Non-melanoma skin cancer in Canada chapter 1: introduction to the guidelines

BACKGROUND: Non-melanoma skin cancer (NMSC), including basal and squamous cell carcinoma, represents the most common malignancy. OBJECTIVE: The aim of this document is to provide guidance to Canadian health care practitioners on NMSC management. METHODS: After conducting a literature review, the group developed recommendations for prevention, management, and treatment of basal cell carcinomas, squamous cell carcinomas, and actinic keratoses. These tumour types are considered separately in the accompanying articles. The Grading of Recommendations Assessment, Development and Evaluation system was used to assign strength to each recommendation. RESULTS: This introduction describes the scope and structure of the guidelines and the methods used to develop them. The epidemiology of NMSC is reviewed, as are the pathophysiologic changes occurring with damage to the skin, which lead to the formation of actinic keratoses and invasive squamous or basal cell carcinomas. CONCLUSIONS: This introduction describes the need for primary prevention and offers an overview of treatment options that are discussed in later chapters of the guidelines.(AU)

Efficacy of ISA247 in plaque psoriasis: a randomised, multicentre, double-blind, placebo-controlled phase III study.

BACKGROUND: The use of systemic calcineurin inhibitors for the treatment of patients with psoriasis is limited by toxicity, particularly nephrotoxicity. ISA247, a novel inhibitor, was effective and well tolerated in a phase II study of patients with plaque psoriasis. Therefore its efficacy was assessed in this phase III study. METHODS: 451 patients aged 18-65 years with plaque psoriasis involving at least 10% of the body surface area were randomly assigned in equal proportions to receive placebo or ISA247 at 0.2 mg/kg, 0.3 mg/kg, or 0.4 mg/kg orally twice a day in dermatology clinics. The primary endpoint was a 75% reduction in the psoriasis area and severity index (PASI 75) score at week 12. Treatment allocation was concealed from patient and physicians doing the assessments by use of sealed envelopes. The method of analysis was by modified intention to treat. The trial is registered at ClinicalTrials.gov, number NCT00244842. FINDINGS: 107, 113, and 116 patients were assigned to the ISA247 0.2 mg/kg, 0.3 mg/kg, and 0.4 mg/kg groups, respectively, and 115 to the placebo group. At week 12, PASI 75 scores were achieved in the ISA247 0.2 mg/kg, 0.3 mg/kg, and 0.4 mg/kg groups by 14 (16%; 95% CI 9-24) of 105, 26 (25%; 17-24) of 111, and 44 (47%; 27-57) of 113 patients, respectively, and in the placebo group by 4 (4%; 0-8) of 113 patients. Efficacy was maintained during 24 weeks. Mild to moderate glomerular filtration rate reductions were noted in seven patients in the ISA247 0.4 mg/kg group and in one in the ISA247 0.3 mg/kg group. ISA247 blood concentrations showed a strong correlation with mean percentage reduction in PASI. INTERPRETATION: ISA247 was safe and effective in the treatment of patients with moderate to severe psoriasis during 24 weeks, with the highest dose providing the best efficacy. The strong correlation between ISA247 concentrations and efficacy might allow for accurate dosing of patients compared with existing calcineurin inhibitors.

Treatment of acne vulgaris and prevention of acne scarring: canadian consensus guidelines.

Acne affects approximately 95% of the population at some point during their lifetime.1 This common disorder can range from mild to severe forms, cause sometimes extensive scarring, and can last well into the fourth and fifth decades. Effective therapeutic agents are available to both treat acne and prevent ongoing disease. Despite this, dermatologists frequently see patients with significant acne scarring because many patients delay seeking medical attention for acne and many practitioners procrastinate over using effective antiscarring options. In patients who already demonstrate scarring, repeated courses of antibiotics only result in recurring acne and additional scarring. This, in turn, exacerbates the despair and other adverse psychosocial effects of the disease. There are a variety of agents and devices to help acne patients with scarring. However, successful treatment cannot be guaranteed, and in most cases residual scarring will be evident. Thus, the most effective way of managing acne scarring is to prevent its occurrence in the first place. Although we currently have a number of effective antiacne agents to control the disease, such as antibiotics and hormonal agents, isotretinoina is the only agent that has been shown to induce long-term drug-free remission and curative potential.

Coordinated mRNA expression of c-Kit with tyrosinase and TRP-1 in melanin pigmentation of normal and malignant human melanocytes and transient activation of tyrosinase by Kit/SCF-R.

The proto-oncogene c-Kit encodes a membrane receptor protein with intrinsic tyrosine kinase activity. Activation of c-Kit induces cell proliferation, differentiation or migration among different cell types. The present study provides evidence that c-Kit plays an important role in the cell differentiation rather than in cell proliferation in pigment cells. We found that normal human melanocytes and a limited number of melanoma cells, e.g. WM35, WM39 and G361 cell lines, expressed the c-Kit gene together with tyrosinase and TRP-1 genes. When exposed to alpha-melanocyte stimulating hormone, these three cell lines also showed an increased tyrosinase (dopa-oxidase) activity. By incubating these cells with 20 ng/ml of stem cell factor (SCF) which is a ligand of c-Kit receptor, we found a transient increase of tyrosinase activity 2-4 h post-incubation, indicating an early response of tyrosinase activation, either by elevating tyrosinase protein expression or by tyrosinase protein modification (e.g. phosphorylation). However, Western blot analysis using anti-tyrosinase antibody suggested that there was no change of tyrosinase protein expression between SCF-treated and non-treated cells. We therefore suggest that protein modulation of tyrosinase (e.g. phosphorylation) plays an important role in c-Kit-induced melanogenesis.

Divalent cations control cell-substrate adhesion and laminin expression in normal and malignant human melanocytes in early and late stages of cellular differentiation.

Integrins are a class of adhesion molecules that depends on divalent cations for proper function. This study examined whether human normal melanocytes and malignant (metastatic) melanocytes with early and late stages of cellular differentiation (G361 and SK-MEL-23, respectively) would differ in integrin-mediated adhesion to fibronectin, laminin, as well as collagens type I and type IV, and whether divalent cations could influence the strength of adhesion ability. Integrin subunit expression was determined by flow cytometry using integrin subunit-specific antibodies as probes. Integrin-specific adhesion was determined using soluble glycine-arginine-glycine-asparagine-serine peptide and integrin subunit-specific antibodies as functional blocking agents. This study shows that both normal and malignant melanocytes adhere to extracellular matrices in a divalent cation-dependent manner, and adhesion strength varies with the cation species. Integrins can be rapidly activated by small alterations in cation concentration, manganese being the most potent. There were marked differences in substrate adhesion between normal melanocytes and metastatic malignant melanoma cells, but these differences were not related to the stage of cellular differentiation. All the three cell types, however, expressed the same integrin subunits at approximately the same levels. This suggests that substrate adhesion of melanocytes and melanoma cells might involve some integrin-independent mechanisms as well. Manganese, in particular, appears to cause adhesion by activating both integrin-dependent and -independent mechanisms.

Underrecognition of chylomicronemia as a cause of acute pancreatitis.

OBJECTIVE: To determine how often chylomicronemia is considered by admitting physicians as a possible cause of acute pancreatitis. DESIGN: Retrospective hospital chart review. SETTING: Tertiary care teaching hospital in an urban centre with a referral population of 1 million. PATIENTS: All patients admitted with acute pancreatitis from Jan. 1, 1985, to Dec. 31, 1987. Episodes of pancreatitis were divided into two groups: those for which a cause was known after history taking, physical examination and laboratory investigation at the time of admission (group 1) and those for which a cause was unknown after full examination (group 2). RESULTS: There were 319 episodes of chylomicronemia in 162 patients. The cause of the pancreatitis was known after examination at the time of admission in 239 (75%) of the episodes; there was hypertriglyceridemia in 7 (3%). No cause was identified after examination in the other 80 episodes (25%); chylomicronemia was considered in 18 cases (29%) and was found in 6 (33%) of them (mean serum triglyceride level 34.4 mmol/L). Of the remaining 62 episodes in group 2, 10 (16%) were later found to be caused by chylomicronemia (mean serum triglyceride level 22.6 mmol/L). Among the 80 episodes in group 2 at least one medical condition associated with chylomicronemia was present in 24. In only 7 (29%) of the 24 was chylomicronemia considered; in 6 the mean serum triglyceride level was 19.7 mmol/L. CONCLUSIONS: Although the overall detection rate of chylomicronemia was low, its presence in patients without other etiologic factors after examination may have been much higher. Consideration of chylomicronemia in this subgroup at the time of presentation may increase diagnostic yield and help prevent further occurrences of pancreatitis.

The epidermal melanin unit in the pathophysiology of malignant melanoma.

The epidermal melanin unit (EMU) denotes the symbiotic relationship between a melanocyte and a pool of associated keratinocytes. We propose to show that alterations in the biology of the EMU are the main determinant of the different patterns of intraepidermal growth of melanocytes in lentigo maligna melanoma (LMM) and superficial spreading melanoma (SSM). They also appear to affect the biosynthesis of melanin and melanosomes during malignant transformation. Findings in histochemical studies with monoclonal antibodies generated against melanosomal proteins to produce different stains of melanocytes of normal skin, dysplastic melanocytic nevi (DMN), common melanocytic nevi (CMN), LMM, and SSM have led to the suggestion that the altered melanosome synthesis is a main phenotype in the pathophysiology in neoplastic transformation of melanocytes. Altered melanin synthesis may also affect the carcinogenesis in malignant melanoma: pheomelanin is increased in malignant melanoma and DMN, but not in normal skin and CMN. Pheomelanin and its precursors could aid the malignant transformation of melanocytes through the generation of mutagenic ultraviolet photoproducts in familial DMN syndrome.

Excipients in topical corticosteroid preparations in Canada.

Topical corticosteroids are widely used for the treatment of dermatoses in Canada. The effects of the various nontherapeutic components of these formulations are less well known than those of the active ingredients and may cause adverse reactions. Information on the components is fragmentary and is scattered throughout the literature. We have attempted to consolidate this information into one source. Recent provincial legislation requiring the generic substitution of interchangeable products and the nondisclosure of all ingredients in product labelling hinder the search for an excipient that has caused an adverse reaction. Practitioner participation in the Cutaneous Adverse Reaction Registry of the Canadian Dermatology Association will identify sensitizing excipients and will support efforts by the profession to obtain more effective and safer products.

Hepatic artery aneurysm presenting as abdominal pain and hemoperitoneum.

Rupture of a hepatic artery aneurysm is one of the commonest causes of hemoperitoneum, second only to abdominal aortic rupture. The authors illustrate the difficulties of diagnosis and therapy in their description of the case of a 65-year-old man with a ruptured hepatic artery aneurysm. There are no pathognomonic features, and definitive diagnosis requires selective angiography of the hepatic artery. Early intervention by ligation or reconstruction may improve outcome but is associated with a high death rate. Selective embolization under fluoroscopic control may be preferable.

Methotrexate pneumonitis in rheumatoid arthritis: potential risk factors. Four case reports and a review of the literature.

Methotrexate pneumonitis is emerging as one of the most unpredictable and potentially serious adverse effects associated with the use of low dose, pulse methotrexate in treating rheumatoid arthritis (RA). We report 4 new cases of methotrexate pneumonitis in patients with RA and review 6 published cases. A greater than expected proportion of patients had a smoking history, preexisting pulmonary disease and were male. Prognosis was better in those patients treated with corticosteroids.