Faculty Bibliography

BACKGROUND AND OBJECTIVE/OBJECTIVE:Methylating agents are effective chemotherapy agents for Hodgkin lymphoma, but are associated with the development of second primary cancers. Cytotoxicity of methylating agents is mediated primarily by the DNA mismatch repair (MMR) system. Loss of MLH1, a major component of DNA MMR, results in tolerance to the cytotoxic effects of methylating agents and persistence of mutagenised cells at high risk of malignant transformation. We hypothesised that a common substitution in the basal promoter of MLH1 (position -93, rs1800734) modifies the risk of cancer after methylating chemotherapy. METHODS:133 patients who developed cancer following chemotherapy and/or radiotherapy (n = 133), 420 patients diagnosed with de novo myeloid leukaemia, 242 patients diagnosed with primary Hodgkin lymphoma, and 1177 healthy controls were genotyped for the MLH1 -93 polymorphism by allelic discrimination polymerase chain reaction (PCR) and restriction fragment length polymorphism assay. Odds ratios and 95% confidence intervals for cancer risk by MLH1 -93 polymorphism status, and stratified by previous exposure to methylating chemotherapy, were calculated using unconditional logistic regression. RESULTS:Carrier frequency of the MLH1 -93 variant was higher in patients who developed therapy related acute myeloid leukaemia (t-AML) (75.0%, n = 12) or breast cancer (53.3%. n = 15) after methylating chemotherapy for Hodgkin lymphoma compared to patients without previous methylating exposure (t-AML, 30.4%, n = 69; breast cancer patients, 27.2%, n = 22). The MLH1 -93 variant allele was also over-represented in t-AML cases when compared to de novo AML cases (36.9%, n = 420) and healthy controls (36.3%, n = 952), and was associated with a significantly increased risk of developing t-AML (odds ratio 5.31, 95% confidence interval 1.40 to 20.15), but only in patients previously treated with a methylating agent. CONCLUSIONS:These data support the hypothesis that the common polymorphism at position -93 in the core promoter of MLH1 defines a risk allele for the development of cancer after methylating chemotherapy for Hodgkin lymphoma. However, replication of this finding in larger studies is suggested.

Vitiligo is a common skin disorder in which pigment is lost from the skin and adnexae. Half of all cases begin before the age of 20 years. Until recently, there was a paucity of published data regarding effective therapy of vitiligo. Current therapy is quite effective, and while many patients may not experience complete repigmentation, 50% to 75% repigmentation of vitiligo with recent onset routinely can be expected with available therapeutics.

BACKGROUND: Vitiligo is an autoimmune disorder characterized by loss of pigmentation. Phototherapy and application of topical corticosteroids are most commonly prescribed. However, these therapies are often not effective and use of corticosteroids on the face may lead to cutaneous atrophy, telangiectasia, and ocular complications. OBJECTIVE: We sought to assess the efficacy of topical tacrolimus ointment in the treatment of pediatric vitiligo. METHODS: A retrospective review was performed of 57 pediatric patients with vitiligo at two clinical sites. Patients were treated with tacrolimus ointment for at least 3 months. Clinical responses were documented during clinic visits, and by pretacrolimus and posttacrolimus photography. RESULTS: At least partial response was noted to tacrolimus ointment on the head and neck in 89%, and on the trunk and extremities in 63% of patients. Facial vitiligo of the segmental type showed the best response rate. Two patients initially experienced burning on application. CONCLUSIONS: Topical tacrolimus ointment is an effective alternative therapy for childhood vitiligo, particularly involving the head and neck.

Corticosteroids and photochemotherapy, using a combination of psoralen and ultraviolet A (PUVA) exposure, are the most widely prescribed therapies for vitiligo. These treatments are not uniformly effective and many patients have inadequate responses. Calcipotriene has been shown to be effective in adults and children with psoriasis when used as monotherapy and in combination with corticosteroids and phototherapy. We hypothesized that since the mechanisms of action for calcipotriene and corticosteroids are different, patients may develop more repigmentation with a combination of the two agents, while decreasing the side effects from both agents. Twelve patients with vitiligo (average age 13.1 years) were advised to use topical corticosteroids in the morning and topical calcipotriene in the evening. Of the 12 patients, 83% responded to therapy, with an average of 95% repigmentation by body surface area. Four of the patients who responded had previously failed trials of topical corticosteroids alone. All of the patients in this group had repigmentation. Eyelid and facial skin responded best to this therapy. None of the patients had adverse reactions to the treatment. Our results show that topical calcipotriene in combination with corticosteroids can repigment vitiligo, even in those patients who were previous topical corticosteroid failures.

Psoriasis is a chronic skin disorder that affects approximately 2% of the US and European populations. Psoriatic lesions are extremely characteristic of the disease, which allows for simple diagnosis. A clear understanding of the pathogenesis of psoriasis does not yet exist. Hyperproliferation of keratinocytes is a further characteristic feature. Studies have depicted that the epidermal cell cycle of psoriatic lesions is shortened by approximately eight-fold more than normal. The lesions are classified as erythrosquamous, due to the erythema which develops asa result of involvement of the vasculature, and the involvement of the epidermis with scale formation. The diagnosis of psoriasis can usually be established on clinical grounds. If the clinician is in doubt, a small cutaneous punch biopsy and subsequent histopathological examination can be performed. There are multiple therapeutic options for psoriasis. First-line therapy for patients with moderate to severe psoriasis is the application of topical agents, followed by phototherapy (UVB) for more extensive disease. If extensive disease does not respond to UVB, second-line agents include psoralen plus UVA (PUVA), methotrexate, cyclosporine or other systemic agents, including novel biologic therapies. New psoriasis treatment regimens have been developed and include combination, rotational and sequential therapy.