Effect of topical imiquimod as primary treatment for lentigo maligna: the LIMIT-1 study.

BACKGROUND: Topical imiquimod is sometimes used for lentigo maligna (LM) in situ melanoma instead of surgery, but frequency of cure is uncertain. Pathological complete regression (pCR) is a logical surrogate marker for cure after imiquimod, although residual LM and atypical melanocytic hyperplasia may not be reliably distinguished. A trial comparing imiquimod vs. surgery might be justified by a high imiquimod pCR rate. OBJECTIVES: Primary: to estimate the pCR rate for LM following imiquimod. Secondary: to assess the accuracy of prediction of pCR, using clinical complete regression (cCR) plus negative post-treatment biopsies, tolerability, resource use, patients' preferences and induced melanoma immunity. METHODS: This was a single-arm phase II trial of 60 imiquimod applications over 12 weeks for LM then radical resection. A pCR rate ≥ 25 out of 33 would reliably discriminate between pCR rates < 60% and ≥ 85%. Clinical response was assessed and biopsies taken after imiquimod. Patients recorded adverse events in diaries. Patient preference was measured after surgery using a standard gamble tool. RESULTS: The pCR rate was 10 of 27 (37%, 95% confidence interval 19-58%). The rate of cCR plus negative biopsies was 12 of 28, of whom seven of 11 had pCR on subsequent surgery. The median dose intensity was 86·7%. Of the 16 surveyed patients, eight preferred primary imiquimod over surgery if the cure rate for imiquimod was 80%, and four of 16 if it was ≤ 40%. CONCLUSIONS: The pCR rate was insufficient to justify phase III investigation of imiquimod vs. SURGERY: Clinical complete response and negative targeted biopsies left uncertainty regarding pathological clearance. Some patients would trade less aggressive treatment of LM against efficacy.

Phase I/II trial of a dendritic cell vaccine transfected with DNA encoding melan A and gp100 for patients with metastatic melanoma.

This trial tested a dendritic cell (DC) therapeutic cancer vaccine in which antigen is loaded using a novel non-viral transfection method enabling the uptake of plasmid DNA condensed with a cationic peptide. Proof of principle required the demonstration of diverse T lymphocyte responses following vaccination, including multiple reactivities restricted through both major histocompatibility complex (MHC) class I and II. Patients with advanced melanoma were offered four cycles of vaccination with autologous DC expressing melan A and gp100. Disease response was measured using Response Evaluation Criteria in Solid Tumours. Circulating MHC class I- and II-restricted responses were measured against peptide and whole antigen targets using interferon-γ ELIspot and enzyme-linked immunosorbent assay assays, respectively. Responses were analyzed across the trial population and presented descriptively for some individuals. Twenty-five patients received at least one cycle. Vaccination was well tolerated. Three patients had reduction in disease volume. Across the trial population, vaccination resulted in an expansion of effector responses to both antigens, to the human leukocyte antigen A2-restricted modified epitope, melan A ELAGIGILTV, and to a panel of MHC class I- and II-restricted epitopes. Vaccination with mature DC non-virally transfected with DNA encoding antigen had biological effect causing tumour regression and inducing diverse T lymphocyte responses.

Toxic epidermal necrolysis: retrospective analysis of 21 consecutive cases managed at a tertiary centre.

BACKGROUND: Toxic epidermal necrolysis (TEN) is a rare, severe blistering disease. Outcome data in British patients is limited to case reports or small series. AIMS: To characterize the aetiology, clinical features, complications and outcome in TEN, and to evaluate the effect of treatments including intravenous immunoglobulin (IVIg). METHODS: This was a retrospective study of 21 consecutive patients with histologically confirmed TEN presenting between 1995 and 2007 to a tertiary referral unit for TEN in a university hospital in the UK. RESULTS: The mean age of the patients was 53.5 years. The mean surface area of denuded skin was 44% (range 30-90%). An adverse drug reaction was implicated in all patients, with mean time of TEN onset being 17 days (range 2-41 days) after initial drug exposure. The SCORTEN index was calculated in 19 patients (median SCORTEN 3, range 2-5). The SCORTEN predicted 7.3 deaths in this cohort, and 7 deaths were seen in the group of patients for whom SCORTEN was calculated. The overall mortality was 8/21 (38%). Ten patients received corticosteroids before transfer to our centre. In the steroid-treated group 4/10 patients (40%) died, and 4/11 patients (36%) who were not treated with steroids also died. Between 1995 and 2000, patients were treated with cyclophosphamide 1.5 mg/kg/day (n=2; both died) and subsequently with ciclosporin 2.5-4 mg/kg/day (n=3; 2 deaths). From 2000, patients were treated with IVIg 0.4-1 g/kg/day (n=14; 3 deaths); the SCORTEN-predicted mortality in this group was 5 deaths. Complications included sepsis (n=18), and organisms included Enterococcus, Acinetobacter, Staphylococcus aureus and methicillin-resistant S. aureus strains). Other complications included anaemia (n=17), lymphopenia (n=11) and neutrophilia (n=9). The presence of neutropenia (n=6; 4 deaths), renal impairment (n=5; 4 deaths) and disseminated intravascular coagulation (n=4; all died) were strong risk factors for mortality. Of 12 patients with ocular involvement, 6 (50%) developed symblepharon and/or visual impairment. CONCLUSIONS: This study confirmed the validity of SCORTEN in our series. In the subgroup treated with IVIg, there were three deaths, compared with the SCORTEN predicted mortality of five deaths. Corticosteroids did not seem to be beneficial.

Adjuvant interferon in high-risk melanoma: the AIM HIGH Study--United Kingdom Coordinating Committee on Cancer Research randomized study of adjuvant low-dose extended-duration interferon Alfa-2a in high-risk resected malignant melanoma.

PURPOSE: To evaluate low-dose extended duration interferon alfa-2a as adjuvant therapy in patients with thick (> or = 4 mm) primary cutaneous melanoma and/or locoregional metastases. PATIENTS AND METHODS: In this randomized controlled trial involving 674 patients, the effect of interferon alfa-2a (3 megaunits three times per week for 2 years or until recurrence) on overall survival (OS) and recurrence-free survival (RFS) was compared with that of no further treatment in radically resected stage IIB and stage III cutaneous malignant melanoma. RESULTS: The OS and RFS rates at 5 years were 44% (SE, 2.6) and 32% (SE, 2.1), respectively. There was no significant difference in OS or RFS between the interferon-treated and control arms (odds ratio [OR], 0.94; 95% CI, 0.75 to 1.18; P =.6; and OR, 0.91; 95% CI, 0.75 to 1.10; P =.3; respectively). Male sex (P =.003) and regional lymph node involvement (P =.0009), but not age (P =.7), were statistically significant adverse features for OS. Subgroup analysis by disease stage, age, and sex did not show any clear differences between interferon-treated and control groups in either OS or RFS. Interferon-related toxicities were modest: grade 3 (and in only one case, grade 4) fatigue or mood disturbance was seen in 7% and 4% respectively, of patients. However, there were 50 withdrawals (15%) from interferon treatment due to toxicity. CONCLUSION: The results from this study, taken in isolation, do not indicate that extended-duration low-dose interferon is significantly better than observation alone in the initial treatment of completely resected high-risk malignant melanoma.

The substrate determines the rate and pattern of neutral lipid synthesized by isolated human sebaceous glands.

Lipogenesis from different substrates was determined in isolated human sebaceous glands after 17-20 h in culture. Rates of total lipogenesis were 1003 +/- 141, 842 +/- 90, 481 +/- 57 pmol.h-1 gland-1 +/- SE from acetate, lactate and glucose, respectively, when present as sole substrates: the rate from glucose was significantly lower (P less than 0.01). Squalene synthesis was greatest from acetate at 479 +/- 44 pmol.h-1.gland-1; significantly higher than from lactate (281 +/- 45 pmol.h-1.gland-1) or glucose at 119 +/- 18 pmol.h-1.gland-1. Wax ester plus cholesterol ester synthesis showed similar dependence on substrate but triglyceride synthesis was unaffected. We conclude that the added substrate determines both the rate and pattern of non-polar lipid synthesized by isolated human sebaceous glands.

Benign pigmented nevi in children. Prevalence and associated factors: the West Midlands, United Kingdom Mole Study.

BACKGROUND AND METHODS: Prevalence of benign melanocytic nevi (moles) has been shown to be a major predictor of malignant melanoma. In this study the prevalence of moles in a group of 2140 children, aged 4 to 11 years, was determined. A standard questionnaire was completed by the parents of each child and included information on environmental and life-style factors. Examination data for each child were linked to the data obtained from the questionnaire. RESULTS: Prevalence increases rapidly throughout childhood and studies of children may indicate which factors contribute to mole development. Boys had more moles than girls, as did white children when compared with other ethnic groups. Prevalence of moles increased with age in children of both sexes. Among whites, skin color had little influence on mole prevalence. The following characteristics, however, were associated with an increased prevalence of moles: a propensity to burn rather than tan, a history of sunburn, a tendency to freckle, and a life-style involving increased sun exposure. A striking positive association between prevalence of moles and number of foreign holidays in a hot climate was observed. This association was independent of a history of sunburn. CONCLUSIONS: The study supports the hypothesis that environmental factors influence the prevalence of moles in childhood.

Effects of isotretinoin on serum lipids and lipoproteins, liver and thyroid function.

Seven patients with severe rosacea were treated with 1 mg/kg per day isotretinoin for 12 wk. There were significant increases in serum triglyceride (p less than 0.001) and cholesterol (p less than 0.001). Triglyceride associated with very low density lipoprotein (VLDL), low density lipoprotein (LDL) and high density lipoprotein (HDL) increased (p less than 0.01), cholesterol in VLDL and LDL increased (p less than 0.01), and levels of HDL cholesterol decreased (p less than 0.01). There were changes in indices of liver function, with increased levels of gamma-glutamyltransferase (GGT) (p less than 0.01), alkaline phosphatase (ALP) (p less than 0.01) and aspartate aminotransferase (AST) (p less than 0.01), and decreased bilirubin levels (p less than 0.05). Although levels of thyroxine and triiodothyronine were lower after treatment (p less than 0.05), there were no changes in basal levels of thyroid-stimulating hormone (TSH), luteinizing hormone (LH) or follicle-stimulating hormone (FSH), and responses to thyrotrophin releasing hormone (TRH) and luteinizing hormone releasing hormone (LHRH) were unchanged. These changes may partially be explained by induction of hepatic microsomal enzymes by isotretinoin.

Evidence for a cerebral cholinergic system and suggested pharmacological patterns of neural organization in the prostomium of the polychaete Nereis virens (SARS).

The histological visualization of choline acetyltransferase (CAT) and acetylcholinesterase (AChE) on frozen sections of prostomia of Nereis virens indicate a concentration of cholinergic activity in the anterior brain. Components are probably sensory epithelial cells with cholinergic axons entering the brain in cephalic nerves and efferent cholinergic axons to prostomial muscle leaving the brain in the same nerves. There are also subepidermal cholinergic cells that may be second order motor neurons serving epidermal mucous cells. The smaller, second lobe of the corpora pedunculata and its associated vertical fibre tract are CAT(+) and appear continuous, on each side of the cerebral ganglion, with a dorsal and ventral longitudinal bundle of AChE(+) fibers. This system tapers to nothing at the level of the posterior eyes. There is a small AChE(+) component to each optic nerve and AChE is present in the nuchal epithelium. These observations are discussed in relation to earlier studies on aminergic and neurosecretory activity in the same ganglion.

Uptake of tritium-labelled biogenic amines by the prostomium of the polychaete Nereis virens (Sars) (Annelida).

The uptake of tritium-labelled 5-HT, noradrenaline, 5-hydroxytrytophan, DOPA and dopamine by the cerebral ganglion and prostomial nervous system of the polychaete Nereis virens has been examined using radioautography at the level of the light microscope. Pronounced uptake of (3)H-5HT occurred in the antennal, palpal, tegumentary and nuchal nerves as well as in ganglionic nuclei 13, 14, 15, 16, 17, 20, 24 and 25, the mid-brain neuropile, the neurosecretory neuropil and the infracerebral organ; (3)H-NA uptake was observed in small cells in the prostomial epidermis, and the infracerebral organ; (3)H-dopamine only in one of two common types of epidermal mucus cells. Prostomial muscles labelled generally with (3)H-NA and at specific sites with (3)H-5HT. These observations support the concept of an efferent serotonergic system originating in several cerebral ganglionic nuclei and serving prostomial muscle and epidermis. Evidence for an afferent adrenergic system is less substantial. The role of dopamine remains obscure.

Evidence that method of use, dose and duration of treatment with benzoyl peroxide and tetracycline determines response of acne.

Treatment of acne prior to referral was recorded retrospectively in 72 patients alleged to have responded inadequately; 60% had used benzoyl peroxide (BP) but most applied it to lesions only. Although 86% had used tetracycline, most did not take it correctly for maximum absorption and took less than 1 g/day. Most patients used both drugs for less than three months. Eight-two patients referred because of inadequate response were treated with: (I) 5% benzoyl peroxide (BP) (23 patients); (II) 5% BP and 0.5 g/day oxytetracycline (OTC) (24 patients); (III) 5% BP and 1 g/day OTC (18 patients); (IV) 5% BP and 1.5 g/day OTC (17 patients). BP was applied incrementally from 30 min up to 8-10 hours daily to the entire area affected and OTC taken as a single morning dose. Median grade of severity (0-10 analogue scale) fell by 2 in Groups I and II (P less than 0.05), by 2.5 in Group III (P less than 0.05) and by 3 in Group IV (P less than 0.05); number of lesions fell by 56% +/- 7% (s.e.), (P less than 0.001) 70% +/- less than 10% (P less than 0.001), 75% +/- 8% (P less than 0.001) and 78% +/- 10% (P less than 0.001) respectively and treatment was well tolerated. Thus, although effective drugs are frequently prescribed in acne, method of use, dose and duration are likely to determine response.

Kasabach-Merritt syndrome exacerbated by platelet transfusion.

Kasabach-Merritt syndrome is a complication of complex haemangiomas. We present a case in which standard treatment including platelet transfusion appeared to prolong and exacerbate subcutaneous bleeding.

Urticaria pigmentosa and acute lymphoblastic leukaemia.

Childhood urticaria pigmentosa is generally considered to have a good prognosis with the majority of cases undergoing spontaneous resolution. However, there have been a number of reports of haematological malignancies occurring in association with urticaria pigmentosa. We describe a child with extensive urticaria pigmentosa and a congenital cardiac anomaly who developed acute lymphoblastic leukaemia and suggest a possible common aetiology.

Melphalan in regional chemotherapy for locally recurrent metastatic melanoma.

In-transit metastases occur in approximately 3% of melanoma patients, can be very symptomatic and survival in this group may be prolonged. Regional chemotherapy with melphalan delivered by isolated limb perfusion (ILP) or isolated limb infusion (ILI) are effective treatment options which are generally well tolerated. ILI is a less invasive and simpler alternative to ILP. ILI is tolerated better than ILP, though is probably less effective. Complete response rates are 45- 69% for ILP and 23-44% for ILI. The limb is often warmed to lower temperatures in ILI compared to ILP and the limb becomes progressively more hypoxic and acidotic during ILI, each of these parameters potentially having an effect on outcome. ILP & ILI are used primarily as palliative options when excision of in-transit metastases is unfeasible but can be used as an adjunctive procedure to surgery, for other tumour types such as merkel cell carcinoma, and can be repeated if indicated. For ILI correction of melphalan dose for ideal body weight has been shown to substantially decrease the rates of severe local toxicity while maintaining complete response rates, but overall response rate is reduced. Combination treatment with tumour necrosis factor α has been used with variable outcomes and new combinations with buthionine sulfoximine and ADH-1 are being investigated.

Revised UK guidelines for the management of cutaneous melanoma 2010.

These guidelines for the management of cutaneous melanoma present an evidence-based guidance for treatment, with identification of the strength of evidence available at the time of preparation of the guidelines, and a brief overview of epidemiology, diagnosis, investigation, and follow-up.