Management of thyroid eye disease in the United Kingdom: A multi-centre thyroid eye disease audit.

This article aims to provide baseline data and highlight any major deficiencies in the current level of care provided for adult patients with thyroid eye disease (TED). We undertook a prospective, nonrandomized cross-sectional multicenter observational study. During a 3-month period June-August 2014, consecutive adult patients with TED who presented to nominated specialist eye clinics in the United Kingdom, completed a standardized questionnaire. Main outcome measures were: demographics, time from diagnosis to referral to tertiary centre, time from referral to review in specialist eye clinic, management of thyroid dysfunction, radioiodine and provision of steroid prophylaxis, smoking, and TED classification. 91 patients (mean age 47.88 years) were included. Female-to-male ratio was 6:1. Mean time since first symptoms of TED = 27.92 (73.71) months; from first visit to any doctor with symptoms to diagnosis = 9.37 (26.03) months; from hyperthyroidism diagnosis to euthyroidism 12.45 (16.81) months. First, 13% had received radioiodine. All those with active TED received prophylactic steroids. Seven patients who received radioiodine and did not have TED at the time went on to develop it. Then, 60% patients were current or ex-smokers. 63% current smokers had been offered smoking cessation advice. 65% patients had active TED; 4% had sight-threatening TED. A large proportion of patients (54%) were unaware of their thyroid status. Not enough patients are being provided with smoking cessation advice and information on the impact of smoking on TED and control of thyroid function.

A 10-year review of orbital biopsy: the Newcastle Eye Centre Study.

PURPOSE: To review the histopathological diagnoses, visual outcome, and complication rate of orbital biopsy in a UK tertiary referral centre. METHODS: This was a retrospective, clinical-pathological, interventional, consecutive case series. All orbital biopsies performed between July 2004 and June 2014 in Newcastle Eye Centre (Newcastle upon Tyne, UK) were included in this study. All relevant data collected from the local electronic database and medical records were analysed. RESULTS: A total of 166 orbital biopsies were identified during the study period: 86 patients (53.1%) were female and the mean age was 53.7 ± 19.7 years. Of all the cases, orbital biopsies were performed unilaterally in 158 (97.5%) patients and bilaterally in 4 (2.5%) patients. The mean follow-up period was 2.2 ± 2.3 years. The two most common histopathological diagnoses were non-specific inflammatory disease (62, 38.3%) and lymphoproliferative disease (40, 24.7%). None of the patients experienced ≥ 2-Snellen line visual loss. There were 7 (4.2%) postoperative complications noted: 1 (0.6%) orbital haemorrhage with no loss of vision, 4 (2.4%) diplopia, 1 (0.6%) short-term symblepharon, and 1 (0.6%) conjunctival granuloma. Postoperative diplopia was associated with lateral orbitotomy (P = 0.044) and excisional biopsy (P = 0.015). CONCLUSIONS: Orbital biopsy serves as a safe diagnostic tool in managing orbital diseases. Patient should be made aware of the risk of postoperative diplopia. Our data provides useful guidance to clinicians when counselling patients for orbital biopsy.

Periocular basal cell carcinoma: 5-year outcome following Slow Mohs surgery with formalin-fixed paraffin-embedded sections and delayed closure.

AIM: The aim of the study was to determine the 5-year outcome of periocular basal cell carcinoma (BCC) managed by Mohs surgery using formalin-fixed, paraffin-embedded sections (Slow Mohs). METHODS: This was a prospective, non-comparative, interventional case series of all patients with periocular BCC treated by Slow Mohs in Newcastle upon Tyne, UK, between 1985 and 1999. Data collected included demographic information, indication for Slow Mohs, tumour site, histology, recurrence rate after 5 years and cosmetic outcome. RESULTS: Of 287 BCCs in 278 patients, 5-year follow-up data were available for 173 (60.2%). Recurrence following Slow Mohs occurred in one patient: 0.34% of total and 0.58% of those with 5-year follow-up. The main indication for Slow Mohs was most frequently due to the tumour site. Cosmetic outcome was deemed excellent in 56%, good in 18%, adequate in 8%, unknown in 14% and revision advised in only 4%. CONCLUSION: The low 5-year recurrence rate (0.58%) reported in this prospective series confirms the importance of margin-controlled removal of recurrent, poorly defined or critically sited BCCs, and illustrates that Slow Mohs is equivalent to standard Mohs. While delayed closure does not appear to compromise cosmetic outcome, this technique offers a histologically superior and cheaper alternative to frozen-section Mohs surgery.

Outcome of orbital decompression for disfiguring proptosis in patients with Graves' orbitopathy using various surgical procedures.

AIM: To compare the outcome of various surgical approaches of orbital decompression in patients with Graves' orbitopathy (GO) receiving surgery for disfiguring proptosis. METHOD: Data forms and questionnaires from consecutive, euthyroid patients with inactive GO who had undergone orbital decompression for disfiguring proptosis in 11 European centres were analysed. RESULTS: Eighteen different (combinations of) approaches were used, the swinging eyelid approach being the most popular followed by the coronal and transconjunctival approaches. The average proptosis reduction for all decompressions was 5.0 (SD 2.1) mm. After three-wall decompression the proptosis reduction was significantly greater than after two-wall decompression. Additional fat removal resulted in greater proptosis reduction. Complications were rare, the most frequent being worsening of motility, occurring more frequently after coronal decompression. The average change in quality of life (QOL) in the appearance arm of the GO-QOL questionnaire was 20.5 (SD 24.8) points. CONCLUSIONS: In Europe, a wide range of surgical approaches is used to reduce disfiguring proptosis in patients with GO. The extent of proptosis reduction depends on the number of walls removed and whether or not fat is removed. Serious complications are infrequent. Worsening of ocular motility is still a major complication, but was rare in this series after the swinging eyelid approach.

A questionnaire survey on the management of Graves' orbitopathy in Europe.

OBJECTIVE: To determine management patterns among clinicians who treat patients with Graves' orbitopathy (GO) in Europe. DESIGN AND METHODS: Questionnaire survey including a case scenario of members of professional organisations representing endocrinologists, ophthalmologists and nuclear medicine physicians. RESULTS: A multidisciplinary approach to manage GO was valued by 96.3% of responders, although 31.5% did not participate or refer to a multidisciplinary team and 21.5% of patients with GO treated by responders were not managed in a multidisciplinary setting. Access to surgery for sight-threatening GO was available only within weeks or months according to 59.5% of responders. Reluctance to refer urgently to an ophthalmologist was noted by 32.7% of responders despite the presence of suspected optic neuropathy. The use of steroids was not influenced by the age of the patient, but fewer responders chose to use steroids in a diabetic patient (72.1 vs 90.5%, P<0.001). Development of cushingoid features resulted in a reduction in steroid use (90.5 vs 36.5%, P<0.001) and increase in the use of orbital irradiation (from 23.8% to 40.4%, P<0.05) and surgical decompression (from 20.9 to 52.9%, P<0.001). More ophthalmologists chose surgical decompression for patients with threatened vision due to optic neuropathy, who were intolerant to steroids than other specialists (70.3 vs 41.8%, P<0.01). CONCLUSION: Deficiencies in the management of patients with GO in Europe were identified by this survey. Further training of clinicians, easier access of patients to specialist multidisciplinary centres and the publication of practice guidelines may help improve the management of this condition in Europe.

The use of porous polyethylene (Medpor) lower eyelid spacers in lid heightening and stabilisation.

BACKGROUND/AIMS: The management of lower eyelid retraction can be challenging, and established techniques to correct it are not always successful. Previous reports have suggested a role for the ultrathin high density porous polyethylene lower eyelid spacer (Medpor LES) in such patients. The authors report the experience of three surgeons implanting Medpor LES over 1 year, and ascertain whether such implants are a safe and effective alternative to autogenous spacers. METHODS: A prospective, interventional, non-comparative case series of consecutive patients. Surgical indications for Medpor LES were noted. Preoperative and postoperative lower marginal reflex distance (L-MRD), vertical palpebral aperture (PA), lagophthalmos, and scleral show inferior to the limbus (LSS) were recorded, together with major and minor complications. RESULTS: 32 patients (35 eyelids) had a Medpor LES inserted, 22/32 under local anaesthetic, and nine with adjunctive procedures. Mean follow up was 22 months (range 15-28 months). The Medpor LES was effective in reducing the palpebral aperture (p<0.001) and lagophthalmos (p = 0.04) and raising the lower eyelid height by reducing both L-MRD (p = 0.006) and LSS (p<0.001). However there were major complications in 7/32 patients and minor complications in 8/32, most requiring further surgery. Final outcome was good in 24/35 eyelids and satisfactory in 5/35. CONCLUSIONS: Despite a good or satisfactory final outcome in the majority of patients, the value of this technique is limited by complications, and should be reserved for those unsuitable for safer techniques.

CTLA4 gene and Graves' disease: association of Graves' disease with the CTLA4 exon 1 and intron 1 polymorphisms, but not with the promoter polymorphism.

OBJECTIVE: Recent studies have shown that Graves' disease (GD) is linked to and associated with alleles of the cytotoxic T lymphocyte antigen-4 (CTLA4) locus. However, the true pathogenic polymorphism(s) at this locus remains uncertain. Moreover, the association studies of the promoter CTLA4(-318)C/T polymorphism in white GD populations have produced conflicting results. Therefore, we have analysed three CTLA4 single nucleotide polymorphisms, including promoter CTLA4(-318)C/T, exon 1 CTLA4(49)A/G and intron 1 CTLA4(1822)C/T in our GD cohort from the UK. PATIENTS AND METHODS: We studied 301 white patients with GD and 349 healthy ethnically matched local controls. Amongst GD probands, 129 had significant thyroid-associated orbitopathy (TAO; NOSPECS class III or worse). The CTLA4(-318)C/T, CTLA4(49)A/G and CTLA4(1822)C/T polymorphisms were genotyped by using the restriction enzymes MseI, Bst71I and HaeIII, respectively. RESULTS: We found no association between GD and alleles of CTLA4(-318)C/T. GD was found to be associated with the G allele of CTLA4(49)A/G[P = 5.9 x 10(-6), odds ratio (OR) 1.65] and the T allele of CTLA4(1822)C/T (P = 7.7 x 10(-6), OR 1.64). The frequencies of these alleles were significantly higher in GD probands with significant TAO than in those without TAO (G allele: P = 0.001, OR 1.68; T allele: P = 0.001, OR 1.70). CONCLUSIONS: The promoter CTLA4(-318)C/T polymorphism is not in linkage disequilibrium with the pathogenic polymorphism(s) at the CTLA4 locus. The alleles of both the exon 1 CTLA4(49)A/G and the intron 1 CTLA4(1822)C/T polymorphisms are associated with GD, which is stronger in patients with TAO.

Development of embryonic cells containing serotonin, catecholamines, and FMRFamide-related peptides in Aplysia californica.

This study demonstrates the presence of a relatively extensive but previously unrecognized nervous system in embryonic stages of the opisthobranch mollusc Aplysia californica. During the trochophore stage, two pairs of cells were observed to be reactive to antibodies raised against the neuropeptides FMRFamide and EFLRIamide. These cells were located in the posterior region of the embryo, and their anterior projections terminated under the apical tuft. As the embryos developed into veliger stages, serotonin-like immunoreactive (LIR) cells appeared in the apical organ and were later observed to innervate the velum. Also, aldehyde-induced fluorescence indicative of catecholamines was present in cells in the foot, oral, and possibly apical regions during late embryonic veliger stages. Just before the embryo hatches as a free-swimming veliger, additional FMRFamide-LIR and catecholamine-containing cells appeared in regions that correspond to the ganglia of what will become the adult central nervous system (CNS). Neurons and connectives that will contribute to the adult CNS appear to develop along the pathways that are pioneered by the earliest posterior FMRFamide-LIR cells. These observations are consistent with the hypothesis that, besides their presumed roles in the control of embryonic behaviors, some elements may also guide the development of the CNS. Embryonic nervous systems that develop prior to and outside of the adult CNS have also been reported in pulmonate and prosobranch species of molluscs. Therefore, the demonstration of early developing neurons and their transmitter phenotypes in A. californica presents new opportunities for a better understanding of the ontogeny and phylogeny of both behavioral and neuronal function in this important model species.

Mohs' surgery of periocular basal cell carcinoma using formalin-fixed sections and delayed closure.

Mohs' surgery of periocular basal cell carcinoma (BCC) ensures a high cure rate with maximal preservation of normal tissue. The formalin-fixed paraffin-embedded tissue technique allows Mohs' surgery to be performed using routine pathology facilities and permits the efficient use of operating room personnel and theatre time. The inevitable delay between excision and closure may potentially result in a poor functional and cosmetic outcome, particularly around the eye. We prospectively studied all patients with periocular BCC treated with this technique at our unit between 1985 and 1996. One hundred and twenty-three periocular BCCs in 120 patients were treated. Microscopic clearance was achieved in all cases. Closure was performed on average 5 days after the initial excisional stage. Closing procedures included direct closure, flaps and grafts. Significant complications affecting outcome were noted in only two patients. Eighty-eight per cent of patients assessed had a functional and cosmetic result regarded as excellent, good or adequate. Mohs' surgery of periocular BCC using formalin-fixed paraffin-embedded tissue and delayed closure results in a satisfactory functional and cosmetic outcome and offers a viable alternative to the frozen section fresh tissue technique.

Expression of the angiogenic factor thymidine phosphorylase/platelet-derived endothelial cell growth factor in primary bladder cancers.

Thymidine phosphorylase (TP), also known as platelet-derived endothelial cell growth factor, has been implicated in bladder cancer angiogenesis. To examine its role more clearly, we have quantified and localized its expression using Western analysis and immunohistochemistry in a series of 105 bladder cancers. We have also assessed the relationship between TP expression and other tumor parameters including quantitative angiogenesis, p53 status, ploidy, and survival. By Western analysis, TP expression was 5-fold higher in tumors than in normal bladder samples (P < 0.02). Expression was 15-fold higher in invasive tumors than in normal bladder (P < 0.001) and 8-fold higher than in superficial tumors (P < 0.005). Immunohistochemistry of the tumors showed TP was present in the neoplastic epithelium in 27% of the tumors, in the inflammatory cells in 72% of the tumors, in stromal cells in 30% of the tumors, and in tumor-associated endothelium in 11% of the tumors. Expression by Western blotting and immunohistochemistry was significantly up-regulated in tumors compared with normal bladder (P < 0.05). Tumor cell TP expression correlated with tumor grade (P < 0.02), but there was no correlation between tumor cell TP expression and tumor stage (P = 0.46), ploidy (P = 0.52), p53 expression (P = 0.9), tumor vascularity (P = 0.8), relapse-free survival (P = 0.57), or overall survival (P = 0.94). TP protein is expressed in bladder cancers, and expression is associated with an aggressive phenotype. Because TP can activate a number of cytotoxic agents, it provides a potential therapeutic target in bladder cancer.

Haemophilia and HIV infection in Hong Kong.

This is a retrospective study of the problems faced and support received by HIV (human immunodeficiency virus) infected haemophilia patients in Hong Kong. Between December 1984 and December 1994, 63 patients were detected to be HIV positive, out of a total of 231 haemophiliacs screened. Infection could be traced back to before August 1985, when safer heat-treated clotting factors were not yet available. Psychosocial impacts were obvious in this group of patients because of the double blow of HIV infection and haemophilia. Amongst the more evident problems were obstacles in schooling, employment difficulties, and disturbed relationships with family and friends, to mention a few. Psychosocial support services have been rendered by both the government and non-governmental organizations in Hong Kong. Financial assistance has also been given by the government since April 1993. To date, only eleven (17.5%) patients were known to have progressed to AIDS. Medical treatment, psychosocial support and financial assistance are integral components of an effective AIDS care programme for HIV-infected haemophilia patients.

PIP: 231 hemophiliacs in Hong Kong were screened for infection with HIV between December 1984 and December 1994. 63 patients were found to be HIV-seropositive, with HIV infection traced back to before August 1985, when safer heat-treated clotting factors were not yet available. The psychological burden of being both a hemophiliac and infected with HIV precipitated problems in schooling, employment, and relationships with family and friends. Psychosocial support services to HIV-infected hemophiliacs have been rendered by both the government and nongovernmental organizations in Hong Kong. The government has also provided financial assistance since April 1993. To date, only 11 of the 63 patients are known to have progressed to AIDS. Medical treatment, psychosocial support, and financial aid are integral components of an effective AIDS care program for HIV-infected hemophilia patients.

A retrospective study of the investigation and management of muscle-invasive bladder cancer in the South West Region.

OBJECTIVE: To evaluate the present management of muscle-invasive bladder cancer in the South West Region and to assess the workload resulting from the rationalization of treatment in specific centres. METHODS: A retrospective survey was undertaken in all the hospitals in the South West Region, to assess the management of all patients presenting with muscle-invasive bladder cancer in the years 1989 and 1993. Data were collected from histopathology records and hospital in-patients' notes. The optimum standard of assessment and treatment were defined by a panel of specialists in urological tumours. The management of patients was compared against these defined standards. RESULTS: A total of 186 and 199 patients in 1989 and 1993, respectively, were evaluated. When comparing their assessment against the defined standard, only 69% of patients in 1989 and 58% in 1993 had an intravenous urogram, with 7% and 4%, respectively, having no upper tract imaging (the remainder undergoing ultrasonography). Evidence from an examination under anaesthetic (EUA) was found for 80% of patients in 1989 and 84% of patients in 1993. Only 23% of patients in 1989 and 36% in 1993 were staged by either computed tomography or magnetic resonance imaging. In both 1989 and 1993, 54% of patients had definitive treatment, 31% had an endoscopic follow-up only and 15% had no treatment; there were no differences in age or co-morbidity among these groups. The median time elapsed between referral and diagnosis was 59 days (1989) and 52 days (1993), and the median delay to definitive treatment was 114 and 96 days, respectively. CONCLUSION: There was insufficient upper tract imaging, poor clinical staging in the EUA and too few investigations for staging. The low rate of definitive treatment may be a consequence of the delays in management, allowing the tumour to progress, and suggesting the need for a more rapid assessment of haematuria.

An immunohistochemical and prognostic evaluation of cathepsin D expression in 105 bladder carcinomas.

Cathepsin D is a widely expressed aspartyl lysosomal protease. Clinical studies in several tumor types have shown a strong correlation between cathepsin D expression and tumor progression. In breast carcinoma, its expression is an independent prognostic factor associated with an increased risk of death. However, there have been no studies evaluating cathepsin D in bladder tumors. Therefore, the aim of this study was to determine the pattern of expression of cathepsin D in a large series of bladder carcinomas and assess its role as a prognostic factor against established variables. The tumors from 105 patients (median age 73) (median follow-up 26 months) with transitional cell carcinoma of bladder were examined. Forty-nine patients had superficial tumors (16 pTa; 33 pT1), 56 had invasive tumors (14 pT2; 42 pT3); there were 35 grade 1/2 tumors and 70 grade 3 tumors. These were stained by a standard immunohistochemical technique with an anti-cathepsin D monoclonal antibody. All 4 normal bladder specimens were positive for cathepsin D. Fifty-four tumors (51%) were positive for cathepsin D and 51 (49%) were negative. Chi square analysis showed a significant positive relationship between negative cathepsin D expression and stage (p < 0.0005), grade (p < 0.0001) and tumor morphology (p = 0.001). There was no relationship between cathepsin D expression and tumor ploidy (p > 0.1) or patient age (p = 0.09). Univariate analysis of disease-free and overall survival showed that negative cathepsin D expression (p = 0.01 and p = 0.0003 respectively), stage (p = 0.004 and p < 0.005 respectively) and grade (p = 0.02 and p = 0.0007 respectively) were associated with significantly worse prognosis. However, in a multivariate analysis of age, stage, grade and cathepsin D expression, only stage remained significant for overall survival (p < 0.005). The observed result for cathepsin D in the univariate analysis is probably due to its strong association with grade and stage. Nevertheless, cathepsin D status was able to provide additional prognostic information for overall survival in invasive tumors when stratifying for grade (p = 0.047), which suggests that it might provide additional prognostic data within particular tumor stages.

The procarcinogen hypothesis for bladder cancer: activities of individual drug metabolizing enzymes as risk factors.

Bladder cancer provides the most definitive example for an association between environmental agents and cancer. However, in the absence of industrial occupational exposure, the primary carcinogen is rarely identified, and the mechanisms involved in cancer formation are poorly understood. The environmental procarcinogen hypothesis of tumour pathogenesis proposes that many carcinogens require metabolic activation by drug metabolizing enzymes to form the proximate carcinogen. A balance of exposure to the carcinogen, the activity of the enzymes involved in either formation of proximate carcinogen, or production of non-toxic metabolites, will determine tumour risk. We have used mephenytoin, debrisoquine and dapsone as selective probes for the phenotypic measures of activity of CYP2C19, CYP2D6, and CYP3A4, respectively. Within subject reproducibility of phenotypic measures, and the lack of cross-inhibition when the three drugs are given in a concurrent cocktail, have been confirmed. We have applied the cocktail drug approach in two, non-overlapping series of cases with bladder cancer and matched controls. In both series, patients with aggressive bladder cancer (GIII histopathology) had a history of excess alcohol intake, an under-representation of poor metabolizers of debrisoquine, a significant mean reduction in dapsone recovery ratio, but no difference in mephenytoin phenotype. Collectively, these observations involving multiple routes of drug metabolism support the procarcinogen environmental hypothesis for bladder cancer and suggest that measurement of activity of selected individual drug metabolizing enzymes involved in the pathogenesis of this tumour can be used to identify subjects at high risk of developing bladder cancer.

Quantification of angiogenesis as an independent predictor of prognosis in invasive bladder carcinomas.

OBJECTIVE: To evaluate angiogenesis as a prognostic marker of transitional cell carcinoma of the bladder and to assess its relationship to established variables for survival. MATERIALS AND METHODS: Forty-five tumours (two G2T2, seven G3T2 and 36 G3T3) from 36 men and nine women with a mean age of 73 years (range 50-91), who had been followed-up for a median of 37 months (range 1-50), were examined. Vessels were immunohistochemically highlighted using an antibody to the platelet endothelial cell adhesion molecule, CD31. Microvessel density was quantified using a Chalkley point eyepiece graticule. RESULTS: Univariate analysis of survival showed stage, grade and vascular count were significant indicators of prognosis (P = 0.002, P = 0.007, P = 0.019 respectively). No relationship was observed between stage and grade and vascular count. In a Cox proportional hazard model, adjusted for age and stage, microvessel density not only remained a significant prognostic indicator (P = 0.026) but was as informative as stage in predicting overall survival. A high vascular count conferred a 2.5 increased risk of mortality. CONCLUSIONS: These findings suggest that assessment of angiogenesis by microvessel quantification is an independent predictor of survival in patients with invasive bladder carcinoma and might be useful in selecting those who would benefit from adjuvant therapy.

Long-term survival after endoscopic transanal resection of rectal tumours.

The outcome and survival of 120 consecutive patients of median age 78 years with rectal tumours who underwent endoscopic transanal resection were assessed. Thirty-eight patients (32 per cent) were treated for large villous adenoma. These patients underwent a median of 2 (range 1-5) resections and the overall 5-year survival rate was 78.2 per cent. Of 82 patients with rectal cancer, 33 (28 per cent of the 120) had tumours amenable to conventional surgery but for the patient's age or infirmity. The 5-year survival rate of these patients was 29.7 per cent. Endoscopic transanal resection was used to palliate the symptoms of 49 patients (41 per cent) with rectal cancer; the 5-year survival rate was 13.7 per cent. Excellent long-term outcome may be achieved with endoscopic transanal resection for patients with benign rectal tumours. This approach also gives acceptable results for selected patients with rectal cancer in whom age, extent of disease or concurrent illness preclude conventional surgical resection.