Patient preferences for topical treatment of actinic keratoses: a discrete-choice experiment.

BACKGROUND: The treatment of actinic keratosis (AK) is a potentially effective strategy for the prevention of cutaneous squamous cell carcinoma (cSCC). However, the patient perspective on potential benefits of AK treatment in terms of skin cancer reduction has received little attention to date. OBJECTIVES: (i) To investigate patient preferences for topical treatments for AK using a discrete-choice experiment (DCE); (ii) to evaluate patient willingness to trade between clinical benefit and medical burden. METHODS: The DCE was conducted as part of a study to establish the feasibility of a phase III randomized controlled trial evaluating the prevention of cSCC using currently available topical interventions. Preferences were elicited by asking patients to make a series of choices between treatment alternatives with different hypothetical combinations of attribute levels. Willingness to trade between treatment attributes was estimated using a flexible-choice model that allows for the heterogeneity of patient preferences. RESULTS: A total of 109 patients with AK completed the DCE. The majority of patients who expressed valid preferences were willing to accept some reduction in both prophylactic and cosmetic efficacy to reduce the burden of the treatment regimen, the severity of skin reaction and other adverse effects. Patients may reject treatment if the perceived therapeutic benefit is outweighed by the subjective burden of treatment. CONCLUSIONS: Evidence of significant variation in the perceived utility of treatments across patients highlights the importance of taking individual patient preferences into account to improve AK treatment acceptability and adherence.

A randomised, double-blind, placebo-controlled, crossover study to assess the efficacy and safety of three dosing schedules of agalsidase alfa enzyme replacement therapy for Fabry disease.

Anecdotal reports suggest that the currently approved dosing interval of agalsidase alfa (0.2 mg/kg/2 weeks) for Fabry disease treatment is too long. This randomised, double-blind, placebo-controlled, crossover study investigated three altered dosing intervals. 18 Fabry patients received three agalsidase alfa dosing schedules, each for four weeks (A: 0.2 mg/kg∗2 weeks, B: 0.1 mg/kg/week, C: 0.2 mg/kg/week). Health state, pain levels, sweat volume and latency and plasma and urinary globotriaosylceramide levels were recorded throughout the study. No significant differences were found among the schedules for the primary efficacy outcome of self-assessed health state, or for pain scores. A trend toward increased sweat volume on QSART testing, and reduced urine globotriaosylceramide concentration were seen with treatment schedule C. Agalsidase alfa was safe and well tolerated with all schedules. In conclusion, the primary analyses did not find weekly infusions of agalsidase alfa to be statistically better than the approved dosing schedule however the data indicates that further studies with more patients over a longer period are required to more accurately determine the optimum dose and schedule.

Effective treatment of an elderly patient with Gaucher's disease and Parkinsonism: a case report of 24 months' oral substrate reduction therapy with miglustat.

We report here the results of 24 months' treatment with oral miglustat of a patient with mild-to-moderate Gaucher's disease (GD) and Parkinsonism. The patient's progressive Parkinsonian tremor, in addition to restricted vascular access, necessitated switching treatment for GD from intravenously infused enzyme replacement therapy (ERT) that had been administered for the previous 7 years. With control of haematological parameters and markers of GD activity improved or maintained and no notable adverse effects, miglustat treatment proved an effective and well-tolerated therapeutic alternative to ERT. Oral miglustat should be considered for the treatment of patients with type I GD and concurrent movement disorders who are unsuitable for ERT.

Intravenous enzyme replacement therapy: better in home or hospital?

This article evaluates satisfaction with enzyme replacement therapy (ERT) at home and at hospital in adult patients with Fabry and Gaucher diseases. A questionnaire was developed and sent to 34 patients with Fabry disease who were receiving ERT with agalsidase alfa (Replagal) and to 49 patients with type I Gaucher disease who were receiving ERT with glucocerebrosidase (Cerezyme). Of the 45 returned questionnaires, 20 were from patients with Fabry disease and 25 from patients with Gaucher disease. Hospital treatment visits were reported as stressful by 18 patients (40%), whereas only 4 (9%) patients reported that home therapy was stressful. Both groups of patients adjusted well to receiving home-based therapy. Nearly all of the patients with Fabry disease (19 patients, 95%) and Gaucher disease (21 patients, 84%) preferred home-based therapy. Treatment in the home was reported as more comfortable, less stressful, more effective and had less impact on family life. Only 4 (9%) patients chose to continue receiving infusions in hospital. The majority of patients with Fabry disease and Gaucher disease found home-based therapy to be more convenient and less stressful than hospital-based therapy.

Acute generalized Hailey-Hailey disease.

A patient with extensive histologically proven Hailey-Hailey disease is described whose initial clinical presentation was suggestive of erythema multiforme or toxic epidermal necrolysis. This potentially misleading morphology of acute proven Hailey-Hailey disease has not been described previously and may be a consequence of bacterial infection exacerbating acantholysis.

Development of a bullous pemphigoid after split-skin grafting.

An elderly female patient developed blisters localised to her split-skin donor and graft sites. Despite repeated swabs, bacteriology and virology returned negative; multiple antibiotic courses did not improve her condition, which generalised within weeks. Histology and immunofluorescence confirmed a clinical diagnosis of bullous pemphigoid and her condition resolved rapidly after treatment with prednisolone. Bullous pemphigoid can be precipitated or exacerbated by surgery and the diagnosis should be considered when patients present with persistent localised or generalised blisters, especially when microbiological investigations are negative.

Faculty perspectives of health promotion in allied health curricula: results of a national survey.

More knowledge and skills related to health promotion/disease prevention are being required of health professionals. Allied health graduates entering the workforce will need academic preparation in these areas. This study assessed faculty perspectives on the status of health promotion content in allied health programs by a survey of 524 program directors. A questionnaire gathered information about perception of importance, level of representation, and method of delivery of health promotion content. Response rate was 41%. The majority of participants thought this content area was important for their programs and was highly or moderately represented in their curricula. Level of representation was significantly associated with requirement for accreditation. Programs in the Northeast were more likely to think health promotion was important and those in the West were more likely to have it integrated into their curricula. The most common delivery modality was guest lecture. Allied health is adopting health promotion curricular content, but further study is needed to assess programs and faculty expertise and identify strategies to ensure greater consistency of delivering material.

CDKN2A variants in a population-based sample of Queensland families with melanoma.

BACKGROUND: Mutations in the CDKN2A gene confer susceptibility to cutaneous malignant melanoma (CMM); however, the population incidence of such mutations is unknown. Polymorphisms in CDKN2A have also been described, but it is not known whether they influence melanoma risk. We investigated the association of CDKN2A mutations and polymorphisms with melanoma risk in a population-based sample of families ascertained through probands with melanoma. METHODS: The 482 Queensland, Australia, families in our sample were characterized previously as having high, intermediate, or low family risk of CMM. Unrelated individuals (n = 200 families/individuals) drawn from the Australian Twin Registry served as control subjects. For individuals in the high-risk group, the entire CDKN2A gene coding region was screened for mutations by use of the polymerase chain reaction, agarose gel electrophoresis, allele-specific oligonucleotide (ASO) hybridization, and single-strand conformation polymorphism analysis. The intermediate- and low-risk families and control subjects were analyzed by ASO hybridization for a total of six recurring mutations as well as for polymorphisms at nucleotides (Nts) 442, 500, and 540. RESULTS: CDKN2A mutations were found only in the high-risk families (nine [10.3%] of 87). The prevalence of the Nt500G (guanosine) polymorphism increased linearly with increasing familial risk (two-sided P = .02) and was highest in the nine (primarily Celtic) families with CDKN2A mutations. After adjustment for ethnic origin, the relationship between risk group and the frequency of the Nt500G allele was weakened (P = .25); however, there was no relationship between ethnic origin and Nt500-polymorphism frequency among the control subjects. CONCLUSIONS: CDKN2A mutations are rare in this population (approximately 0.2% of all melanoma cases in Queensland) and appear to be associated with melanoma in only the most affected families. The Nt500G allele appears to be associated with familial risk, but this association probably reflects Celtic ancestry.

Involvement of p16CDKN2A in cell cycle delays after low dose UV irradiation.

Ultraviolet (UV) radiation contributes to the aetiology of melanoma, but the precise mechanistic details are still unclear. The CDKN2A gene which is associated with familial and sporadic melanoma, encodes a tumour suppressor, p16. We have previously shown that in response to low doses of UV radiation the level of p16 increases, and that this correlates with a G2 delay. Here we report that in melanoma cell lines which do not express p16, or express a mutant p16, no G2 delay is observed in response to UV. The loss of functional p16 also correlates with an increase in DNA damage as judged by increased numbers of bi- and multinuclear cells and cells containing 1-2 micronuclei following UV irradiation. This work provides a further link between UV radiation, CDKN2A and melanoma, suggesting that the functional inactivation of CDKN2A disrupts a p16-dependent G2 cell cycle checkpoint, thus contributing to the development of this neoplasm.

Acne fulminans and bone lesions may present to other specialties.

Acne fulminans is a rare form of acne vulgaris of acute onset, affecting mostly teenage boys and associated with a number of systemic symptoms and abnormal investigations. The occurrence of bone lesions in this condition is rare but well recognized, and often bone biopsies are performed to rule out malignancy or infection. We report a 13-year-old boy referred to the pediatric oncologists with multiple osteolytic bone lesions. He was noted to have severe acne. A potentially painful sternal bone biopsy was averted following dermatologic referral when a diagnosis of acne fulminans was made. Pediatricians and dermatologists need to be aware of this association so that unnecessary anguish and investigations can be avoided.

Oxidative signalling and gene expression during lymphocyte activation.

We previously have demonstrated an obligatory requirement for intracellular reactive oxygen species (ROS) generation during T lymphocyte activation, and have proposed that ROS may act as signalling agents in the regulation of certain cellular processes, for example, during cell cycle entry. In order to test this hypothesis, we have been interested to determine which, if any, cell cycle entry events are affected by oxidative signalling. Given the requirement for both oxidative signalling and altered gene expression during the G0 to G1 phase transition, we have attempted to establish the extent to which oxidative signalling affects global gene expression patterns during cell cycle entry, and to isolate and characterize mRNAs whose expression patterns are responsive to oxidative signalling during this process. Using differential display in a phenotypic screening approach, we have identified 10 mRNA species whose expression patterns were altered in response to inhibition of oxidative signalling during cell cycle entry. The expression patterns of 4 of these 10 mRNAs were unaffected during cell cycle arrest caused by a different mechanism, cyclosporin A-induced interference with calcineurin-mediated signalling events, implying that the altered expression patterns seen were not simply a consequence of cell cycle arrest. This suggests that the expression of these 4 mRNAs is regulated by a mechanism both necessary for cell cycle entry and sensitive to oxidative signalling. RNAse protection assays confirmed that 2 of these 4 mRNAs were indeed responsive to redox regulation. These observations strongly suggest an involvement for oxidative signalling in the regulation of gene expression during the G0 to G1 phase transition, in peripheral blood mononuclear cells at least.

Accumulation of p16CDKN2A in response to ultraviolet irradiation correlates with late S-G(2)-phase cell cycle delay.

p16 is the product of the CDKN2A locus, which is mutated or deleted in many human tumors. In response to nonlethal UVC irradiation, HeLa cells accumulate elevated levels of p16. The accumulation of p16 is delayed 8-12 h following irradiation and correlates with S-phase and G2 delays, decreasing as the cells recover and recommence normal cell growth. The maximum levels of p16 correlated with G2 delay. The UVC-induced cell cycle delay was absent in cell lines derived from HeLa that did not express p16 and in a melanoma line deleted for p16.

Keratin expression in cutaneous lichen planus.

The characteristic expression of keratins by keratinocytes is well documented. A typical 'hyperproliferative' profile of epidermal keratin expression occurs in psoriasis, wound healing and warts. This study analyses keratin expression in cutaneous lichen planus to determine abnormalities of differentiation occurring in this inflammatory disorder. Using a panel of monoclonal antibodies 28 samples (20 patients) were studied. The results showed that squamous differentiation was unaffected, with keratins K1 and K10 being expressed normally for the site sampled. The main abnormalities included extension of reactivity of the basal cell marker, LH8, into the suprabasal compartment. Keratin K17, usually restricted to adnexal structures, was variably expressed in the basal and suprabasal layers of the interfollicular epithelium of affected epidermis. Keratins K6 and K16, found suprabasally in hyperproliferative states, were detected both basally and suprabasally in all diseased samples. The keratin profile in lichen planus is analogous to the wound healing response. Suprabasal keratin K17 is found in psoriasis, wound healing and viral warts so the changes in keratin K17 may reflect hyperproliferative changes. It is likely that the changes in epidermal keratin expression are due to up-regulation of specific keratin genes by the production of cytokines and inflammatory mediators from the lymphocytic infiltrate typical of lichen planus.

The effect of interstitial hyperthermia on local pulmonary blood flow and lung parenchyma.

Hyperthermia has shown promise as an anticancer therapy, but its application to lung neoplasms has been limited by whole body hyperthermia complications and the intrathoracic location of lung neoplasms. Previous studies have shown that interstitial hyperthermia could be performed through a thoracotomy approach and that animals tolerated the procedure without biochemical or hematologic abnormalities. The normal lung's local blood flow pattern and parenchymal changes due to hyperthermia of various temperatures and durations were studied. The experimental protocol applied hyperthermia through interstitial electrodes at temperatures of 39 degrees, 41 degrees, 43 degrees, and 45 degrees C. Tissue blood flow was measured with radioactive microspheres at 20, 40, and 60 minutes of hyperthermia. Histologic examination was performed of biopsy specimens taken from the heated area, from 2 and 5 cm from the heated area, and from distant parenchyma. These initial studies demonstrate that interstitial hyperthermia in the normal lung does not cause a decrease in pulmonary vascular resistance, that interstitial hyperthermia in the normal lung at temperatures of 43 degrees or 45 degrees C for durations of longer than 20 minutes decreases local pulmonary blood flow, that interstitial hyperthermia causes mild vascular disruption at temperatures of 39 degrees C or greater in the heated area but does not affect adjacent or distant lung parenchyma, and that lung hyperthermia causes generalized vascular disruption with severe widening of the pulmonary interstitium and severe hemorrhage in the heated areas when temperatures of 43 degrees or 45 degrees C are applied. Because interstitial hyperthermia affected only local lung damage, it may be applicable in the treatment of localized lung tumors.