Cutaneous hyperpigmentation and familial gastrointestinal stromal tumour associated with KIT mutation.

Gastrointestinal stromal tumours (GISTs) are mesenchymal tumours arising in the gastrointestinal tract. Early detection, before metastasis occurs, is important as complete surgical excision achieves cure. Approximately 85% of GISTs are associated with mutations in the KIT gene, and although the majority of GISTs are sporadic, familial GISTs have been identified. Several families with multiple GIST tumours have also been described with various cutaneous findings including hyperpigmentation, multiple lentigines, vitiligo and urticaria pigmentosa. We discuss a 6-year-old boy who presented with an unusual pattern of hyperpigmentation in association with a family history of GIST. A causative KIT mutation was identified in DNA from the pigmented skin and from the resected GIST, and the patient was referred to the Paediatric Gastroenterology department for GIST screening. The term 'GIST cutaneous hyperpigmentation disease' has been suggested previously for the association of familial GIST with cutaneous hyperpigmentation caused by a germline KIT mutation.

Management of naevus sebaceous: a national survey of UK dermatologists and plastic surgeons.

Naevus sebaceous (NS) is a congenital cutaneous hamartoma, which typically occurs on the head and neck. Historically, the treatment of choice was excision in infancy because of the potential for malignant transformation; however, recent studies suggest that this risk is < 1% and unlikely in childhood. We sent a questionnaire to UK dermatologists and plastic surgeons to investigate current management practice of NS. We found that almost a third of dermatologists still recommend excision for malignancy prevention, while over 90% of plastic surgeons consider excision, with 64% citing malignancy prevention as the reason. Plastic surgeons most commonly recommended excision in childhood, whereas dermatologists waited until adulthood. We have shown there is significant variation in practice across the UK in the management of naevus NS. It is important that patients across the UK receive the same standard of care, and therefore we advocate the development of evidence-based guidance for treatment of naevus NS.

Propranolol in the treatment of infantile haemangiomas: lessons from the European Propranolol In the Treatment of Complicated Haemangiomas (PITCH) Taskforce survey.

BACKGROUND: Oral propranolol is widely prescribed as first-line treatment for infantile haemangiomas (IHs). Anecdotally, prescribing practice differs widely between centres. OBJECTIVES: The Propranolol In the Treatment of Complicated Haemangiomas (PITCH) Taskforce was founded to establish patterns of use of propranolol in IHs. METHODS: Participating centres entered data on all of their patients who had completed treatment with oral propranolol for IHs, using an online data capture tool. RESULTS: The study cohort comprised 1097 children from 39 centres in eight European countries. 76·1% were female and 92·8% had a focal IH, with the remainder showing a segmental, multifocal or indeterminate pattern. The main indications for treatment were periocular location (29·3%), risk of cosmetic disfigurement (21·1%) and ulceration and bleeding (20·6%). In total 69·2% of patients were titrated up to a maintenance regimen, which consisted of 2 mg kg(-1) per day (85·8%) in the majority of cases. 91·4% of patients had an excellent or good response to treatment. Rebound growth occurred in 14·1% upon stopping, of whom 53·9% were restarted and treatment response was recaptured in 91·6% of cases. While there was no significant difference in the treatment response, comparing a daily maintenance dose of < 2 mg kg(-1) vs. 2 mg kg(-1) vs. > 2 mg kg(-1) , the risk of adverse events was significantly higher: odds ratio (OR) 1 vs. adjusted OR 0·70, 95% confidence interval (CI) 0·33-1·50, P = 0·36 vs. OR 2·38, 95% CI 1·04-5·46, P = 0·04, Ptrend < 0·001. CONCLUSIONS: The PITCH survey summarizes the use of oral propranolol across 39 European centres, in a variety of IH phases, and could be used to inform treatment guidelines and the design of an interventional study.

Phenotypic analysis of perennial airborne allergen-specific CD4+ T cells in atopic and non-atopic individuals.

BACKGROUND: Accumulating evidence suggests that T cells play an important role in the pathogenesis of atopic dermatitis (AD); yet, little is known of the differentiation status of CD4+ T cells specific for common environmental allergens, such as the major cat allergen, Fel d 1. OBJECTIVE: To determine the frequency, differentiation phenotype and function of circulating Fel d 1-specific CD4+ T cells in adult individuals with severe persistent AD in comparison with healthy controls. METHODS: Using HLA class II tetrameric complexes based on a HLA-DPB1*0401-restricted Fel d 1 epitope, ex vivo and cultured T cell frequency and phenotype were analysed in individuals with AD and healthy controls. Cytokine secretion was measured by ex vivo and cultured IL-4 and IFN-γ ELISpots. RESULTS: Ex vivo Fel d 1-specific DPB1*0401-restricted CD4+ T cells in both atopics and non-atopics express high levels of CCR7, CD62L, CD27 and CD28, placing the cells largely within the central memory subgroup. However, the functional phenotype was distinct, with greater IL-4 production from the cells derived from atopics, which correlated with disease severity. CONCLUSIONS AND CLINICAL RELEVANCE: Circulating Fel d 1-specific DPB1*0401-restricted CD4+ T cells in both atopic and non-atopic donors maintain a central memory phenotype; however in atopics, the cells had greater Th2 effector function, compatible with a disease model of altered antigen delivery in atopic individuals.

The high rate of familial lichen sclerosus suggests a genetic contribution: an observational cohort study.

BACKGROUND: Familial lichen sclerosus (LS) has been described in only 37 families. We feel that the association is under-reported. OBJECTIVES: To determine the percentage of patients with LS who have a positive family history. METHOD: A large observational-cohort study of a total of 1052 females at vulval clinics within a University Hospital with a diagnosis of LS of the vulva (clinical diagnosis was confirmed in 80% of cases by histology). Patients were questioned as to family history of LS or balanitis xerotica obliterans; male circumcision for medical reasons; vulval cancer; and routine medical and family history. The outcome was the presence or absence of personal or family history of LS, autoimmune disorder or vulval cancer. RESULTS: In total 1052 patients were investigated. Of these, 126 (12%) had a positive family history of LS. These patients belonged to 95 families. Vulval cancer was significantly increased in those with a family history of LS compared with those without (4.1% vs. 1.2%, P < 0.05). There was more associated autoimmune disease in familial LS than in sporadic LS, although this was not statistically significant. (7% vs. 5%, P > 0.2). CONCLUSION: Our data from a large cohort of patients with LS provide evidence of an increased risk for family members to develop LS. This indicates a likely genetic component in the aetiology of LS.

Frequencies of circulating allergen-specific T cells temporally associate with longitudinal changes in severity of cutaneous atopic disease.

Increased levels of allergen-specific T-cells have been documented in the peripheral blood of patients with atopic dermatitis (AD) compared with nonatopic controls. However, little is known about how these relate to disease severity. This study sought to examine if frequencies of circulating allergen-specific T cells correlate with changes in clinical disease severity in a cohort of seven adults with AD who were positive for human leucocyte antigen DRB1*1501. We found that frequencies of allergen-specific CD4+ T cells across the study group were not significantly (P > 0.05) associated with clinical disease severity; however, longitudinal changes within an individual did correlate significantly (P < 0.01) with changes in disease severity. These findings support a role for allergen-specific T-cells in disease pathogenesis.

Spontaneous resolution of basal cell carcinoma in naevoid basal cell carcinoma syndrome/Gorlin's syndrome.

We describe a 10-year-old patient with naevoid basal cell carcinoma syndrome (NBCCS) which was diagnosed when she was 3 years old. She has developed multiple basal cell carcinomas (BCCs) over this time, in particular on her face and trunk. However, we are interested to report that at least two have resolved spontaneously over 2 years without any treatment. This phenomenon has not previously been reported and we believe that it could be important for understanding lesional biology and for future approaches to management.

Platelet-derived growth factor receptor-alpha-associated hypereosinophilic syndrome and lymphomatoid papulosis.

Fip1-like 1/platelet-derived growth factor receptor-alpha (FIP1L1/PDGFRA)-positive hypereosinophilic syndrome is a rare disorder with a poor prognosis if untreated and for which treatment with imatinib mesilate is highly effective. A 33-year-old man presented with recurrent papular skin lesions and marked peripheral eosinophilia. Skin biopsy revealed proliferation of CD30(+) T cells consistent with lymphomatoid papulosis (LyP), whereas molecular analysis of peripheral blood mononuclear cells demonstrated the presence of the FIP1L1/PDGFRA fusion gene. As the presence of this gene has important prognostic and therapeutic implications, this report underscores the importance of molecular testing in the evaluation of patients with LyP and peripheral eosinophilia.

Brief substance use screening instruments for primary care settings: a review.

Chemical dependence, including nicotine, alcohol, prescription drugs, and illicit drugs, is one of the leading causes of morbidity and mortality in the United States. Primary care physicians and nurses routinely provide preventive health care and rely on routine screening to detect diseases and promote wellness. These primary care practitioners are in a unique position to assess and detect such dependence at its earliest stages. However, previous research indicates that little such screening is actually conducted. This literature review gathered and examined substance use screening instruments in four categories to assess their feasibility for use in primary care settings. Although substance use screening tools are available, most are not appropriate for screening in a primary care setting. There clearly remains a need for the development of a valid, reliable screening instrument that can be easily incorporated into the practices and procedures found in primary care settings.

Small intestinal submucosa: a rapidly resorbed bioscaffold for augmentation cystoplasty in a dog model.

The extracellular matrix (ECM) of porcine small intestinal submucosa (SIS) has been shown to serve as a resorbable scaffold for tissue repair and remodeling in several body locations including the urinary bladder. The rate of resorption and extent of SIS degradation are unknown. Nine dogs were divided into three equal groups. Approximately 40% of the anterior dome of the urinary bladder was resected in each dog and replaced with porcine SIS. One group of dogs was sacrificed at each of 4, 8, and 12 weeks after surgery and the fate of the implanted SIS determined by immunohistochemical methods using a monoclonal antibody specific for porcine-derived SIS. By 4 weeks after surgery, only scattered remnants of SIS were present in the remodeled urinary bladder and these positively staining foci were surrounded by an extensive new host derived ECM and neovascularization. There was a continuous layer of transitional epithelium on the luminal surface by 4 weeks. No evidence for the originally implanted SIS could be found at either 8 or 12 weeks and bundles of organized smooth muscle cells were present at the operative site. In summary, SIS is rapidly and extensively degraded when used as a bioscaffold for augmentation cystoplasty in the dog model.

Grafting of ethylene glycol-butadiene block copolymers onto dimethyl-dichlorosilane-coated glass by gamma-irradiation.

Amphipathic ethylene glycol-butadiene block copolymers (PEG-PB) with different chain lengths of poly(ethylene glycol) (PEG) were synthesized by reacting poly(ethylene glycol methyl ether) (m-PEG, mol. wt = 350, 550, 750, 2000 and 5000) with telechelic polybutadiene (PB). The PEG-PB copolymers formed were covalently grafted to dimethyldichlorosilane-coated glass (DDS-glass) by gamma-irradiation. The PEG-grafted surface was characterized by measuring advancing and receding contact angles, fibrinogen adsorption, the number of adherent platelets and the area of spread platelets. The grafting efficiency was measured indirectly from the ability of the surface to prevent platelet adhesion. The total dose of gamma-irradiation necessary for grafting of PEG-PB onto DDS-glass in aqueous solutions was less than 0.24 Mrad at atmospheric pressure and ambient temperature. For successful grafting, the surface-adsorbed copolymers should be gamma-irradiated in the presence of water. gamma-Irradiation in the dried state did not result in copolymer grafting. The adsorption of copolymers for 30 min before exposure to gamma-irradiation was enough for effective grafting. The grafting was equally effective whether or not DDS-glass was exposed to the air-copolymer solution interface when the DDS-glass was introduced into the copolymer solution. The copolymers were able to prevent platelet adhesion only when they were adsorbed onto DDS-glass at certain bulk concentrations. Too low or too high copolymer concentrations in the adsorption solution resulted in a surface where platelets could adhere and activate. The range of copolymer concentration which prevented platelet adhesion was larger as the PEG chain length of the grafted copolymers became longer. Our data indicate that platelet-resistant surfaces can be made by grafting PEG-PB onto chemically inert surfaces by a simple gamma-irradiation process.

Improved survival in patients with poor-prognosis malignant melanoma treated with adjuvant levamisole: a phase III study by the National Cancer Institute of Canada Clinical Trials Group.

Five hundred forty-three patients with completely resected malignant melanoma who were considered to have a significant risk of developing recurrent disease were randomized to one of four study groups. One group received levamisole 2.5 mg/kg on 2 consecutive days weekly for 3 years, a second group received bacillus Calmette-Guérin (BCG) for 3 years. A third group alternated 8-week courses of BCG and levamisole for 3 years and a fourth group underwent clinical assessment at the same frequency as the three treatment groups. The median duration of follow-up is 8.5 years. The percentage of reduction in the death rate and the recurrence rate in the treatment groups compared with the control group was calculated using the Cox proportional hazards model and adjusted for age, sex, and stage as covariants. The patients treated with levamisole were estimated to have a 29% reduction in both the death rate (P = .08) and the recurrence rate (P = .09) compared with patients receiving no further treatment. Fifty-five patients discontinued levamisole early because of gastrointestinal intolerance or arthralgia, myalgia, fever, and immune leukopenia. The patients treated with BCG alternating with levamisole experienced a 10% reduction in the death rate and a 6% reduction in the recurrence rate, and the patients treated with BCG alone experienced a 4% reduction in the death rate and a 3% increase in the recurrence rate compared with the control group. The degree of improvement experienced by the patients that were treated by levamisole is of sufficient magnitude to warrant further investigation of this dose of levamisole as adjuvant treatment in patients with melanoma.

Adjuvant chemoimmuno- and immunotherapy in Dukes' stage B2 and C colorectal carcinoma: a 7-year follow-up analysis.

A prospectively randomised controlled clinical trial of adjuvant therapy was undertaken, at a single-centre, population-based cancer institute, in patients with Dukes' stages B2 and C colorectal carcinoma after curative surgery. Between 1976 and 1983, 253 patients were randomised to either control (no further therapy after surgery), immunotherapy (oral bacille Calmette-Guérin [BCG] 120 mg once a month) for 5 years or chemoimmunotherapy (oral BCG as above with methyl-cyclohexyl-chloroethyl nitrosourea [meCCNU] 130 mg/m2 on day 1 and 5-fluorouracil [5-FU] 325 mg/m2/day on days 1-5 and 375 mg/m2/day on days 36-40) repeated every 10 weeks for 8 cycles. The median follow-up of patients is now 6.95 years. Of the control, immunotherapy, and chemoimmunotherapy groups 22.35%, 39.28%, and 28.57%, respectively, have relapsed. The log-rank analysis of results shows no disease-free or overall survival advantage for patients receiving adjuvant therapy compared with the control group. Patients receiving adjuvant immunotherapy for stage B2 appear to have a significantly inferior disease-free survival compared with other groups, but their overall survival is similar. There are no significant differences in disease-free or overall survival in the three groups of patients with stage C tumour. Of 82 patients dying, 78.05% died of progressive colorectal carcinoma, 13 patients developed a second malignancy; the remainder died of seemingly unrelated causes.

Natural human interferon-beta in metastatic malignant melanoma. A phase II study.

A phase II trial of natural human fibroblast interferon (HuIFN-beta) in 15 previously untreated patients with advanced metastatic malignant melanoma is reported. It was given as out-patient treatment by 30 min i.v. infusion of 60 x 10(6) U/m2/day on 4 consecutive days each week. Systemic toxicity was acceptable to all patients except one who declined further treatment. Performance status of treated patients was good. Three patients had a partial response and 3 patients had stable disease. The median time to response was 13.3 weeks and the duration of response was 22.6 weeks. Responses were seen in lungs and soft tissues only and relapses were seen particularly in the central nervous system and the liver. Overall survival of the patients was only 20.7 weeks. Those who achieved a partial remission had a median survival of 34.7 weeks and those with disease stabilisation a survival of 22.0 weeks. HuIFN-beta is shown to have anti-tumour activity in advanced metastatic melanoma, although the unit dose of HuIFN-beta is much larger than that required to achieve similar anti-tumour activity with interferon-alpha.

Adjuvant chemoimmunotherapy after regional lymphadenectomy for malignant melanoma.

Thirty patients with malignant melanoma metastatic to regional lymph nodes who underwent either a full or partial node dissection were treated with adjuvant chemoimmunotherapy (CIT). In this pilot study, 11 patients were given intravenous (i.v.) DTIC plus intradermal (i.d.) BCG (D/BCG), 19 patients received i.v. DTIC, BCNU, and hydroxyurea plus oral BCG (DBH/BCG). Their overall survival (OS) and disease-free interval (DFI) following node dissection and CIT were compared with 33 historical control (HC) patients from the preceding 4 years, matched for the known prognostic factors in melanoma. The D/BCG group received a median of five courses, the DBG/BCG group six courses. Minimum follow-up of all patients is in excess of 7 years. No significant differences were observed in either DFI or OS from diagnosis between the two treatment groups or between CIT patients and HC patients. A highly significant difference was observed in DFI and OS in favor of the partial node dissection (PND) group when compared with full node dissection (FND) group. No other known variables in the PND group accounting for their improved survival are noted. Five patients in DBH/BCG and three in D/BCG group are still alive 84-114 months after completing therapy.

Combination of fibroblast interferon (HuIFN beta), carboxamide (DTIC), and cimetidine for advanced malignant melanoma.

In vitro synergism between interferons (IFNs) and chemotherapeutic drugs has been demonstrated, and an enhancement of IFN's antiproliferative effects when combined with cimetidine has been suggested in melanoma patients. In this pilot study, 12 patients with advanced malignant melanoma received HuIFN beta by 30 min i.v. infusion at 30 X 10(6) u/m2 day for 4 days, followed by i.v. decarbazine (DTIC) 1.0 g/m2 on day 5, repeated every 4 weeks. Oral cimetidine, 300 mg q.i.d., was given continuously. All the patients had visceral (bulky) metastases. No objective responses were observed; however, two patients had stable diseases for 16 and 20 weeks, respectively. Mild chills and fever with IFN, and mild to moderate emesis with DTIC, were noted. No additive haemopoietic or hepatic toxicity was observed. Combination of HuIFN beta, DTIC, and cimetidine is relatively nontoxic, but does not appear to have a significant antitumor activity in patients with advanced malignant melanoma.

Radioiodinated peanut lectin: clinical use as a tumour-imaging agent and potential use in assessing renal-tubular function.

Peanut lectin (PNA) has been shown to have a high affinity for Thomsen-Friedenreich (T) antigen, which is associated with the membrane of many solid tumour cells. PNA labelled with 131I was used as a tumour-imaging substance in patients with known metastatic cancer. Serial gamma scintiscans were obtained in 17 patients following a single injection of 131I-labelled PNA. Only in 1 patient was this technique able to reveal a known metastasis at analogue imaging. In the remaining patients, no visible uptake of 131I-PNA could be demonstrated at sites of known metastases. PNA is rapidly excreted through the kidneys and localizes in the renal tubules. As a tumour-imaging agent, 131I-PNA appears to be without value, but its renal-excretory characteristics make it a potentially useful agent for the in vivo assessment of renal-tubular disorders.

Extended phase I study of human beta-interferon in human cancer.

Ten patients with advanced cancer were treated with weekly intravenous escalating doses of human beta-interferon (HuIFN beta) 4 days each week. The starting dose of HuIFN beta was 3.0 X 10(6) units/m2 and the dose was doubled each week until dose-limiting toxicity was observed. Subjective toxicity included mild fevers and chills, malaise and flu-like symptoms. The lowest dose which caused suppression of the platelet and/or white cell count was 64 X 10(6) units daily, and the maximum dose given was 320 X 10(6) units daily. Both subjective and objective toxicity were not dose-related, easily managed and reversible. Serum interferon levels and the duration of measurable interferon activity on natural killer cells was in general dose-dependent. Two patients had an objective partial response, and two others showed stable disease while receiving HuIFN beta.