Management of patients in a combined thyroid eye clinic in secondary care.

The European Group on Graves' Orbitopathy (EUGOGO) recommends the use of specialised multidisciplinary clinics for the management of thyroid eye disease (TED). In the UK, many patients with TED are managed outside of specialised clinics. We describe the organisation of a combined TED clinic in a secondary care setting and present the result of a prospective audit of the patient characteristics and outcomes during the first four years of a combined TED clinic. Of a total of 132 patients referred to the TED clinic, 114 (86 %) had TED (90 females, median age 56 years; range 17-90 years). At presentation, 77 (67 %) were current or ex-smokers and 99 (87 %) were biochemically euthyroid. Median duration of eye symptoms was 12 months. Fifty-two percent, 45 and 3 had mild, moderate-to-severe and sight-threatening TED, respectively. Only 18 % of patients had a clinical activity score (CAS) of ≥3. Sixty-nine patients (61 %) required follow-up appointments in the TED clinic. In those who required follow-up, 43 % (n = 30) received either immunosuppressive or surgical treatment. CAS improved from first to final visit, with 29 % (n = 20) having a CAS of ≥3 at the first visit and 1 % (n = 1) at the final visit (p = 0.0001). There was also a decrease in prevalence of smoking and thyroid dysfunction at the final visit. A multidisciplinary specialised TED clinic offers an optimal setting for managing patients with TED; however, patients are often referred late to a specialist TED clinic.

Human homolog of patched, a candidate gene for the basal cell nevus syndrome.

The basal cell nevus syndrome (BCNS) is characterized by developmental abnormalities and by the postnatal occurrence of cancers, especially basal cell carcinomas (BCCs), the most common human cancer. Heritable mutations in BCNS patients and a somatic mutation in a sporadic BCC were identified in a human homolog of the Drosophila patched (ptc) gene. The ptc gene encodes a transmembrane protein that in Drosophila acts in opposition to the Hedgehog signaling protein, controlling cell fates, patterning, and growth in numerous tissues. The human PTC gene appears to be crucial for proper embryonic development and for tumor suppression.

Refractive outcomes after cataract surgery with primary lens implantation in infants.

AIMS: To show the refractive outcomes, accuracy of intraocular lens power selection, and visual outcomes and complications in infants undergoing cataract surgery. METHODS: The refraction (spherical equivalent) of 14 operated eyes in 8 children aged <1 year was plotted over time. Preoperative and final recorded visual acuities were assessed. RESULTS: The median follow-up was 37.25 months. The median initial postoperative refraction was (+)6.75 dioptres. CONCLUSIONS: Refractive outcomes for each eye were not entirely predictable and were variable between infants. However, there was a consistent pattern in each infant who underwent bilateral surgery, with both eyes following a similar pattern of refractive change with time: a decreasing myopic shift was seen in 8 eyes, possibly demonstrating emmetropisation. The two unilateral cases appeared to show a linear myopic shift. 4 eyes in 2 patients did not follow a myopic shift curve and one of these patients showed an early trend towards increased hyperopia. Definite causes for this erratic refractive change were not identified. A postoperative refraction >4.5 dioptres avoided early onset myopia. The range of difference between postoperative and predicted refraction using SRK-T was (-)2.85 to 2.97 dioptres. Most of the visual results are encouraging compared with historical data in older children.

Basal cell carcinomas and squamous cell carcinomas of human skin show distinct patterns of chromosome loss.

Although basal cell carcinomas and squamous cell carcinomas are clinically and pathologically distinct, the molecular basis for these differences is not clear. We have used polymorphic microsatellite markers to determine the pattern and extent of chromosome losses in a series of 44 basal cell carcinomas and 47 squamous cell neoplasms of the skin. Basal cell carcinomas showed a distinctive allelotype with chromosome loss largely confined to a single chromosome arm, 9q (26 of 44 informative tumors). In contrast to the predominance of loss on a single chromosome arm in basal cell carcinomas, squamous cell neoplasms showed more widespread loss with loss of heterozygosity of markers from 35 of 39 chromosome arms in one or more of the tumors studied. The pattern of loss was also different from basal cell carcinomas with frequent loss of heterozygosity of markers from 9p (41%), 13q (46%), 17p (33%), 17q (33%), and 3p (23%) in squamous cell neoplasms. The frequent loss of markers from these chromosome arms relative to other chromosome losses suggests that these arms may contain genes important in the development of cutaneous squamous cell carcinomas.

Wavelength specific patterns of p53 induction in human skin following exposure to UV radiation.

We report that, in human skin, exposure to equally erythemogenic doses of UVA, UVB, and UVC increases immunocytochemically detected p53 in a wavelength-specific pattern. UVC produced immunostaining confined to the upper epidermis. With UVB, staining was seen throughout the epidermis, whereas with UVA staining predominated in the basal layer. The results with UVB and UVC are understandable on the basis of their known differences in penetration, whereas those with UVA are not. This suggests that within one cell type the pattern of p53 response to UV radiation is wavelength dependent.

Use of 1,2:5,6-dianhydrogalactitol in studies on cell kinetics-directed chemotherapy schedules in human tumors in vivo.

Recently, it has been shown that 1,2:5,6-dianhydrogalactitol (DAG) can cause reversible alterations in cell cycle kinetics. Following treatment of CHO cells in vitro and Ehrlich ascites tumor cells in vivo, significant increases in the fraction of cells in S phase were observed to occur, and this was followed by an increase in the fractions of cells in G2 and mitosis. Treatments with S or G2-M phase-specific drugs at the peak enrichment times after DAG was given resulted in greater cell kills than when given by any other schedule. We have extended these kinetics-directed drug schedule studies to human tumors in vivo. The first phase was to determine whether DAG could be used to perturb cell kinetics in vivo as effectively in patients as it was in vitro. In 14 of 17 tumors studied, increases in the S-phase fractions were observed (ranging from 30 to 240% increases). The hr at which the S-phase peaks were observed (post-DAG treatment) was variable among the patients and among the tumors studied. However, this points out the value of obtaining actual cell kinetics data from serially biopsied tumors growing on the body surface and illustrates the importance that these data may have in helping to select an optimal time at which to give an S phase-specific drug. If such tumor cell kinetics-directed scheduling is ultimately shown to be effective, it will represent a means of individualizing therapy for a large fraction of tumor patients whose tumors are growing on or near the surface of the body. The tumors utilized in these studies were squamous carcinomas of the head and neck, skin, anus, and cervix; adenocarcinomas of the breast and rectum; and malignant melanoma. The second phase of this study will be to determine the tumor responses in patients treated with such kinetics-directed schedules.

Chromosome 9 allele loss occurs in both basal and squamous cell carcinomas of the skin.

Linkage studies of kindreds with the nevoid basal cell carcinoma syndrome and the high frequency of chromosome 9 allele loss in sporadic basal cell carcinomas indicate that chromosome 9 may contain tumor suppressor genes important in the development of sporadic and familial basal cell carcinomas. The recent mapping of the Ferguson-Smith syndrome, which predisposes affected individuals to the development of multiple lesions histologically indistinguishable from squamous cell carcinomas, suggests that tumor suppressor genes on 9q may also be important in the development of squamous cell neoplasms of the skin. Fifty-four non-melanoma skin cancers (24 basal cell carcinomas, 14 squamous cell carcinomas, and 16 cases of Bowen's disease) were examined for loss of heterozygosity on chromosome 9. Allelic loss at one or more loci on chromosome 9 was observed in 14 of 24 basal cell carcinomas, four of 14 squamous cell carcinomas, and three of 16 cases of Bowen's disease. Allelic deletion of one or more 9q markers was seen in 14 basal cell carcinomas, three squamous cell carcinomas, and three cases of Bowen's disease. Five basal cell carcinomas had interstitial deletions and in one the breakpoint mapped within the nevoid basal cell carcinoma syndrome locus. 9p loss occurred in three of nine informative squamous cell carcinomas. Allelic deletion of 9p markers was not seen in 19 basal cell carcinomas and seven cases of Bowen's disease. These findings suggest that chromosome 9 contains one or more tumor suppressor genes important in the development of both basal and squamous cell carcinomas of the skin.

Low frequency of loss of heterozygosity at the nevoid basal cell carcinoma locus and other selected loci in appendageal tumors.

Previous studies of loss heterozygosity (LOH) have revealed distinct patterns of allelic loss in some skin tumors. In basal cell carcinomas (BCCs) loss of heterozygosity is virtually restricted to chromosome 9, whereas in squamous cell carcinomas (SCCs) and actinic keratoses loss is more widespread involving chromosomes 3, 9, 13, and 17. Because there are histological similarities between BCCs and some appendageal tumors, and because lines of evidence suggest that BCCs are appendageal in origin, we carried out a limited allelotype in 41 appendageal tumors. The overall frequency of allelic loss was low (4 out of 247 informative loci; 1.6%). LOH was seen in a proliferating trichilemmal cyst (17p), a sebaceous epithelioma (17q), an eccrine porocarcinoma (17q), a trichoepithelioma (9q), and in two basal cell carcinomas showing eccrine or granular cell differentiation that were originally misdiagnosed (9Q). The pattern of loss in this mixed group of appendageal tumors shows differences from both BCCs and SCCs, and further emphasizes the unique genetic profile and behavior of BCCs. The finding of 9q loss in BCCs with eccrine or granular cell differentiation shows that 9q loss occurs in differential histological subtypes of BCCs.

Microsatellite instability in human non-melanoma and melanoma skin cancer.

Microsatellite instability secondary to replication errors (RER), characterized by length changes at repetitive loci scattered throughout the genome, is a recently recognized genetic mechanism important in the development of some human cancers. Although RER has been reported in sebaceous gland tumors from patients with the Muir-Torre syndrome, the frequency of RER in human non-melanoma and melanoma skin cancers is not known. In this study, we investigated the importance of RER in human skin carcinogenesis. RER was identified in three of four actinic keratoses from a patient belonging to a kindred with documented Muir-Torre syndrome, which indicates that defective DNA replication may contribute to skin cancer development in such patients. Examination of a series of tumors from patients without Muir-Torre, including 137 skin cancers (47 basal cell carcinomas, 49 squamous cell carcinomas, and 41 primary malignant melanomas), 19 actinic keratoses, and 20 cases of Bowen's disease, using 10 or more microsatellite markers, identified repeat-sequence instability in less than 5% of the tumors studied. In six of the eight tumors, the sole change was an alteration 2 base pairs in length at a single locus. One patient with a squamous cell carcinoma showed changes at multiple loci suggesting defective mismatch repair. Although the low frequency of RER found in this study of a large series of human skin tumors suggests that this phenomenon is uncommon in patients with skin cancer, the identification of RER at multiple loci in two patients suggests that error-prone replication may be important in skin cancer development in some individuals.

p53 mutations are common and early events that precede tumor invasion in squamous cell neoplasia of the skin.

Mutations of the p53 gene are the most common genetic abnormality described in human cancer; p53 mutations have recently been reported in more than half of the cases of squamous cell carcinomas of the skin. We have previously reported positive p53 immunostaining in Bowen's disease and actinic keratosis. To determine if this abnormal immunostaining reflects p53 mutation or alternative pathways of p53 protein inactivation we have performed direct sequencing of p53 in 20 further cases of Bowen's disease. We found eight mutations in 20 cases, seven of which would produce alterations in the p53 protein product. Our results suggest that p53 mutation is an early event in malignant conversion, frequently preceding invasion in squamous cell neoplasia of the skin. The type and site of the observed mutations reflect known mutational hotspots and support the role of ultraviolet radiation in the pathogenesis of these tumors.

Expression of the peptide antibiotics human beta defensin-1 and human beta defensin-2 in normal human skin.

Normal human skin is remarkably resistant to infection from the large numbers of microorganisms that routinely colonize its surface. In addition to the role of skin as a mechanical barrier, it has long been recognized that skin and other epithelia can produce a range of anti-microbial chemicals that play an important part in eliminating potential cutaneous pathogens. Anti-microbial peptides are an important evolutionarily conserved innate host defense mechanism in many organisms. Human beta defensin-1 and -2 are cysteine-rich, cationic, low molecular weight anti-microbial peptides that have recently been shown to be expressed in epithelial tissues. In this study, we describe the characterization of human beta defensin-1 and -2 mRNA and peptide expression in normal human skin. Using reverse transcription-polymerase chain reaction we demonstrate that human beta defensin-1 is consistently expressed in skin samples from various body sites. Human beta defensin-2 demonstrates expression that is more variable and is more readily detectable in facial skin and foreskin compared with skin from abdomen and breast. In situ hybridization localizes the human beta defensin-1 and -2 transcripts to keratinocytes within interfollicular skin. Using specific antibodies, we have shown that human beta defensin-1 and -2 peptides are localized to the Malpighian layer of the epidermis and/or stratum corneum and that there are interindividual and site-specific differences in intensity of immunostaining and the pattern of peptide localization. The localization of human beta defensins to the outer layer of the skin is consistent with the hypothesis that human beta defensins play an essential part in cutaneous innate immunity.

Gli1 protein is expressed in basal cell carcinomas, outer root sheath keratinocytes and a subpopulation of mesenchymal cells in normal human skin.

Genetic studies of patients with the nevoid basal cell carcinoma syndrome have led to the recognition of the importance of the hedgehog signaling pathway in the development of basal cell carcinomas of the skin. Although hedgehog signaling is known to be important in hair follicle development, the function of this pathway in adult skin and the mechanism by which activation of this pathway leads to basal cell carcinoma development remain to be established. The Gli1 family of transcription factors mediates hedgehog signaling in mammalian cells and we have shown in previous studies that Gli1 mRNA is differentially expressed in basal cell carcinomas. Using antibodies to epitopes on the N and C terminal regions of Gli1 we show now that Gli1 protein is present in basal cell carcinomas and that the protein is mainly localized to the cytoplasmic compartment. Focal nuclear staining was seen in a small number of basal cell carcinomas with the C terminal antibody which suggest that nuclear localization is not dependent on loss of the C terminus of Gli1 due to proteolysis. Strong Gli1 immunostaining was seen in the outer root sheath keratinocytes of some hair follicles, a subpopulation of mesenchymal cells in the vicinity of the bulge region of adult hair follicles and the dermal sheath cells of developing hair follicles. Quantitation of Gli1 mRNA in basal cell carcinomas using northern blot analysis indicates that Gli1 is highly expressed in basal cell carcinomas. This suggests that the lower intensity of Gli1 immunostaining in basal cell carcinoma islands relative to outer root sheath keratinocytes is not simply a reflection of differences in gene expression. The continued expression of Gli1 in adult hair follicles and in the mesenchyme of adult human skin suggest that Hh signaling may play a part in hair cycling and in epidermal mesenchymal interactions important in normal skin maintenance.

An association between sebaceous carcinoma and microsatellite instability in immunosuppressed organ transplant recipients.

Sebaceous carcinomas are rare cutaneous appendageal tumors that may occur sporadically or in association with an internal malignancy in Muir-Torre syndrome. In Muir-Torre syndrome microsatellite instability can often be demonstrated in tumor DNA as a result of an inherited mutation in one of several known mismatch repair genes; however, the role of microsatellite instability in sporadic sebaceous carcinomas has not been previously studied. In this report we describe the clinicopathologic characteristics of a series of unselected sebaceous carcinomas and examine them for the presence of microsatellite instability. Of 10 consecutive tumors identified over a 10 y period, only one was from a patient known to have Muir-Torre syndrome. Of the nine presumed sporadic cases, five were from four renal transplant recipients and four from otherwise healthy individuals. Microsatellite instability was demonstrable in three cases: in the Muir-Torre syndrome-associated tumor and in two tumors from transplant patients. Microsatellite instability was subsequently also found in a sebaceous carcinoma from a further transplant patient prospectively sought from another institution. The presence of microsatellite instability in post-transplant sebaceous carcinomas was associated with loss of expression of the mismatch repair protein hMSH2. In summary, sebaceous gland carcinomas, while characteristic of Muir-Torre syndrome, are commonly found outside this context. Among presumed sporadic cases, our data suggest they may be over-represented in immunosuppressed renal transplant recipients. The presence of microsatellite instability in transplant-associated lesions, together with loss of hMSH2 expression suggests that immunosuppression might unmask a previously silent Muir-Torre syndrome phenotype in some cases. Alternatively, there is experimental evidence to suggest that immunosuppressive drugs, most plausibly azathioprine, could select for the emergence of a mutator phenotype and thus predispose to the development of sebaceous carcinomas. The role of mismatch repair defects in other post-transplant skin malignancies remains to be established.

Microsatellite instability in benign skin lesions in hereditary non-polyposis colorectal cancer syndrome.

The coexistence of cutaneous and extra-cutaneous malignancies within one family could be explained by shared genetic mechanisms such as common tumor suppressor gene mutations or oncogene activation, as well as mutations in DNA repair genes. Hereditary non-polyposis colorectal cancer syndrome (HNPCC) and its variant Muir-Torre syndrome (MTS) are caused by germline DNA mismatch repair gene mutations. Colonic and endometrial tumors from HNPCC patients exhibit microsatellite instability (MSI), as do sebaceous lesions in MTS. We recruited individuals from cancer prone families to determine if MSI is found in benign and malignant skin lesions and to assess whether MSI in the skin is predictive of genomic instability with susceptibility to tumors characteristic of HNPCC. One hundred and fifteen benign, dysplastic, and malignant skin lesions from 39 cancer prone families were analyzed. Thirteen benign skin lesions from three individuals belonging to two HNPCC pedigrees showed MSI. No mutations in hMSH2 and hMLH1 were found in two of the three individuals with RER + skin lesions. We found MSI in non-sebaceous non-dysplastic skin lesions in HNPCC pedigrees. MSI was not found in skin lesions within other family cancer syndromes. These results have important clinical implications as the detection of MSI in prevalent readily accessible skin lesions could form the basis of noninvasive screening for HNPCC families. It may also be a valuable tool in the search for new mismatch repair genes.

Human beta defensin-1 and -2 expression in human pilosebaceous units: upregulation in acne vulgaris lesions.

A rich residential microflora is harboured by the distal outer root sheath of the hair follicle and the hair canal - normally without causing skin diseases. Although the basic mechanisms involved in the development of inflammation during acne vulgaris remain unclear, microbial agents might play an important role in this process. In this study we have analyzed by in situ hybridization and immunohistochemistry the expression patterns of two antimicrobial peptides, human beta defensin-1 and human beta defensin-2, in healthy human hair follicles as well as in perilesional and intralesional skin of acne vulgaris lesions such as comedones, papules, and pustules. Strong defensin-1 and defensin-2 immunoreactivity was found in all suprabasal layers of the epidermis, the distal outer root sheath of the hair follicle, and the pilosebaceous duct. Marked defensin-1 and defensin-2 immunoreactivity was also found in the sebaceous gland and in the basal layer of the central outer root sheath including the bulge region. The majority of acne biopsies displayed a marked upregulation of defensin-2 immunoreactivity in the lesional and perilesional epithelium - in particular in pustules - and a less marked upregulation of defensin-1 immunoreactivity. The upregulation of beta-defensin expression in acne vulgaris lesions compared to controls suggests that beta-defensins may be involved in the pathogenesis of acne vulgaris.

Ovarian choriocarcinoma: a difficult diagnosis of an unusual tumor and a review of the hook effect.

Ovarian choriocarcinoma is difficult to diagnose in the reproductive-age patient. A case of nongestational ovarian choriocarcinoma is discussed which presented like a molar pregnancy initially. Because of falsely low beta-hCG values (283 mIU/L) caused by the high-dose "hook effect" in the double antibody immunoassay system, however, a diagnosis of ectopic pregnancy was entertained. At laparotomy, a large necrotic ovarian choriocarcinoma was found along with large theca lutein cysts. The hook effect may mislead the clinician, and it is important to recognize this effect to avoid misdiagnosis.

Traumatic rupture of the medial rectus muscle.

Traumatic rupture of an extraocular muscle, in the absence of significant injury to the globe and adnexa, is uncommon. We report the case of a patient with an isolated mid-belly rupture of the medial rectus muscle following ocular trauma and describe the technique of repairing the ruptured muscle by suturing the distal segment to the Tenon sleeve of the proximal segment. This was combined with postoperative botulinum toxin injection to the ipsilateral lateral rectus muscle. Good primary position alignment was achieved 7 months after surgery. The patient regained a useful horizontal field of binocular single vision totaling 27 degrees.

Pediatric tetracycline-induced pseudotumor cerbri.

BACKGROUND: Tetracyclines have long been recognized as a cause of pseudotumor cerebri in adults, but the role of tetracyclines in the pediatric age group has not been well characterized in the literature and there have been few reported cases. We present 6 cases to better delineate the problem, the patient profile, the response to treatment, and the sequelae. METHODS: We retrospectively analyzed the records of all patients admitted with a diagnosis of pseudotumor cerebri who had documented usage of a tetracycline-class drug immediately before presentation at the Hospital For Sick Children in Toronto, Canada, from January 1, 1986, to March 1, 1996. RESULTS: Six patients (5 female, 1 male) who met all inclusion and exclusion criteria were identified; their ages ranged from 12 to 17 years. All were being treated for acne vulgaris. Duration of use before diagnosis was as short as 2 weeks and as long as 10 months, with a mean of 4.4 months. Duration of symptoms ranged from 0.57 to 4 weeks. Symptoms included headache (6 of 6), nausea (5 of 6), and diplopia (4 of 6). All for whom height and weight data were known (5 of 6) were in the upper quartile for body mass index. Visual acuity was 6/6 in all but 1 eye of one patient (6/9) at diagnosis, and final visual acuity was 6/6 in all patients. All had normal color vision, where this was recorded (5 of 6). The only recorded field defect was enlargement of the blind spot (4 of 6). All patients responded to treatment, with loss of symptoms in 1 day to 4 weeks. CONCLUSIONS: Pseudotumor cerebri as a result of tetracycline-class drugs does occur in the pediatric population. With prompt and appropriate medical treatment, long-term sequelae can almost always be avoided. Physicians who treat patients with tetracyclines need to be aware of the potential complications in children.

A prospective evaluation of anterior transposition of the inferior oblique muscle, with and without resection, in the treatment of dissociated vertical deviation.

BACKGROUND: Anterior transposition of the inferior oblique muscle (ATIO) has become a popular surgical treatment for dissociated vertical deviation (DVD), particularly in patients with coexisting inferior oblique muscle overaction (IOOA). We wanted to assess whether adding a resection improves the outcome compared with standard anteriorization. METHODS: We undertook a prospective, randomized evaluation of ATIO, with and without a 7-mm resection, in patients with DVD of at least 5 PD in one eye. We included 51 eyes of 30 patients, 26 eyes treated with the standard ATIO and 25 treated with a 7-mm resection added. We recorded the size of the preoperative and final DVD, grade of the preoperative and final IOOA, rates of reoperation, and complications. Mean follow-up was 15.4 months in the standard group and 25.0 months in the resection group, with a minimum of 4 months for all cases. RESULTS: The median preoperative and postoperative DVD was 12 PD and 4 PD in the standard group, respectively. This compared with 14 PD and 4 PD, respectively, in the resection group, representing no statistically significant difference in outcome. The presence or absence of IOOA did not influence the result of ATIO for either group. No significant complications of surgery occurred in either group. CONCLUSIONS: ATIO is an effective treatment for DVD and can be used to treat DVD in patients with or without IOOA, with few adverse effects. Our study revealed no advantage to adding a 7-mm resection to the standard procedure.

Relative strength of a new suture technique for fascial closure.

In an attempt to decrease the risk of fascial dehiscence, a new suture technique for fascial closure is proposed, referred to as the "secured" stitch. The secured interrupted stitch is performed by taking a double bite of fascia at each traditional site of fascial puncture. Relative strength of the secured interrupted stitch in comparison with the simple interrupted stitch is determined in samples of fresh bovine fascia. A significantly greater force is required to disrupt fascia repaired with the secured stitch compared with a simple interrupted repair. The secured stitch may afford a greater degree of protection from fascial dehiscence.