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Biomedical subjects

P E Hutchinson

Publications and source records attributed to P E Hutchinson.

At least 19 recordsLinked to original sources
PubMed2005

Vitamin D receptor gene polymorphisms, particularly the novel A-1012G promoter polymorphism, are associated with vitamin D3 responsiveness and non-familial susceptibility in psoriasis.

Psoriasis is a genetically determined disease characterized by hyperproliferation and disordered maturation of the epidermis. Th1 lymphocytes are implicated in its pathogenesis. The vitamin D receptor (VDR) is a candidate modifying gene, having immunosuppressive effects and being involved in anti-proliferative and pro-differentiation pathways in keratinocytes. There is suggestive evidence that the A allele of the A-1012G polymorphism is associated with down-regulation of the Th1 response, via GATA-3. The F and T alleles of Fok1 and Taq1 have been associated with increased VDR activity. The present study aimed to test the hypothesis that the A allele of A-1012G is protective for occurrence and severity of psoriasis and enhances therapeutic response to vitamin D analogues and that these effects would be additive to those of Fok1 and Taq1. The study group comprised 206 psoriasis patients who had received topical calcipotriol treatment and 80 controls. There was no significant linkage disequilibrium between any pair of the three polymorphic sites (P=0.3-0.8). The A, F and T alleles were positively associated with calcipotriol response: AA genotype (compared to AG/GG), odds ratio (OR)=2.18 (P=0.04); TT, OR=1.97 (P=0.03); AAFF genotype combination, OR=4.11 (P=0.03); AATT, OR=5.64 (P=0.005); and FFTT, OR=3.22 (P=0.01). Comparing patients without, to patients with, a family history of psoriasis, the A allele was under represented (P=0.01) and the AAFF genotype combination even more so (compared to residual genotypes) (OR=0.24; P=0.005). AAFF was also under-represented in patients without a family history compared to controls (OR=0.31; P=0.04). There were no associations of family history with Fok1 and Taq1. There were no associations of severity of psoriasis with any polymorphism. In conclusion, the A-1012G, Fok1 and Taq1 VDR polymorphisms were associated with response to calcipotriol. A-1012G and Fok1 were associated with susceptibility to non-familial psoriasis.

Adolescent↗
PubMed2005

'Atrophic telogen effluvium' from cytotoxic drugs and a randomized controlled trial to investigate the possible protective effect of pretreatment with a topical vitamin D analogue in humans.

BACKGROUND: Hair loss from cytotoxic drugs is classically ascribed to the loss of fractured hairs (anagen effluvium). Telogen hair loss has also been described but some authors have denied any effect on the hair cycle. There are conflicting reports on a protective effect of pretreatment with a vitamin D analogue on cytotoxic drug-induced hair loss in rodents. OBJECTIVES: To investigate the process of cytotoxic hair loss and any protective effect on the hair of pretreatment with topical calcipotriol. METHODS: Breast cancer patients who were about to receive cycles of chemotherapy with cyclophosphamide 600 mg m(-2), methotrexate 40 mg m(-2) and 5-fluorouracil 600 mg m(-2) were recruited and randomized to receive calcipotriol scalp solution 50 microg mL(-1) or vehicle. The solution was applied twice daily from 4 days prior to chemotherapy and continued for 14 days in each treatment cycle. Shed, plucked and cut hairs were sampled. Absolute shed rates, the proportion of major hair types, the presence of proximal hair shaft changes, regrowth (using the new anagen hair count) and hair density were assessed. RESULTS: Ten patients receiving calcipotriol and 14 receiving vehicle completed three treatment cycles and nine from both groups completed six cycles. There was no detectable effect of calcipotriol on the proportion of patients experiencing minimal hair loss from chemotherapy, shed rates, plucked telogen and fractured hair counts, the morphology of shed and plucked hair, hair regrowth or hair density. Combining results of the treatment groups, there was a large variation in the impact of chemotherapy on hair loss, from total loss in five patients to no obvious loss in five. Excluding the latter, during chemotherapy shed telogen hairs (mean 81% of shed hairs) predominated over fractured (12%) and anagen hairs (6%) (P = 0.0002). The major pathological change was proximal hair shaft tapering, baseline mean 3% of shed hairs rising to 48% (P = 0.0005) during treatment, and there was a consequent decrease in normal telogen hairs, baseline mean 98% of all telogen hairs falling to 55% (P = 0.0005) during treatment. The pathological tapered telogen hairs had normal or small, sometimes diminutive, bulbs. Fracturing of hairs with diminutive bulbs produced typical 'exclamation mark' hairs. CONCLUSIONS: The cardinal effects of cytotoxic drugs found in this study were tapering of the proximal hair shaft and premature entry of the follicle into telogen, conflicting with the conventional view that affected hair follicles continue in anagen. There was a resulting effluvium of a mixture of tapering telogen hairs and fractured hairs. As entry into telogen is an integral part of the process, cytotoxic hair loss may be regarded as a variant of the conventional 'telogen effluvium' and we propose the term 'atrophic telogen effluvium'. There was no obvious protective effect on the hair loss of prior treatment with topical calcipotriol.

Administration, Topical↗
PubMed2005

Toxic epidermal necrolysis: current evidence, practical management and future directions.

Toxic epidermal necrolysis (TEN) is a rare disorder characterized by extensive epidermal death. Almost all cases appear to be caused by an idiosyncratic drug reaction. Proposed pathogenic mechanisms are conflicting, and the evidence for the benefits of individual treatments is inadequate, and in some cases contradictory. The mortality rate remains high. We review the literature pertaining to the pathogenesis of TEN and drug reactions in general. The rationale for therapeutic interventions, together with reported evidence of efficacy, are considered. We present a composite model of TEN, based on previous work and suggested pathogeneses of TEN, mechanisms of drug reactions and reported cytotoxic lymphocyte (CTL) cytolytic pathways. In this system, TEN, like some other cutaneous drug eruptions, is an HLA class I-restricted, specific drug sensitivity, resulting in clonal expansion of CD8+ CTLs. Cytotoxicity is mediated by CTL granzyme and possibly death receptor (DR) ligand (DR-L), probably Fas ligand (FasL). Particular to TEN, there is then an amplification sequence involving further DR-L expression. FasL is likely to be particularly important but tumour necrosis factor (TNF) may well contribute, via the TNF receptor 1 (TNF-R1) death pathway. Alternatively, we suggest the possibility of upregulation of an antiapoptotic TNF-R1-nuclear factor kappaB pathway, which would proscribe treatments which downregulate this pathway. None of the published data on individual treatment efficacies is sufficiently strong to suggest a definitive single treatment. Currently a multifaceted regimen appears indicated, targeting various likely intermediary mechanisms, including elimination of residual drug, immunosuppression, inhibition of DR pathways, general antiapoptotic strategies, and aggressive supportive care. Particular attention has been directed at avoiding potential conflicts between different treatments and avoiding agents that theoretically might have a net proapoptotic rather than antiapoptotic effect. Nursing on a specialized unit is of paramount importance.

Adrenal Cortex Hormones↗
PubMed2004

A novel polymorphism in the 1A promoter region of the vitamin D receptor is associated with altered susceptibilty and prognosis in malignant melanoma.

The association of Taq 1 and Fok 1 restriction fragment length polymorphisms of the vitamin D receptor with occurrence and outcome of malignant melanoma (MM), as predicted by tumour (Breslow) thickness, has been reported previously. We now report a novel adenine-guanine substitution -1012 bp relative to the exon 1a transcription start site (A-1012G), found following screening by single-stranded conformational polymorphism of this promoter region. There was a total of 191 MM cases, which were stratified according to conventional Breslow thickness groups, cases being randomly selected from each group to form a distribution corresponding to the known distribution of Breslow thickness in our area, and this population (n=176) was compared to 80 controls. The A allele was over-represented in MM patients and, with GG as reference, odds ratio (OR) for AG was 2.5, 95% confidence interval (CI) 1.1-5.7, (P=0.03) and AA 3.3, CI 1.4-8.1, (P=0.007). The outcome was known in 171 of 191 patients and the A allele was related to the development of metastasis, the Kaplan-Meier estimates of the probability of metastasis at 5 years being: GG 0%; AG 9%, CI 4-16%; AA 21%, CI 12-36%; (P=0.008), and to thicker Breslow thickness groups (P=0.04). The effect on metastasis was independent of tumour thickness and A-1012G may have predictive potential, additional to Breslow thickness. Neither the Fok 1 nor Taq 1 variants (f and t) were significantly related to the development of metastasis, although there was a strong relationship of fftt with the thickest Breslow thickness group (P=0.005). There was an interaction between the A-1012G and Fok 1 polymorphisms (P=0.025) and the Fok 1 variant enhanced the effect of the A allele of the A-1012G polymorphism on metastasis, the probability of metastasis for AAff at 5 years follow-up being 57%, CI 24-92%.

DNA Mutational Analysis↗
PubMed2003

Comparison of diagnostic accuracy for cutaneous malignant melanoma between general dermatology, plastic surgery and pigmented lesion clinics.

BACKGROUND: Since the 1980s there have been dedicated pigmented lesion clinics (PLCs) in the U.K. Important considerations when comparing the efficacy of the PLC with other referral clinics include diagnostic accuracy. OBJECTIVES: To compare the false-negative rate of clinical diagnosis (FNR) in the PLC with that in the other clinics of primary referral of malignant melanoma (MM) in the same geographical area. We have previously shown that certain clinical features are risk factors for diagnostic failure of MM. A further aim of this study was to correct for any differences in frequency of these factors in the melanoma populations between clinics and to estimate the false-positive diagnostic rate (FPR) in the PLC. METHODS: To compare the FNR between clinics, the case notes of all patients presenting with histologically proven cutaneous MM in Leicestershire between 1987 and 1997 were examined retrospectively. A false-negative diagnosis was defined as documentation of another diagnosis and/or evidence in the case notes that the diagnosis was not considered to be MM. The FNR was estimated as the number of false-negative clinical diagnoses/number of true-positive histological diagnoses. To estimate the diagnostic FPR, which was defined as the number of false-positive clinical diagnoses of MM/total number of positive clinical diagnoses, in the PLC, the outcome of 500 consecutive patients attending the PLC was surveyed. RESULTS: The case notes of 731 patients were available, of whom approximately two-thirds initially attended the PLC, one-fifth the General Dermatology clinics (D) and the remainder were divided approximately equally (one-twentieth each) between Plastic Surgery clinics (P), other clinics (O) and the surgery of the general practitioner (GP). The last was regarded as the primary referral clinic if the lesion were excised there prior to any referral. The FNR was lowest for the PLC, at 10%, compared with 29% (D), 19% (P), 55% (O) and 54% (GP) (P < 0.0001). Lesions with risk factors for diagnostic failure were under-represented in the PLC (P < 0.0001), the mean frequencies of the risk factors being 20% (PLC), 25% (D), 22% (P), 31% (O) and 30% (GP). Differences were not large but still could partially explain the lower FNR of the PLC. However, when the FNR was estimated for lesions exhibiting each of these risk factors, the PLC was found to have the lowest rate in every case (PLC vs. all clinics combined, P = 0.04 to P < 0.0001). The mean FNR for the risk factors combined was 18% (PLC), 45% (D), 50% (P), 68% (O) and 71% (GP). Also on logistic multivariable analysis of the PLC vs. all the other clinics on FNR and the above factors, the higher FNR of the other clinics retained significance (odds ratio 5.9, P < 0.0001). In the 500 patients surveyed separately in the PLC, the MM pick-up rate on biopsy was 32% and the diagnostic FPR was 41%. CONCLUSIONS: The FNR of MM was lower in the PLC than in the other clinics, while the pick-up rate for MM on biopsy and the FPR were acceptably low.

Aged↗
PubMed2002

Vitamin D and systemic cancer: is this relevant to malignant melanoma?

1,25-dihydroxyvitamin D3[1,25(OH)2D3] is a well-known potent regulator of cell growth and differentiation and there is recent evidence of an effect on cell death, tumour invasion and angiogenesis, which makes it a candidate agent for cancer regulation. The classical synthetic pathway of 1,25(OH)2D3 involves 25- and 1 alpha-hydroxylation of vitamin D3, in the liver and kidney, respectively, of absorbed or skin-synthesized vitamin D3. There is recent focus on the importance in growth control of local metabolism of 1,25(OH)2D3, which is a function of local tissue synthetic hydroxylases and particularly the principal catabolizing enzyme, 24-hydroxylase. The classical signalling pathway of 1,25(OH)2D3 employs the vitamin D nuclear receptor (VDR), which is a transcription factor for 1,25(OH)2D3 target genes. Effects of this pathway include inhibition of cellular growth and invasion. Cytoplasmic signalling pathways are increasingly being recognized, which similarly may regulate growth and differentiation but also apoptosis. 1,25(OH)2D3 has a major inhibitory effect on the G1/S checkpoint of the cell cycle by upregulating the cyclin dependent kinase inhibitors p27 and p21, and by inhibiting cyclin D1. Indirect mechanisms include upregulation of transforming growth factor-beta and downregulation of the epidermal growth factor receptor. 1,25(OH)2D3 may induce apoptosis either indirectly through effects on the insulin-like growth receptor and tumour necrosis factor-alpha or more directly via the Bcl-2 family system, the ceramide pathway, the death receptors (e.g. Fas) and the stress-activated protein kinase pathways (Jun N terminal kinase and p38). Inhibition of tumour invasion and metastasis potential has been demonstrated and mechanisms include inhibition of serine proteinases, metalloproteinases and angiogenesis. The lines of evidence for an effect of vitamin D3 in systemic cancer are the laboratory demonstration of relevant effects on cellular growth, differentiation, apoptosis, malignant cell invasion and metastasis; epidemiological findings of an association of the occurrence and outcome of cancers with derangements of vitamin D3/1,25(OH)2D3 and the association of functional polymorphisms of the VDR with the occurrence of certain cancers. In addition, vitamin D3 analogues are being developed as cancer chemotherapy agents. There is accumulating evidence that the vitamin D3/1,25(OH)2D3/VDR axis is similarly important in malignant melanoma (MM). MM cells express the VDR, and the antiproliferative and prodifferentiation effects of 1,25(OH)2D3 have been shown in cultured melanocytes, MM cells and MM xenografts. Recently, an inhibitory effect on the spread of MM cells has been demonstrated, low serum levels of 1,25(OH)2D3 have been reported in MM patients and the VDR polymorphisms have been shown to be associated with both the occurrence and outcome of MM. The relationship between solar irradiation and MM is more complex than for the systemic cancers. As in other cancers, there is evidence of a protective effect of vitamin D3 in MM, but ultraviolet radiation, which is a principal source of vitamin D3, is mutagenic. Further work is necessary on the influence of serum vitamin D3 levels on the occurrence and prognosis of MM, the effects of sun protection measures on serum vitamin D3 levels in temperate climates and epidemiological studies on geographical factors and skin type on the prognosis of MM. Meanwhile, it would seem mandatory to ensure an adequate vitamin D3 status if sun exposure were seriously curtailed, certainly in relation to carcinoma of breast, prostate and colon and probably also MM.

Breast Neoplasms↗
PubMed2002

The importance of accurate dosage of topical agents: a method of estimating involved area and application to calcipotriol treatment failures.

Little attention is given to accurate dosage of topical medication which is a potential source of side-effects and treatment failure. There are studies on the dosage for 'sparing' application relevant to topical steroids but not for 'liberal' application. Though calcipotriol is a first line topical treatment for psoriasis, approximately one-third of patients do not respond adequately. The aims of the present study were to define liberal dosage, to develop a method of calculation of area of involved skin and to evaluate the efficacy of calcipotriol in optimized liberal dosages, based on preliminary studies, in calcipotriol treatment failures. Weight/unit area of ointment and cream base, constituting liberal application, was determined in six normal volunteers. The area of psoriatic involvement in 24 calcipotriol non-responders was estimated by a 'fill-up' method and a modified 'hand' method. The results of the two methods were similar (Pearson correlation coefficient 0.68, P < 0.0001) but the 'hand' method proved easier in use and was the preferred method for the rest of the study. The patients applied calcipotriol at their accustomed rates for at least 2 weeks and then at the calculated liberal rates, using cream in the morning and ointment at night, for 4 weeks. The efficacy measures were Psoriasis Area and Severity Index (PASI) (primary measure), a four-point efficacy score and a visual analogue scale. As a result of the preliminary study and the actual amounts used by the patients in the psoriasis treatment study reported below, liberal application has been defined as 50 g/m2 per application for ointment base and 40 g/m2 per application for cream. At this dosage, an average individual would use approximately 100 g of medication/week to treat 10% of the body surface. During the 4-week treatment study, the psoriasis patients used an average of 39 g (SD 17 g)/m2 per application of cream and 52 g (SD 13 g)/m2 per application of ointment. All efficacy measures showed marked improvement (P < 0.0001). The frequency distribution of the PASI reduction defined responsive (70% of patients) and poorly responsive groups (30%), with mean PASI reduction of 60% and 17%, respectively.

Administration, Topical↗
PubMed2002

A follow-up study to investigate the efficacy of initial treatment of lentigo maligna with surgical excision.

Recurrence rates following conventional surgery for lentigo maligna (LM) are reported to be between 7% and 15%. However, the studies are few, contain small numbers of patients and have relatively short follow-up. The principle aim of this study was to determine the efficacy of conventional surgery for LM in a large unbiased sample of all LM presenting in a defined geographical area. All LM cases occurring in Leicestershire between 1987 and 1996 were identified. Data were gathered from case notes, general practitioners and the Office for National Statistics (for any mortality data) and patients were invited to attend for examination. There were 89 evaluable patients treated with primary excision, representing the largest reported series to date. There was a false positive rate for diagnostic biopsy for LM (when the correct diagnosis was lentigo maligna melanoma, LMM) of 5% (95% confidence interval, CI: 1% to 14%). The initial excision was histologically incomplete in 9% (4% to 17%) of cases. In completely excised lesions (n=81) the observed recurrence rate was 20% (CI: 12% to 30%) at a mean follow-up of 42 months, which is similar to previous reports. However, Kaplan-Meier analysis yielded an estimated probability of recurrence of 31% (CI: 19% to 50%); time to relapse was up to 66 months. The age and sex of the patient and the site of the lesion were not associated with outcome, but, surprisingly, smaller lesions were associated with incomplete excision and recurrence. Fifteen current lesions were excised with similar success rates: the incomplete re-excision rate was 7% (CI: 0.2% to 32%) and the recurrence rate was 31% (CI: 12% to 83%) at 28 months. The estimated rate of transformation to LMM after initial surgical treatment was 1.5% (CI: 0.3% to 8%), and LMM was not the cause of death in any patient. These recurrence rates following complete primary excision and re-excision following recurrence were high compared with general expectations, which is largely the result of the method of analysis and the long follow-up. The high rate calls into question the accuracy of the routine histological assessment of clearance. The development of LMM was rare following surgery.

Adult↗