Practice patterns in management of differentiated thyroid cancer since the 2014 British Thyroid Association (BTA) guidelines.

BACKGROUND: The updated 2014 BTA guidelines emphasised a more conservative, risk adapted model for the management of low-risk differentiated thyroid cancer (DTC). In comparison to historical approach of total thyroidectomy combined with radioactive iodine, treatment de-escalation is increasingly supported. AIMS: To evaluate the impact of the updated BTA guidelines on the management of DTC cases at regional UK centre. METHODS: All DTC patients were retrospectively identified from regional thyroid MDT database between Jan2009-Dec2020. Oncological treatment and clinico-pathological characteristics were analysed. RESULTS: 623 DTC cases were identified; 312 (247 female: 65 male) between 2009 and 2014 and 311 (225 female: 86 male) between 2015 and 2020. Median age is 48 years (range 16-85). By comparing pre- and post-2015 cohorts, there was a significant drop in total thyroidectomy (87.1% vs 76.8%, p = 0.001) and the use of radioactive iodine (RAI) (73.1% vs 62.1%, p = 0.003) in our post-2015 cohort. When histological adverse features were analysed, extra-thyroidal extension (4.2% vs 17.0%, p=< 0.001), lymphovascular invasion (31.4% vs 50.5%, p=<0.001) and multi-centricity (26.9% vs 43.4%, p = 0.001) were significantly increased in the post 2015 cohort. Nonetheless, total thyroidectomy (TT) remains the treatment choice for low risk T1/2 N0 M0 disease in 65.3% (124/190) in post-2015 cohort for several reasons. Reasons include adverse histological features (50.8%), benign indications (32.5%), contralateral nodules (11.7%), patient preference (2.5%), and diagnostic uncertainty (2.5%). CONCLUSION: Our study confirms a move towards a more conservative approach to patients with low-risk DTC in the UK, which is in keeping with the BTA 2014 guideline and international trends, but total thyroidectomy remains prevalent for low risk T1/2 N0 M0 disease for other reasons.

A quantitative assessment of the number of disease foci in papillary thyroid cancer.

AIM: Multifocality is a frequent feature of papillary thyroid carcinoma (PTC). Its prognostic value is controversial although national guidelines recommend treatment intensification if present. However, multifocality is not a binary but discrete variable. This study aimed to examine the association between increasing number of foci and risk of recurrence following treatment. METHODS: 577 patients with PTC were identified with median follow-up of 61 months. Number of foci were taken from pathology reports. Log-rank test was used to assess significance. Multivariate analysis was performed and Hazard Ratios were calculated. RESULTS: Of 577 patients, 206(35%) had multifocal disease and 36(6%) recurred. 133(23%), 89(15%) and 61(11%) had 3+, 4+ or 5+ foci respectively. The 5-year RFS stratified by number of foci was 95%v93% for 2+foci (p = 0.616), 95%v96% for 3+foci (p = 0.198) and 89%v96% for 4+foci (p = 0.022). The presence of 4 foci was associated with an over 2-fold risk of recurrence (HR 2.296, 95% CI 1.106-4.765, p = 0.026) although this was not independent of TNM staging. Of the 206 multifocal patients, 31(5%) had 4+foci as their sole risk factor for treatment intensification. CONCLUSION: Although multifocality per se does not confer worse outcome in PTC, finding 4+foci is associated with worse outcome and could therefore be appropriate as a cut-off for treatment intensification. In our cohort, 5% of patients had 4+foci as a sole indication for treatment intensification, suggesting that such a cut off could impact clinical management.

Neoadjuvant tyrosine kinase inhibitor therapy in locally advanced differentiated thyroid cancer: a single centre case series.

OBJECTIVE: Primary surgical resection remains the mainstay of management in locally advanced differentiated thyroid cancer. Tyrosine kinase inhibitors have recently shown promising results in patients with recurrent locally advanced differentiated thyroid cancer. This study discussed four patients with locally advanced differentiated thyroid cancer managed with tyrosine kinase inhibitors used prior to surgery in the 'neoadjuvant' setting. METHOD: Prospective data collection through a local thyroid database from February 2016 identified four patients with locally advanced differentiated thyroid cancer unsuitable for primary surgical resection commenced on neoadjuvant tyrosine kinase inhibitor therapy. RESULTS: All cases had T4a disease at presentation. Three cases tolerated tyrosine kinase inhibitor therapy for more than 14 months while the last case failed to tolerate treatment at 1 month. All patients subsequently underwent total thyroidectomy to facilitate adjuvant radioactive iodine treatment. Disease-specific survival remains at 100 per cent currently (range, 29-75 months). CONCLUSION: Neoadjuvant tyrosine kinase inhibitors in locally advanced differentiated thyroid cancer can be effective in reducing primary tumour extent to potentially facilitate a more limited surgical resection for local disease control.

What is the Operative Cost of Managing Acute Appendicitis in the NHS: The Impact of Stump Technique and Perioperative Imaging.

BACKGROUND: Acute appendicitis is a common surgical emergency that is typically managed with laparoscopic appendicectomy in UK centres. A number of variables influence the cost of managing this condition. Our aim was to identify the major influencing factors in our centre by performing a cumulative cost analysis. METHODS: We retrospectively analysed the costs associated with 99 cases of acute appendicitis managed with laparoscopic appendicectomy at Ninewells Hospital, Dundee, from January 2014 to February 2016. Costs were categorised according to blood tests, imaging, medications, operative costs and length of stay. RESULTS: Our cohort included 66 males, 33 females and 28 paediatric cases. The total cost was £220030.52 with a mean of £2222.53 per patient. The factor with the greatest influence on overall cost was operative time (53.2%) followed by length of stay (39.2%). There was no cost difference between adults and children (p = 0.24) or males and females (p = 0.38). Mean cost in adults ≥50 years was greater than those <50 years (£2899.32 vs £2152.97, p = 0.008) and greater in those who underwent imaging as opposed to no imaging (£2789.53 vs £2010.65, p = 0.0001). For appendiceal stump technique, polymer clips were cheaper (£1844.70) than ligatures (£2380.11, p = 0.006). CONCLUSIONS: Operative time (53.2%) and length of stay (39.2%) had the greatest impact on the cost in our cohort. Older patients have a greater overall cost, and this is associated with increased utilisation of imaging. Further studies assessing the safety and feasibility of methods to reduce operative time and to investigate the safety of reducing length of stay are required.

Polymeric clips are a quicker and cheaper alternative to endoscopic ligatures for securing the appendiceal stump during laparoscopic appendicectomy.

Introduction The use of polymeric clips in securing the appendiceal stump has been increasingly reported as a viable alternative to current methods in emergency laparoscopic appendicectomy. We evaluated the operative outcomes following the use of polymeric clips versus endoscopic ligatures. The primary endpoint was operative time, with secondary outcomes including complications, inpatient stay, and cost analysis. Materials and methods Operative records were retrospectively analysed to identify patients undergoing laparoscopic appendicectomy between January 2014 and June 2015. Data collected included age, gender, body mass index, duration of surgery, length of hospital stay, antibiotic use, preoperative haematological and biochemical parameters, 30-day readmission rate and complications. Results A total of 125 patients were included within the study, with 78 within the endoloop group and 47 in the polymeric clip group. There were no differences in age, gender, body mass index, hospital stay, antibiotic use, 30-day readmission rates or postoperative complications. Operative time was significantly reduced in the polymeric clip group (59 vs. 68 minutes, P = 0.00751). The use of polymeric clips cost £21 compared with £49 for endoloops per operation, which rose to £70 if both clips and endoloops were used during the procedure. Discussion Polymeric clips are a safe, viable and economical method for securing the appendiceal stump during laparoscopic appendicectomy. The clinical significance of nine minutes of reduced operating time in the polymeric clip cohort warrants further study with an adequately powered randomised controlled trial.

GSK3ß inhibition confers survival advantage in Burkholderia pseudomallei-infected hyperglycaemic mice by regulating inflammatory response.

Burkholderia pseudomallei, the etiologic agent of melioidosis is a common cause of sepsis mainly in diabetic individuals in South East Asia. Glycogen synthase kinase-3ß (GSK3ß) plays a pivotal role in modulating inflammatory balance in Gram-negative bacterial infections. In this study, we demonstrate that inhibition of GSK3ß significantly improved survival of hyperglycaemic mice acutely infected with B. pseudomallei. With GSK3ß inhibition, we found significant modulation between pro- (IL-12, TNF-alpha) and anti-inflammatory (IL10) serum cytokines which may have contributed to bacterial clearance in multiple organs of B. pseudomallei-infected hyperglycaemic mice. Concurrently, an increase in phosphorylation of GSK3ß at Ser-9 was observed in the liver of B. pseudomallei-infected hyperglycaemic mice. Likewise, B. pseudomallei-infected non-hyperglycaemic mice upon GSK3ß inhibition showed similar trends of bacterial clearance and modulation of serum cytokines; however, the effect of enhanced survival was less substantial than in infected hyperglycaemic mice. Taken together, we demonstrate that inhibition of GSK3ß confers survival advantage of hyperglycaemic mice infected with B. pseudomallei and offers a potential therapeutic strategy for the treatment of diabetic patients with melioidosis.

Regulatory role of GSK3ß in the activation of NF-κB and modulation of cytokine levels in Burkholderia pseudomallei-infected PBMC isolated from streptozotocin-induced diabetic animals.

Increased susceptibility of diabetics to melioidosis, a disease caused by the Burkholderia pseudomallei bacterium is believed to be attributed to dysfunction of the innate immune system. However, the underlying mechanism of the innate susceptibility is not well-understood. Glycogen synthase kinase-3ß (GSK3ß) plays an important role in the innate inflammatory response caused by bacterial pathogens. The present study was conducted to investigate the effects of GSK3ß inhibition by LiCl on levels of pro- and anti-inflammatory cytokines; and the activity of transcription factor NF-κB in B. pseudomallei-infected peripheral blood mononuclear cells (PBMC) derived from diabetic-induced and normal Sprague Dawley rats. In addition, the effects of LiCl on intracellular bacterial counts were also investigated. Infection of PBMC from diabetic and normal rats with B. pseudomallei resulted in elevated levels of cytokines (TNF-α, IL-12 and IL-10) and phosphorylation of NF-κB in both cell types. Intracellular bacterial counts decreased with time in both cell types during infection. However bacterial clearance was less prominent in diabetic PBMC. Burkholderia pseudomallei infection also caused inactivation (Ser9 phosphorylation) of GSK3ß in normal PBMC, an effect absent in infected diabetic PBMC. Inhibition of GSK3ß by LiCl lowered the levels of pro-inflammatory cytokines (TNF-α and IL-12) in both normal and diabetic PBMC. Similarly, phosphorylated NF- κB (pNF-κB) levels in both cell types were decreased with LiCl treatment. Also, LiCl was able to significantly decrease the intracellular bacterial count in normal as well as diabetic PBMC. Interestingly, the levels of anti-inflammatory cytokine IL-10 in both normal and diabetic PBMC were further elevated with GSK3ß inhibition. More importantly, GSK3ß in infected diabetic PBMC was inactivated as in their non-diabetic counterparts upon LiCl treatment. Taken together, our results suggest that inhibition of dysregulated GSK3ß in diabetic PBMC resulted in the inactivation of NF-κB and modulation of inflammatory cytokine levels. This is evidence that dysregulation of GSK3ß is a contributing factor in the molecular basis of innate dysfunction and susceptibility of diabetic host to melioidosis infection.

Regulatory role of GSK3β in the activation of NF-κB and modulation of cytokine levels in Burkholderia pseudomallei-infected PBMC isolated from Streptozotocin-induced diabetic animals

Increased susceptibility of diabetics to melioidosis, a disease caused by the Burkholderia pseudomallei bacterium is believed to be attributed to dysfunction of the innate immune system. However, the underlying mechanism of the innate susceptibility is not well-understood. Glycogen synthase kinase-3β (GSK3β) plays an important role in the innate inflammatory response caused by bacterial pathogens. The present study was conducted to investigate the effects of GSK3β inhibition by LiCl on levels of pro- and anti-inflammatory cytokines; and the activity of transcription factor NF-κB in B. pseudomallei-infected peripheral blood mononuclear cells (PBMC) derived from diabetic-induced and normal Sprague Dawley rats. In addition, the effects of LiCl on intracellular bacterial counts were also investigated. Infection of PBMC from diabetic and normal rats with B. pseudomallei resulted in elevated levels of cytokines (TNF-α, IL-12 and IL-10) and phosphorylation of NF-κB in both cell types. Intracellular bacterial counts decreased with time in both cell types during infection. However bacterial clearance was less prominent in diabetic PBMC. Burkholderia pseudomallei infection also caused inactivation (Ser9 phosphorylation) of GSK3β in normal PBMC, an effect absent in infected diabetic PBMC. Inhibition of GSK3β by LiCl lowered the levels of pro-inflammatory cytokines (TNF-α and IL-12) in both normal and diabetic PBMC. Similarly, phosphorylated NF- κB (pNF-κB) levels in both cell types were decreased with LiCl treatment. Also, LiCl was able to significantly decrease the intracellular bacterial count in normal as well as diabetic PBMC. Interestingly, the levels of anti-inflammatory cytokine IL-10 in both normal and diabetic PBMC were further elevated with GSK3β inhibition. More importantly, GSK3β in infected diabetic PBMC was inactivated as in their non-diabetic counterparts upon LiCl treatment. Taken together, our results suggest that inhibition of dysregulated GSK3β in diabetic PBMC resulted in the inactivation of NF-κB and modulation of inflammatory cytokine levels. This is evidence that dysregulation of GSK3β is a contributing factor in the molecular basis of innate dysfunction and susceptibility of diabetic host to melioidosis infection.

Nocturnal penile tumescence activity unchanged after long-term intracavernous injection therapy.

PURPOSE: Anecdotal evidence suggests that some men have restored erectile function after long-term intracavernous injection therapy for erectile dysfunction. We objectively assessed this phenomenon using nocturnal penile tumescence testing. MATERIALS AND METHODS: In our retrospective study 19 men with a mean age of 53.5 years who had organic erectile dysfunction underwent nocturnal penile tumescence testing before and after prostaglandin E1 based intracavernous injection at least 6 months in duration. The nocturnal penile tumescence parameters measured included the number of erectile episodes, base and tip tumescence, and percent of time with rigidity greater than 70% at the penile base and tip. A 5-item questionnaire was given to all patients after the intracavernous injection period to assess subjective changes in erectile quality. RESULTS: Mean time on intracavernous injection was 2.42 years and mean injection frequency was 3.74 times monthly. Prostaglandin E1 only, and combined prostaglandin E1, phentolamine and papaverine were used in 7 and 9 cases, respectively. Nine patients believed that unaided erection improved after intracavernous injection and 6 achieved intercourse without injection who were unable to do so before injection. No statistically significant changes were noted in any of the 5 objectively measured nocturnal penile tumescence parameters. CONCLUSIONS: Long-term prostaglandin E1 based intracavernous injection may provide subjective improvement in erectile function in some men. However, as measured by nocturnal penile tumescence testing, no objective improvement in spontaneous erectile function occurs.

Renal artery pressure gradients in patients with angiographic evidence of atherosclerotic renal artery stenosis.

From October 1979 to August 1991, 231 patients underwent renal artery balloon angioplasty at The Ohio State University Hospitals. Atherosclerotic renal vascular disease was present in 171 of these patients. From this cohort, 138 patients undergoing their first angioplasty had renal artery pressure gradients performed before and after renal artery angioplasty. The demographics of this group included age 66.9 +/- 10 years (+/- SD), male 51%, white 94%, black 6%, diabetes mellitus 28%, systolic blood pressure 157 +/- 26 mm Hg, diastolic blood pressure 86 +/- 13 mm Hg, standard daily doses of antihypertensive medications 4.2 +/- 3, and serum creatinine 2.6 +/- 2.3 mg/dL. Plasma renin activity was measured in 25 patients and was shown to be elevated in 16. The renal artery stenoses were main renal artery 75%, orificial 22%, distal renal artery 1.4%, and combinations of the above 2.2%. Solitary kidneys were present in six patients (4.3%). Bilateral renal artery stenosis was present in 45% of patients and bilateral angioplasties were performed in one third of these patients. The preangioplasty systolic blood pressure gradient was 109 +/- 50 mm Hg (range, 20 to 230 mm Hg) and the postangioplasty renal artery pressure gradient was 12 +/- 16 mm Hg (range, 0 to 78 mm Hg) (P < 0.001). There were no complications related to measurement of the pressure gradients. The magnitude of the renal artery pressure gradients did not correlate with blood pressure level, number of antihypertensive medications, or serum creatinine level.(ABSTRACT TRUNCATED AT 250 WORDS)