient remains well three-years post-surgery. When cytopathology suggests a medullary thyroid carcinoma, serum calcitonin, pro-calcitonin, carcinoembryonic antigen and calcitonin-gene-related peptide should be measured to identify cases of calcitonin-negative medullary thyroid carcinoma. They should also be measured post-treatment for monitoring purposes. This will aid future calcitonin-negative medullary thyroid carcinoma diagnoses and will inform prognostic stratification and influence treatment decisions.

Conservation of the behavioral and transcriptional response to social experience among Drosophilids.

While social experience has been shown to significantly alter behaviors in a wide range of species, comparative studies that uniformly measure the impact of a single experience across multiple species have been lacking, limiting our understanding of how plastic traits evolve. To address this, we quantified variations in social feeding behaviors across 10 species of Drosophilids, tested the effect of altering rearing context on these behaviors (reared in groups or in isolation) and correlated observed behavioral shifts to accompanying transcriptional changes in the heads of these flies. We observed significant variability in the extent of aggressiveness, the utilization of social cues during food search, and social space preferences across species. The sensitivity of these behaviors to rearing experience also varied: socially naive flies were more aggressive than their socialized conspecifics in some species, and more reserved or identical in others. Despite these differences, the mechanism of socialization appeared to be conserved within the melanogaster subgroup as species could cross-socialize each other, and the transcriptional response to social exposure was significantly conserved. The expression levels of chemosensory-perception genes often varied between species and rearing conditions, supporting a growing body of evidence that behavioral evolution is driven by the differential regulation of this class of genes. The clear differences in behavioral responses to socialization observed in Drosophilids make this an ideal system for continued studies on the genetic basis and evolution of socialization and behavioral plasticity.

An analysis of signal processing algorithm performance for cortical intrinsic optical signal imaging and strategies for algorithm selection.

Intrinsic Optical Signal (IOS) imaging has been used extensively to examine activity-related changes within the cerebral cortex. A significant technical challenge with IOS imaging is the presence of large noise, artefact components and periodic interference. Signal processing is therefore important in obtaining quality IOS imaging results. Several signal processing techniques have been deployed, however, the performance of these approaches for IOS imaging has never been directly compared. The current study aims to compare signal processing techniques that can be used when quantifying stimuli-response IOS imaging data. Data were gathered from the somatosensory cortex of mice following piezoelectric stimulation of the hindlimb. The effectiveness of each technique to remove noise and extract the IOS signal was compared for both spatial and temporal responses. Careful analysis of the advantages and disadvantages of each method were carried out to inform the choice of signal processing for IOS imaging. We conclude that spatial Gaussian filtering is the most effective choices for improving the spatial IOS response, whilst temporal low pass and bandpass filtering produce the best results for producing temporal responses when periodic stimuli are an option. Global signal regression and truncated difference also work well and do not require periodic stimuli.

Recent Developments in the Pathology of Thyroid Cancer.

The histopathological features of thyroid cancers can be used to risk stratify patients, allowing prognostication and treatment decisions. A detailed accurate histological assessment by experienced pathologists working within a multidisciplinary context is crucial. Experience is also essential for interpretation of preoperative thyroid cytology specimens, which can be challenging. There is now more international harmonisation of numerical reporting systems for thyroid cytology. Understanding of the molecular basis of thyroid cancer has increased dramatically in recent years. Preoperative molecular pathology testing, when available, can refine cytological diagnosis to rule in or out for surgery, as well as assisting prognostication and enabling targeted treatment for thyroid tumours.

Thyroid cytology-histology correlation using the RCPath terminology for thyroid cytology reporting.

AIMS: The Royal College of Pathologists Thy1-5 thyroid cytology guidance, 2009, second edition 2016, invites audits of its use. This report documents the experience of one department, assessing percentage usage of each Thy category, correlation with subsequent histology and comparison with other published studies. METHODS: Thyroid cytology and subsequent histology reports for 7 years (1 January 2008-31 December 2014) were reviewed, excluding referrals. Years 2008-2010 were compared with 2011-2014. RESULTS: There were 1090 specimens in 2008-2010, 1239 in 2011-2014. Thy usage for 2008-2010/2011-2014, respectively was: Thy1 16.1%/9.8%; Thy1c 10.6%/10.7%; Thy2/2c 52.4%/45.2%; Thy3a 9.6%/14.4%; Thy3f 5.8%/10.9%; Thy4 2.3%/3.6%; Thy5 1.8%/5.4%. 772 specimens had subsequent histology: 415 non-neoplastic lesions; 357 neoplasms (110 benign, 247 malignant). Risk of malignancy (ROM) (including non-histology cases) for 2008-2010/2011-2014: Thy1/1c 5.2%/4.0%; Thy2/2c 1.4%/1.4%; Thy3a 10.0%/14.5%; Thy3f 25.4%/26.7%. Positive predictive values (PPVs) for neoplasia (histology cases only): Thy3a 20.3%/56.9%; Thy3f 60.0%/64.8%; Thy4 58.3%/90.9%; Thy5 100%/100%. PPVs for malignancy (histology cases only): Thy3a 10.2%/36.1%; Thy3f 35.4%/33.3%; Thy4 50.0%/81.8%; Thy5 100%/100%. The Thy3a/Thy5 ratio for 2011-2014 was 2.7. CONCLUSIONS: Numerical reporting categories facilitate audit and comparison with other published results. Technique-related inadequates (Thy1) have reduced but cystic lesions (Thy1c) are stable, in keeping with increased use of ultrasound scanning (USS). Thy2/2c has reduced, probably reflecting increased USS selection of non-benign nodules for sampling. ROMs for Thy1/1c/2/2c are low. Usage of all positive categories, Thy3a, Thy3f, Thy4 and Thy5, has increased. As others have reported for atypia of undetermined significance or follicular lesion of undetermined significance, Thy3a is followed by malignancy more frequently than expected. There is stable prediction of malignancy by Thy3f and Thy5, the latter being 100% throughout.

Probiotics and prevention of Clostridium difficile infection.

The role of probiotics as adjunctive measures in the prevention of Clostridium difficile infection (CDI) has been controversial. However, a growing body of evidence has suggested that they have a role in primary prevention of CDI. Elements of this controversy are reviewed and the proposed mechanisms of action, the value and cost effectiveness of probiotics are addressed with a focus on three agents, Saccharomyces boulardii, Lactobacillus rhamnosus GG and the combination of Lactobacillus acidophilus CL1285, Lactobacillus casei LBC80R, Lactobacillus rhamnosus CLR2 (Bio-K+).

Correlation of Ki-67 indices from biopsy and resection specimens of neuroendocrine tumours.

INTRODUCTION Neuroendocrine tumours (NETs) are a heterogeneous group of tumours with a highly variable presentation and prognosis. Management decisions are complex. Ki-67 levels in tissue samples are a key indicator used to grade tumours and guide treatment. This study assessed whether the Ki-67 index and tumour grade generated from tissue samples correlated with that assessed in resection specimens. METHODS This was a retrospective cohort analysis of all patients who had both a tissue sample and a resection specimen analysed in our trust, a tertiary referral centre, during 2012 and 2013. RESULTS Data from 36 patients were reviewed. Ki-67 indices from tissue samples and resection specimens showed strong correlation (r=0.95, p<0.001). Tumour grading was the same in the tissue sample and resection specimens for 22 patients (61.1%). In four patients (11.1%), the tissue sample overestimated the grade while in ten (27.8%), the sample underestimated the grade. CONCLUSIONS In most cases, the Ki-67 index and tumour grade from the tissue sample matched that of the resection specimen. However, in nearly 40% of cases, the tissue sample grading did not match the resection tumour grading. In the majority of these, the tissue sample underestimated disease activity. A low Ki-67 index in a tissue sample should therefore be taken as provisional and should not, in isolation, persuade clinicians to choose a more conservative treatment approach if there is clinical, biochemical or radiological evidence suggestive of a more aggressive disease pathology.

A combined cumulative threshold spectra and digital reconstruction analysis reveal structural alterations of microglia within the prefrontal cortex following low-dose LPS administration.

Sickness behaviors have become the focus of great interest in recent years as they represent a clear case of how peripheral disturbances in immune signaling can disrupt quite complex behaviors. In the current study, we were interested in examining whether we could identify any significant morphological disturbances in microglia associated with these sickness-like behaviors in adult male Sprague-Dawley rats. We chose lipopolysaccharide (LPS 100 µg/kg/i.p.), to induce sickness-like behaviors as it is the most well-validated approach to do so in rodents and humans. We were particularly interested in examining changes in microglia within the prefrontal cortex (PFC) as several recent neuroimaging studies have highlighted significant functional changes in this region following peripheral LPS administration. Paraformaldehyde-fixed tissue was collected from animals 24h post LPS administration and labeled immunohistochemically with an antibody directed to bind to Iba-1, a protein known to be involved in the structural remodeling of microglia. To analyze changes, we have made use of two recently described image analysis procedures. The first is known as cumulative threshold spectra (CTS) analysis. The second involves the unsupervised digital reconstruction of microglia. We undertook these complementary analysis of microglial cells in the both the pre- and infralimbic divisions of the PFC. Our results indicated that microglial soma size was significantly enlarged, while cell processes had contracted slightly following LPS administration. To our knowledge this study is to first to definitely demonstrate substantial microglial disturbances within the PFC following LPS delivered at a dose that was sufficient to induce significant sickness-like behavior.

Economic costs associated with moderate and late preterm birth: a prospective population-based study.

OBJECTIVE: We sought to determine the economic costs associated with moderate and late preterm birth. DESIGN: An economic study was nested within a prospective cohort study. SAMPLE: Infants born between 32(+0) and 36(+6)  weeks of gestation in the East Midlands of England. A sample of infants born at ≥37 weeks of gestation acted as controls. METHODS: Data on resource use, estimated from a National Health Service (NHS) and personal social services perspective, and separately from a societal perspective, were collected between birth and 24 months corrected age (or death), and valued in pounds sterling, at 2010-11 prices. Descriptive statistics and multivariable analyses were used to estimate the relationship between gestational age at birth and economic costs. MAIN OUTCOME MEASURES: Cumulative resource use and economic costs over the first two years of life. RESULTS: Of all eligible births, 1146 (83%) preterm and 1258 (79%) term infants were recruited. Mean (standard error) total societal costs from birth to 24 months were £12 037 (£1114) and £5823 (£1232) for children born moderately preterm (32(+0) -33(+6)  weeks of gestation) and late preterm (34(+0) -36(+6)  weeks of gestation), respectively, compared with £2056 (£132) for children born at term. The mean societal cost difference between moderate and late preterm and term infants was £4657 (bootstrap 95% confidence interval, 95% CI £2513-6803; P < 0.001). Multivariable regressions revealed that, after controlling for clinical and sociodemographic characteristics, moderate and late preterm birth increased societal costs by £7583 (£874) and £1963 (£337), respectively, compared with birth at full term. CONCLUSIONS: Moderate and late preterm birth is associated with significantly increased economic costs over the first 2 years of life. Our economic estimates can be used to inform budgetary and service planning by clinical decision-makers, and economic evaluations of interventions aimed at preventing moderate and late preterm birth or alleviating its adverse consequences. TWEETABLE ABSTRACT: Moderate and late preterm birth is associated with increased economic costs over the first 2 years of life.

The relationships among work stress, strain and self-reported errors in UK community pharmacy.

BACKGROUND: Changes in the UK community pharmacy profession including new contractual frameworks, expansion of services, and increasing levels of workload have prompted concerns about rising levels of workplace stress and overload. This has implications for pharmacist health and well-being and the occurrence of errors that pose a risk to patient safety. Despite these concerns being voiced in the profession, few studies have explored work stress in the community pharmacy context. OBJECTIVES: To investigate work-related stress among UK community pharmacists and to explore its relationships with pharmacists' psychological and physical well-being, and the occurrence of self-reported dispensing errors and detection of prescribing errors. METHOD: A cross-sectional postal survey of a random sample of practicing community pharmacists (n = 903) used ASSET (A Shortened Stress Evaluation Tool) and questions relating to self-reported involvement in errors. Stress data were compared to general working population norms, and regressed on well-being and self-reported errors. RESULTS: Analysis of the data revealed that pharmacists reported significantly higher levels of workplace stressors than the general working population, with concerns about work-life balance, the nature of the job, and work relationships being the most influential on health and well-being. Despite this, pharmacists were not found to report worse health than the general working population. Self-reported error involvement was linked to both high dispensing volume and being troubled by perceived overload (dispensing errors), and resources and communication (detection of prescribing errors). CONCLUSIONS: This study contributes to the literature by benchmarking community pharmacists' health and well-being, and investigating sources of stress using a quantitative approach. A further important contribution to the literature is the identification of a quantitative link between high workload and self-reported dispensing errors.

Pilot of BRAF mutation analysis in indeterminate, suspicious and malignant thyroid FNA cytology.

BACKGROUND: BRAF V600E mutation has been reported to show a high specificity for papillary thyroid carcinoma (PTC). Using this marker to upgrade 'indeterminate' or 'suspicious' thyroid fine needle aspiration (FNA) cytology to 'malignant' could potentially allow one-stage therapeutic total thyroidectomy. METHODS: For a 14-month period, FNA cytology specimens in the Thy3-5 categories, which are the UK equivalents of indeterminate (Thy3a, atypical; Thy3f, follicular), suspicious for malignancy (Thy4) and malignant (Thy5) in the Bethesda System, underwent BRAF mutation testing by melt curve analysis. The results were correlated with histology. RESULTS: We tested 123 cytology specimens of which 12 (9.8%) failed. The BRAF mutation rate in the remainder was 16.2% (18/111), with 93 showing the wild-type. Seventeen mutations were V600E and one was non-V600E. The rate of mutation increased significantly (P < 0.0001 if Thy3a and Thy3f were combined) with the cytology category: 1/42 Thy3a (2.4%), 1/36 Thy3f (2.8%), 4/15 Thy4 (26.7%), 12/18 Thy5 (66.7%). All BRAF mutations correlated with PTC on histology, except for one recurrent PTC without histology. One mutation-positive case with Thy3a cytology showed the target lesion to be a 10-mm follicular adenoma on histology with an immediately adjacent 4-mm micro-PTC, in a patient who did not require total thyroidectomy. CONCLUSION: BRAF mutational analysis by melt curve analysis is feasible in routine thyroid cytology, and in our series had a 100% specificity for PTC in subsequent histology. The application of BRAF analysis could be useful for indeterminate cytology, but we suggest that it would be most appropriate and cost-effective for Thy4/suspicious cases, for which it could enable one-stage therapeutic surgery in the context of multidisciplinary discussion. In contrast, the sensitivity is low and there is no role for avoiding diagnostic thyroid surgery if wild-type BRAF is found.

Spontaneous Regression of a Carcinoid Tumor following Pregnancy.

We present a case of spontaneous regression of a neuroendocrine tumor following pregnancy in the absence of chemotherapy, radiotherapy, or alternative medicine (including herbal medicine). The diagnosis of a nonsecretory carcinoid tumor was confirmed using CT imaging, octreotide scan, and histology. Furthermore, serial imaging has demonstrated spontaneous regression of the carcinoid suggesting that pregnancy did not worsen the course of the disease but instead may have contributed to tumour regression. We discuss mechanisms underlying tumour regression and the possible effect of pregnancy on these processes.

Does elastography reduce the need for thyroid FNAs?

OBJECTIVE: Ultrasound elastography (USE) assesses lesion stiffness by evaluating tissue distortion in response to stress; it is emerging as a potentially useful tool to augment the ultrasound characterisation of thyroid nodules. The aim of this study was to assess the accuracy of USE examination of thyroid nodules compared with pathological outcome, especially to determine whether USE could reliably detect benign nodules and reduce the numbers of ultrasound guided fine needle aspiration cytology (USgFNAC). DESIGN: Over a three-year period, thyroid nodules were initially characterised by B-mode ultrasound (US) findings. Where USgFNAC was indicated by clinical concern and/or the sonographic appearances, the lesion was then subjected to USE by an experienced operator prior to the USgFNAC. PATIENTS: 147 thyroid nodules were examined by USE and USgFNAC in 146 patients. MEASUREMENTS: The elastographic appearance was subjectively categorized at the time of the examination (soft, intermediate or hard) and subsequently compared with the cytological/histological outcome. RESULTS: A total of 122 nodules were non-neoplastic, 5 nodules were benign neoplasms, 10 nodules had indeterminate cytology and 10 were malignant neoplasms. The sensitivity of USE for malignancy was 90.0%, specificity was 79.6%, PPV was 24.3%, NPV was 99.1% and accuracy was 80.3%. CONCLUSION: Thyroid nodules that are soft at USE have a high likelihood of being non-neoplastic and subjective USE assessment of thyroid nodules by an experienced operator can be a useful means of avoiding USgFNAC for benign nodules. In contrast, we suggest that all nodules that are intermediate or hard on USE undergo USgFNAC.

Comparing current definitions of return to work: a measurement approach.

INTRODUCTION: Return-to-work (RTW) status is an often used outcome in work and health research. In low back pain, work is regarded as a normal activity a worker should return to in order to fully recover. Comparing outcomes across studies and even jurisdictions using different definitions of RTW can be challenging for readers in general and when performing a systematic review in particular. In this study, the measurement properties of previously defined RTW outcomes were examined with data from two studies from two countries. METHODS: Data on RTW in low back pain (LBP) from the Canadian Early Claimant Cohort (ECC); a workers' compensation based study, and the Dutch Amsterdam Sherbrooke Evaluation (ASE) study were analyzed. Correlations between outcomes, differences in predictive validity when using different outcomes and construct validity when comparing outcomes to a functional status outcome were analyzed. RESULTS: In the ECC all definitions were highly correlated and performed similarly in predictive validity. When compared to functional status, RTW definitions in the ECC study performed fair to good on all time points. In the ASE study all definitions were highly correlated and performed similarly in predictive validity. The RTW definitions, however, failed to compare or compared poorly with functional status. Only one definition compared fairly on one time point. CONCLUSIONS: Differently defined outcomes are highly correlated, give similar results in prediction, but seem to differ in construct validity when compared to functional status depending on societal context or possibly birth cohort. Comparison of studies using different RTW definitions appears valid as long as RTW status is not considered as a measure of functional status.

Virtual reality, ultrasound-guided liver biopsy simulator: development and performance discrimination.

OBJECTIVES: The aim of this article was to identify and prospectively investigate simulated ultrasound-guided targeted liver biopsy performance metrics as differentiators between levels of expertise in interventional radiology. METHODS: Task analysis produced detailed procedural step documentation allowing identification of critical procedure steps and performance metrics for use in a virtual reality ultrasound-guided targeted liver biopsy procedure. Consultant (n=14; male=11, female=3) and trainee (n=26; male=19, female=7) scores on the performance metrics were compared. Ethical approval was granted by the Liverpool Research Ethics Committee (UK). Independent t-tests and analysis of variance (ANOVA) investigated differences between groups. RESULTS: Independent t-tests revealed significant differences between trainees and consultants on three performance metrics: targeting, p=0.018, t=-2.487 (-2.040 to -0.207); probe usage time, p = 0.040, t=2.132 (11.064 to 427.983); mean needle length in beam, p=0.029, t=-2.272 (-0.028 to -0.002). ANOVA reported significant differences across years of experience (0-1, 1-2, 3+ years) on seven performance metrics: no-go area touched, p=0.012; targeting, p=0.025; length of session, p=0.024; probe usage time, p=0.025; total needle distance moved, p=0.038; number of skin contacts, p<0.001; total time in no-go area, p=0.008. More experienced participants consistently received better performance scores on all 19 performance metrics. CONCLUSION: It is possible to measure and monitor performance using simulation, with performance metrics providing feedback on skill level and differentiating levels of expertise. However, a transfer of training study is required.

Direct costs and survival of medicare beneficiaries with early and advanced Parkinson's disease.

BACKGROUND: No recent analysis details Parkinson's Disease (PD) costs or survival for Medicare beneficiaries. This study assesses excess direct costs and survival in Medicare beneficiaries with early and advanced PD. METHODS: Patients with ≥ 2 PD diagnoses (ICD-9-CM: 332.0), ≥ age 65, continuously enrolled in Parts A&B during one-year baseline and study periods were selected from the Medicare 5% sample (N = 3.2 million, 1999-2008). Newly diagnosed patients were defined as having no baseline claims for movement disorder, dementia, Alzheimer's, bipolar disorder, psychosis, falls or related injuries, ambulatory assistance device (walker or wheelchair), or skilled nursing facility. Controls without PD were demographically matched 1:1. Costs to Medicare were compared via Wilcoxon rank-sum tests and inverse probability weighted multivariate regression. Survival was assessed via Cox proportional hazards analysis. RESULTS: Costs in the year post-diagnosis were higher for newly diagnosed patients (N = 9,201, $7423) than controls ($5024), resulting in excess PD-associated costs of $2399 (p < 0.001). Cumulative excess costs were $28,422 from the year prior to index quarter to five years following (p < 0.01). PD patients receiving their first claim for an ambulatory assistance device (N = 11,294) had excess cumulative costs of $50,923 (p < 0.001) over the same period; those receiving their first claim for a skilled nursing facility (N = 10,152) had excess costs of $102,750 (p < 0.001). Hazard rates of mortality were higher among newly diagnosed PD (1.43, p < 0.001), ambulatory assistance device (2.37, p < 0.001) and skilled nursing facility (3.34, p < 0.001) cohorts than in corresponding non-PD groups. CONCLUSIONS: Medicare beneficiaries with PD have substantially and progressively higher costs and mortality compared with controls.

Metachronous testicular teratoma, testicular seminoma and papillary thyroid carcinoma occurring in a single individual: a report of two unrelated cases.

We describe two unrelated men who both developed teratomas in one testis followed by seminomas in the contralateral testis followed by papillary thyroid carcinomas. Neither man had a family history of cancers. Although random occurrence is possible, genetic predisposition and/or environmental influence would seem a likely explanation for this previously unreported combination of tumours.

Impact of standardised reporting in adrenocortical carcinoma: a single centre clinicopathological review.

AIMS: Structured multicentre efforts are needed if the prognosis of adrenocortical carcinoma (ACC) is to be improved. Data collection may be enhanced through standardised histopathological reporting using criteria such as the recently published Royal College of Pathologists' (UK) minimum dataset (MDS). This study aimed to perform a clinicopathological review of the adult patients treated at the Royal Victoria Infirmary, Newcastle upon Tyne, in the 10 years preceding the MDS. METHODS: Case records were examined for all patients diagnosed with ACC between 1996 and 2006. Pathology was reviewed and compared with the Royal College of Pathologists' MDS along with the original reports. A systematic evaluation of Ki-67 immunolabelling was also performed. RESULTS: Eleven patients with ACC were diagnosed and treated. Histopathological reporting according to the MDS identified more features of malignancy than in the original reports (8.5+/-1.2 versus 5.1+/-0.8, p<0.02). The median number of microscopic criteria of malignancy was 7 (range 5-10), with > or =5 features occurring in all cases. The most commonly observed features of malignancy were diffuse architecture, <25% clear cells, confluent necrosis, abnormal mitoses and mitotic count > or =6 per 50 high-power fields. Capsular invasion and > or =8 MDS criteria of malignancy were associated with a worse outcome (each p<0.01). Median Ki-67 index was 19.0% (range 3.7-44.1%) and was not apparently related to survival. CONCLUSIONS: Standardised criteria for histopathological reporting of ACC will improve the accuracy of data for cancer registration and may also assist in individual patient stratification. An elevated Ki-67 index is a feature of ACC, although it does not appear to predict individual patient survival.