Implementation of behaviour change training in practice amongst pharmacy professionals in primary care settings: Analysis using the COM-B model.

BACKGROUND: The Pharmacy Integration Fund (PhIF) was established in England in 2016, with funded learning programmes or 'pathways' designed to support the development of clinical pharmacy practice in a range of settings. Despite pharmacy staff being well positioned to provide more clinical work, limited research has investigated behaviour change training targeted at widespread practice transformation. OBJECTIVE(S): To investigate implementation of PhIF learning in practice, using the COM-B model of behaviour change. METHODS: An online survey distributed in February and October 2020 included questions on motivations for learning, confidence in target behaviours and impact of PhIF training on behaviour. The October 2020 survey also included questions exploring the effect of the COVID-19 pandemic. Quantitative data were analysed in SPSS. v.27 (IBM). Inferential statistics were used to compare between the pathways (Primary care pathways [PCP], Post-registration pathway [PRP] and Accuracy Checking Pharmacy Technician [ACPT] pathway). Free text comments were categorised and themed. RESULTS: Three-hundred and eighty-three responses were received (49% PRP learners, 39% PCP learners and 12% ACPT learners). Learners generally had the capacity and opportunities to apply learning, and were strongly motivated to implement behaviours in practice, although learners based in community pharmacy (those on the PRP) were less likely to report receiving employer support. Enhanced knowledge/skills (capacity) were more commonly reported than change to patient-facing activities, leading clinical services and conducting medication reviews with patients with complex needs (clinical practice behaviours targeted by the pathways). The COVID-19 pandemic heightened barriers to implementing practice change. CONCLUSIONS: Implementation of a range of clinical practice behaviours following at scale training appears to have been largely successful. Despite this, the community pharmacy context, where funded service opportunities may be lacking, continues to present challenges to workforce transformation plans. More work is needed to understand how training can be implemented to promote practice change for pharmacy professionals in all settings.

Therapeutic glucocorticoids prevent bone loss but drive muscle wasting when administered in chronic polyarthritis.

BACKGROUND: Patients with rheumatoid arthritis (RA) experience extra-articular manifestations including osteoporosis and muscle wasting, which closely associate with severity of disease. Whilst therapeutic glucocorticoids (GCs) reduce inflammation in RA, their actions on muscle and bone metabolism in the context of chronic inflammation remain unclear. We utilised the TNF-tg model of chronic polyarthritis to ascertain the impact of therapeutic GCs on bone and muscle homeostasis in the context of systemic inflammation. METHODS: TNF-tg and wild-type (WT) animals received either vehicle or the GC corticosterone (100 µg/ml) in drinking water at onset of arthritis. Arthritis severity and clinical parameters were measured, serum collected for ELISA and muscle and bone biopsies collected for µCT, histology and mRNA analysis. In vivo findings were examined in primary cultures of osteoblasts, osteoclasts and myotubes. RESULTS: TNF-tg mice receiving GCs showed protection from inflammatory bone loss, characterised by a reduction in serum markers of bone resorption, osteoclast numbers and osteoclast activity. In contrast, muscle wasting was markedly increased in WT and TNF-tg animals receiving GCs, independently of inflammation. This was characterised by a reduction in muscle weight and fibre size, and an induction in anti-anabolic and catabolic signalling. CONCLUSIONS: This study demonstrates that when given in early onset chronic polyarthritis, oral GCs partially protect against inflammatory bone loss, but induce marked muscle wasting. These results suggest that in patients with inflammatory arthritis receiving GCs, the development of interventions to manage deleterious side effects in muscle should be prioritised.

11ß-HSD1 plays a critical role in trabecular bone loss associated with systemic glucocorticoid therapy.

BACKGROUND: Despite their efficacy in the treatment of chronic inflammation, the prolonged application of therapeutic glucocorticoids (GCs) is limited by significant systemic side effects including glucocorticoid-induced osteoporosis (GIOP). 11ß-Hydroxysteroid dehydrogenase type 1 (11ß-HSD1) is a bi-directional enzyme that primarily activates GCs in vivo, regulating tissue-specific exposure to active GC. We aimed to determine the contribution of 11ß-HSD1 to GIOP. METHODS: Wild type (WT) and 11ß-HSD1 knockout (KO) mice were treated with corticosterone (100 µg/ml, 0.66% ethanol) or vehicle (0.66% ethanol) in drinking water over 4 weeks (six animals per group). Bone parameters were assessed by micro-CT, sub-micron absorption tomography and serum markers of bone metabolism. Osteoblast and osteoclast gene expression was assessed by quantitative RT-PCR. RESULTS: Wild type mice receiving corticosterone developed marked trabecular bone loss with reduced bone volume to tissue volume (BV/TV), trabecular thickness (Tb.Th) and trabecular number (Tb.N). Histomorphometric analysis revealed a dramatic reduction in osteoblast numbers. This was matched by a significant reduction in the serum marker of osteoblast bone formation P1NP and gene expression of the osteoblast markers Alp and Bglap. In contrast, 11ß-HSD1 KO mice receiving corticosterone demonstrated almost complete protection from trabecular bone loss, with partial protection from the decrease in osteoblast numbers and markers of bone formation relative to WT counterparts receiving corticosterone. CONCLUSIONS: This study demonstrates that 11ß-HSD1 plays a critical role in GIOP, mediating GC suppression of anabolic bone formation and reduced bone volume secondary to a decrease in osteoblast numbers. This raises the intriguing possibility that therapeutic inhibitors of 11ß-HSD1 may be effective in preventing GIOP in patients receiving therapeutic steroids.

11 Beta-hydroxysteroid dehydrogenase type 1 regulates synovitis, joint destruction, and systemic bone loss in chronic polyarthritis.

OBJECTIVE: In rheumatoid arthritis, the enzyme 11 beta-hydroxysteroid dehydrogenase type 1 (11ß-HSD1) is highly expressed at sites of inflammation, where it converts inactive glucocorticoids (GC) to their active counterparts. In conditions of GC excess it has been shown to be a critical regulator of muscle wasting and bone loss. Here we examine the contribution of 11ß-HSD1 to the pathology of persistent chronic inflammatory disease. METHODS: To determine the contribution of 11ß-HSD1 to joint inflammation, destruction and systemic bone loss associated with persistent inflammatory arthritis, we generated mice with global and mesenchymal specific 11ß-HSD1 deletions in the TNF-transgenic (TNF-tg) model of chronic polyarthritis. Disease severity was determined by clinical scoring. Histology was assessed in formalin fixed sections and fluorescence-activated cell sorting (FACS) analysis of synovial tissue was performed. Local and systemic bone loss were measured by micro computed tomography (micro-CT). Measures of inflammation and bone metabolism were assessed in serum and in tibia mRNA. RESULTS: Global deletion of 11ß-HSD1 drove an enhanced inflammatory phenotype, characterised by florid synovitis, joint destruction and systemic bone loss. This was associated with increased pannus invasion into subchondral bone, a marked polarisation towards pro-inflammatory M1 macrophages at sites of inflammation and increased osteoclast numbers. Targeted mesenchymal deletion of 11ß-HSD1 failed to recapitulate this phenotype suggesting that 11ß-HSD1 within leukocytes mediate its protective actions in vivo. CONCLUSIONS: We demonstrate a fundamental role for 11ß-HSD1 in the suppression of synovitis, joint destruction, and systemic bone loss. Whilst a role for 11ß-HSD1 inhibitors has been proposed for metabolic complications in inflammatory diseases, our study suggests that this approach would greatly exacerbate disease severity.

Lack of evidence on mental health and well-being impacts of individual-level interventions for vulnerable adolescents: systematic mapping review.

OBJECTIVES: To review empirical evaluations of individual-level interventions intended to improve mental health or well-being for vulnerable adolescents. STUDY DESIGN: This is a systematic mapping review. METHODS: Thirteen databases covering academic and gray literature were searched for published reviews and randomised controlled trials, and gray literature (2005-2016) and the results quality-assessed to prioritise best available evidence. We aimed to identify well-conducted systematic reviews and trials that evaluated individual-level interventions, for mental health/well-being outcomes, where the population was adolescents aged 10-24 years in any of 12 vulnerable groups at high risk of poor health outcomes (e.g. homeless, offenders, 'looked after', carers). RESULTS: Thirty systematic reviews and 16 additional trials were identified. There was insufficient evidence to identify promising individual-level interventions that improve the mental health/well-being of any of the vulnerable groups. CONCLUSIONS: Despite Western policy to promote health and well-being among vulnerable young people, the dearth of evidence suggests a lack of interest in evaluating interventions targeting these groups in respect of their mental health/well-being outcomes.

Impact of providing patients with copies of their medical correspondence: a randomised controlled study.

BACKGROUND: In Australia, correspondence is routinely sent to general practitioners following a specialist consultation. Written communication is an important way to enhance patient experiences and understanding, yet most patients do not receive copies of their medical correspondence. AIMS: To determine whether providing clinic correspondence and endoscopy reports to patients leads to improved understanding, satisfaction or anxiety. METHODS: This is a prospective, randomised controlled study conducted at an Australian tertiary hospital from October 2013 to February 2015. New adult referrals to the general gastroenterology clinic requiring an urgent endoscopic procedure were eligible for the study. The intervention group received a copy of their clinic correspondence and endoscopy report, while the control group received neither. Participants completed questionnaires, including visual analogue scales and the Hospital Anxiety and Depression Scale, at three time points. Primary outcomes were patient understanding, anxiety and satisfaction. RESULTS: A total of 70 participants was included in the study. There was no reduction in anxiety levels (P = 0.52), no increase in understanding (P = 0.73) or any increase in satisfaction (P = 0.33) in participants receiving correspondence. However, 97% of participants indicated that they wished to receive correspondence in the future, and 94% of participants in the correspondence group reported that receiving correspondence had helped them to understand their medical condition. CONCLUSION: Patients wish to receive copies of their correspondence and feel it improves their understanding of their medical condition. Although we were unable to demonstrate a measurable reduction in anxiety, increase in understanding or satisfaction, we recommend that patients be offered the choice of receiving copies of their clinic correspondence and endoscopy reports.

Gene expression profile in cardiovascular disease and preeclampsia: a meta-analysis of the transcriptome based on raw data from human studies deposited in Gene Expression Omnibus.

INTRODUCTION: Cardiovascular disease (CVD) and preeclampsia (PE) share common clinical features. We aimed to identify common transcriptomic signatures involved in CVD and PE in humans. METHODS: Meta-analysis of individual raw microarray data deposited in GEO, obtained from blood samples of patients with CVD versus controls and placental samples from women with PE versus healthy women with uncomplicated pregnancies. Annotation of cases versus control samples was taken directly from the microarray documentation. Genes that showed a significant differential expression in the majority of experiments were selected for subsequent analysis. Hypergeometric gene list analysis was performed using Bioconductor GOstats package. Bioinformatic analysis was performed in PANTHER. RESULTS: Seven studies in CVD and 5 studies in PE were eligible for meta-analysis. A total of 181 genes were found to be differentially expressed in microarray studies investigating gene expression in blood samples obtained from patients with CVD compared to controls and 925 genes were differentially expressed between preeclamptic and healthy placentas. Among these differentially expressed genes, 22 were common between CVD and PE. DISCUSSION: Bioinformatic analysis of these genes revealed oxidative stress, p-53 pathway feedback, inflammation mediated by chemokines and cytokines, interleukin signaling, B-cell activation, PDGF signaling, Wnt signaling, integrin signaling and Alzheimer disease pathways to be involved in the pathophysiology of both CVD and PE. Metabolism, development, response to stimulus, immune response and cell communication were the associated biologic processes in both conditions. Gene set enrichment analysis showed the following overlapping pathways between CVD and PE: TGF-ß-signaling, apoptosis, graft-versus-host disease, allograft rejection, chemokine signaling, steroid hormone synthesis, type I and II diabetes mellitus, VEGF signaling, pathways in cancer, GNRH signaling, Huntingtons disease and Notch signaling. CONCLUSION: CVD and PE share same common traits in their gene expression profile indicating common pathways in their pathophysiology.

Exenatide and sitagliptin are not associated with increased risk of acute renal failure: a retrospective claims analysis.

AIM: This study evaluated whether the risk of acute renal failure (ARF) increases with exenatide and sitagliptin use. METHODS: A retrospective cohort study of a large medical and pharmacy claims database was performed. Data for 4 91 539 patients were analysed. Cox proportional hazard models were used to compare the risk of ARF between diabetic and non-diabetic subjects and between diabetic patients treated with exenatide, sitagliptin and control medications. RESULTS: Adjusted Cox analyses showed diabetic subjects had a higher risk of ARF [HR 1.51, confidence interval (CI) 1.26-1.81, p < 0.001] than non-diabetic controls. Compared with diabetic controls, neither exenatide (HR 0.77, CI 0.42-1.41, p = 0.40) nor sitagliptin (HR 1.17, CI 0.82-1.65, p = 0.39) increased the risk of ARF. CONCLUSION: Our study revealed an increased incidence of ARF in diabetic versus non-diabetic patients but no association between use of exenatide or sitagliptin and ARF. Because of the limitations of this observational analysis, we cannot exclude the possibility of a very small increased risk.

Parenting interventions for male young offenders: a review of the evidence on what works.

Approximately one in four incarcerated male young offenders in the UK is an actual or expectant father. This paper reviews evidence on the effectiveness of parenting interventions for male young offenders. We conducted systematic searches across 20 databases and consulted experts. Twelve relevant evaluations were identified: 10 from the UK, of programmes for incarcerated young offenders, and two from the US, of programmes for young parolees. None used experimental methods or included a comparison group. They suggest that participants like the courses, find them useful, and the interventions may improve knowledge about, and attitudes to, parenting. Future interventions should incorporate elements of promising parenting interventions with young fathers in the community, for example, and/or with older incarcerated parents. Young offender fathers have specific developmental, rehabilitative, and contextual needs. Future evaluations should collect longer-term behavioural parent and child outcome data and should use comparison groups and, ideally, randomization.

Association between circulating hemostatic measures and dementia or cognitive impairment: systematic review and meta-analyzes.

BACKGROUND AND OBJECTIVES: Hemostasis and thrombosis may be important contributors to cognitive decline and dementia. Certain blood markers may assist in diagnosis or management. OBJECTIVES: To collate evidence for the association of circulating hemostatic variables and dementia or cognitive impairment. METHODS: A systematic review of studies describing blood markers of hemostatic function and cognition/dementia. Abstracts were reviewed by two independent assessors and studies selected based on pre-specified criteria. We described methodological quality and performed meta-analyzes where data allowed. RESULTS: From 7103 titles, 485 abstracts and included 21 studies (n = 32,773) were assessed. In two longitudinal studies, the incident of vascular dementia risk was greater for higher D-dimer [hazard ratio (HR): 1.50, 95% confidence interval (CI): 1.15-1.96]. For case-control data, we calculated standardized mean differences (SMD) and 95% CI. Higher levels of: factor (F)VII (SMD: 0.93; 95% CI: 0.60-1.26), fibrinogen (SMD: 1.53; 95% CI: 1.17-1.87), prothrombin fragment 1 and 2 (SMD: 0.64; 95% CI: 0.32-0.96), plasminogen activator inhibitor (SMD: 0.68; 95% CI: 0.26-1.10), D-dimer (SMD: 2.00; 95% CI: 1.59-2.40) and von Willebrand factor (VWF) (SMD: 1.68; 95% CI: 1.30-2.06) showed modest but significant associations with vascular dementia. For patients with any dementia diagnosis, associations were with higher D-dimer (SMD: 0.36; 95% CI: 0.15-0.56) and VWF (SMD: 0.31; 95% CI: 0.11-0.51). For specific cognitive domains, significant (P < 0.001) positive correlations were fibrinogen and speed of processing (0.76; 95% CI: 0.67-0.84), verbal memory (0.69; 95% CI: 0.59-0.79) and non-verbal reasoning (0.57; 95% CI: 0.49-0.65). CONCLUSIONS: The present results suggest a modest association between hemostasis and vascular dementia including increased levels of thrombin generation markers (D-dimer and prothrombin fragment 1 + 2) and endothelial dysfunction (VWF and plasminogen activator inhibitor). Associations are weaker for specific cognitive tests and when all dementias are combined.

An initial evaluation of virtual reality simulation in teaching pre-clinical operative dentistry in a UK setting.

The use of virtual reality (VR) training in dentistry is a recent innovation and little research has been conducted to evaluate its use. For each preclinical exercise carried out the VR software currently records a final mark for the procedure, the time taken to complete the procedure and the number of 'internal' assessments carried out by the student. The aims of this study were two fold; a critical appraisal of the software by the students using a structured feedback together with an assessment of any link between the preparation time, final mark and number of evaluations. Sixteen 2nd year undergraduate dental students spent 6 hours cutting an unlimited number of Class I cavities and Class II cavities. The final mark awarded by the VR software together with the overall preparation time and number of evaluations for each cavity were recorded. For the Class I cavity the mean mark obtained was 66.8, the mean preparation time was 12.5 mins and the mean number of evaluations was 6.7. For the Class II cavity the mean mark was 26.5, the mean preparation time was 18 mins and the mean number of evaluations was 7.0. Final marks were also stratified into quartiles (0-24, 25-49, 50- 74, 75-100). For the Class II cavity the time taken to complete the cavity and the number of evaluations made were greater for those cavities that gained a mark of 50 or more. In conclusion, this initial evaluation of the DentSim VR package was a generally positive undergraduate educational experience. The class II cavity was more difficult to cut than the class I which was reflected in the mean scores. There was also a trend towards higher marks being associated with longer preparation times and more evaluations during the preparation.

[Condyloms, dysplasia and carcinomas of cervix: a twenty years experience (1980 - 1999)]. / Condylomes, dysplasies et carcinomes du col utérin: notre expérience en vingt ans (1980 - 1999).

After twenty years of semi-regular detection(1980-1990) concerning 100,358 cervical smears carried out in the Cytology Laboratory in the CHU of Dakar, we have determined the types of cervical lesions in our study. We've found 21.03% of precancerous and cancerous lesions with 17.56% of CIN1, 2.49% of CIN2 and 0.49% of CIN3 and carcinomas. We've observed 9.07% of normal smears, 69.89% of benign cellular modifications, 17.56% of low grade lesions of Bethesda and 3.47% of high grade lesions of Bethesda. These very high figures show that on the one hand precancerous cervical lesions represent a serious public health concern in Senegal, on the other hand regular detection has become an urgent need in Dakar and in the other regions of Senegal where it's not carried out at all at the present time.

Nitrotyrosine, inducible nitric oxide synthase (iNOS), and endothelial nitric oxide synthase (eNOS) are increased in thyroid tumors from children and adolescents.

Nitric oxide (NO) is a reactive cell signal that controls vascular tone and is generated by inducible (iNOS), endothelial (eNOS) and neuronal (nNOS) NO synthase (NOS). We hypothesized that NO could be important for growth of thyroid tumors and tested this hypothesis, by staining 41 papillary thyroid carcinoma (PTC), 9 follicular thyroid carcinoma (FTC), and 15 benign thyroid lesions for iNOS, eNOS and nitrotyrosine (N-TYR). Staining intensity was determined by 2 blinded, independent examiners, and quantified from grade 1 (absent) to grade 4 (intense). Average N-TYR staining of benign adenomas (2.5+/-0.42, p=0.009), PTC (3.10+/-0.12, p=0.001), FTC (2.44+/-0.30, p=0.001), and autoimmune lesions (3.25+/-0.48, p=0.019) were greater than that of multinodular goiter (1.0 for all 3) and surrounding normal thyroid (1.1+/-0.1). Average iNOS staining of benign adenomas (2.6+/-0.37), PTC (2.7+/-0.16), FTC (2.4+/-0.26) and autoimmune lesions (3.5+/-0.29) were all greater than that of surrounding normal thyroid (1.1+/-0.1, p<0.008), but there were too few multinodular goiters to achieve a significant difference (no.=2, 3.0+/-1.0). Average eNOS staining of benign adenomas (2.9+/-0.40), multinodular goiters (3.5+/-0.5), PTC (3.24+/-0.18), FTC (3.5+/-0.50), and autoimmune lesions (2.8+/-0.6) were also greater than that of surrounding normal thyroid (mean=1.4+/-0.2, p<0.001). N-TYR staining correlated with that of vascular endothelial growth factor (VEGF, r=0.36, p=0.007) and the number of lymphocytes/high power field (r=0.39, p=0.004). Recurrent disease developed only from carcinoma with moderate-intense N-TYR staining, but there were too few recurrent tumors to achieve statistical significance (p=0.08). We conclude that NO is produced by benign adenomas, PTC and FTC suggesting that NO could be important in vascularization of thyroid tumors and autoimmune thyroid diseases.

Matrix metalloproteinase (MMP) expression by differentiated thyroid carcinoma of children and adolescents.

The factor(s) that control metastasis of thyroid carcinoma are unknown, but the matrix metalloproteinases (MMPs) are excellent candidates. MMP-1, membrane-type-1 MMP (MT1-MMP), and tissue inhibitor of MMP-1 (TIMP-1) have all been implicated, but the site of production and importance are disputed. In vitro, normal thyroid cells secrete TIMP-1, while thyroid cancer cells secrete TIMP-1 and MMP-1. However, previous pathological studies identified MMP-1 and TIMP-1 only in the stroma surrounding thyroid carcinoma. These data suggest that thyroid carcinoma or tumor-associated inflammatory cells might secrete a factor(s) which stimulates MMP-1 or TIMP-1 expression by surrounding tissues. We hypothesized that MMP-1, MT1-MMP, and TIMP-1 would be directly expressed by thyroid carcinoma and might promote invasion or metastasis. We used immunohistochemistry to determine the expression of MMP-1, MT1-MMP, and TIMP-1 in 32 papillary thyroid carcinoma (PTC), 10 follicular thyroid carcinoma (FTC) and 13 benign thyroid lesions from children and adolescents. The intensity of staining was graded from absent (grade 0) to intense (grade 3). Average MMP-1 expression (mean relative intensity units+/-SE) was significantly greater among PTC (1.97+/-0.15; p=0.004) and FTC (2.2+/-0.25; p=0.006) compared to benign lesions (1.30+/-0.15); but there was no relationship between MMP-1 expression and invasion, metastasis, or recurrence. Expression of MT1-MMP and TIMP-1 was similar for benign and malignant lesions; but recurrent PTC expressed lower levels of TIMP-1 when compared to non-recurrent PTC (p=0.049). Only the expression of TIMP-1 correlated with the presence of tumor-associated lymphocytes (r=0.35, p=0.032). We conclude that MMP-1, MT1-MMP and TIMP-1 are all expressed by thyroid carcinoma and could be important in promoting recurrence.

Thyroid carcinomas that express telomerase follow a more aggressive clinical course in children and adolescents.

With each cell division, DNA is lost from the telomeres, limiting the number of divisions, and leading to senescence. Malignant tumors maintain immortality by expressing a specific DNA repair enzyme, telomerase, that replaces this DNA. We hypothesized that tumors which express telomerase would have the highest recurrence risk and we tested this by determining telomerase expression in 27 papillary thyroid carcinomas (PTC), 5 follicular thyroid carcinomas (FTC) and 13 benign thyroid lesions from children and adolescents. Patients were 6-21 yr of age (mean+/-SE=16.6+/-4.1 yr) and followed from 0-14.1 yr (mean+/-SE=4.71+/-3.5 yr). Original tumors were sectioned, and immunostained for telomerase. Telomerase-specific staining was determined by two independent, blind examiners and graded from absent (Grade 0) to intense (Grade 3). Telomerase was detected in a similar majority of benign (11/13, 85%) and malignant tumors (24/32, 75%). However, the intensity of telomerase expression was greater among FTC (mean+/-SE=2.4+/-0.5 relative intensity) followed by PTC (mean+/-SE=1.9+/-1.0 relative intensity) and benign tumors (mean+/-SE=1.8+/-1.0 relative intensity). Autoimmune lesions had lower telomerase expression (mean+/-SE=1.25+/-0.5 relative intensity) compared to FTC (p=0.01), PTC (p=0.06) and benign lesions (p=0.15). Among PTC, 19 (70%) expressed telomerase, and 8 (30%) did not. Direct invasion (no.=4, 21%), distant metastasis (no.=2, 10%) and recurrence (no.=7, 37%) developed exclusively in PTC that expressed telomerase (p=0.02). Disease-free survival was also shorter for PTC that expressed telomerase (p=0.06). Recurrence developed in 1/2 (50%) FTC that expressed telomerase. We conclude that childhood thyroid cancers which express telomerase have an increased risk of tissue invasion, metastasis, and recurrence.

Nuclear localization of thyroid transcription factor-1 correlates with serum thyrotropin activity and may be increased in differentiated thyroid carcinomas with aggressive clinical course.

Thyroid transcription factor 1 (TTF-1) is essential for thyroid differentiation and regulates expression of thyroglobulin, thyroid peroxidase, sodium/iodide symporter, and thyrotropin receptor (TSH-R) genes. Because thyrotropin (TSH) upregulates these same genes, we hypothesized TSH-R activation might increase TTF-1 and that TTF-1 might be differentially expressed in benign and malignant thyroid disease. TTF-1 expression and sub-cellular localization were determined by immunohistochemistry in 62 thyroid carcinomas, 15 benign lesions, and 2 normal thyroids. Nuclear TTF-1 was detected in benign (77%) and malignant lesions (69%), with similar intensity in both (1.1+/-0.19 versus 1.0+/-0.10). Nuclear TTF-1 staining correlated with the effective serum TSH level (p = 0.02) and patient age (p < 0.05). Nuclear TTF-1 was detected in 35 papillary thyroid carcinomas (PTC), of which 23% developed recurrent or persistent disease, and was absent from 18 PTC, of which only 6% recurred (p = 0.06). We conclude that nuclear TTF-1 correlates with serum TSH activity, increases with age, and may be increased in persistent or recurrent PTC.

Intensity of vascular endothelial growth factor expression is associated with increased risk of recurrence and decreased disease-free survival in papillary thyroid cancer.

BACKGROUND: Vascular endothelial growth factor (VEGF) induces proliferation of endothelial cells, stimulates angiogenesis, and increases vascular permeability. Increased VEGF expression has been associated with poor clinical outcomes in many malignancies. Several recent reports have documented over expression of VEGF in papillary thyroid cancer. We hypothesized that increased expression of VEGF would be associated with either an increased risk of recurrence or a decreased recurrence-free survival in papillary thyroid cancer. METHODS: Immunohistochemistry was used to detect VEGF expression in archival paraffin-embedded surgical thyroid specimens from 96 subjects with papillary thyroid cancer. RESULTS: VEGF expression was detected in 98% (94/96) of the samples, predominantly of slight-to-moderate intensity in the majority of malignant cells. However, the specific finding of a diffuse pattern of intense immunostaining for VEGF was detected significantly more often than less intense, patchy immunostaining patterns in subjects with distant metastasis at diagnosis (63% versus 15%, P =.005), local recurrence (58% versus 13%, P =.001), and distant recurrence (83% versus 14%, P =.001). Furthermore, this specific pattern of diffuse, intense VEGF expression was associated with a significantly shorter recurrence-free survival than other staining patterns (P =.007). CONCLUSIONS: These data demonstrate that the immunohistochemical pattern of VEGF staining in the initial surgical specimen is strongly associated with the incidence of local and distant metastasis in papillary thyroid cancer.