C. Lok

Randomised trial of interferon α-2a as adjuvant therapy in resected primary melanoma thicker than 1·5 mm without clinically detectable node metastases

Summary Background Owing to the limited efficacy of therapy on melanoma at the stage of distant metastases, a well-tolerated adjuvant therapy is needed for patients with high-risk primary melanoma. Our hypothesis was that an adjuvant treatment with low doses of interferon a could be effective in patients with localised melanoma. Methods After resection of a primary cutaneous melanoma thicker than 1·5 mm, patients without clinically detectable node metastases were randomly assigned to receive either 3X106 IU interferon α-2a, three-times weekly for 18 months, or no treatment. The primary endpoint was the relapse-free interval. Findings 499 patients were enrolled, of whom 489 were eligible. When used as part of a sequential procedure, interferon α-2a was of significant benefit for relapse-free interval (p=0·038). A long-term analysis, after a median follow-up of 5 years, showed a significant extension of relapse-free interval (p=0·035) and a clear trend towards an increase in overall survival (p=0·059) in interferon α-2a-treated patients compared with controls. There were 100 relapses and 59 deaths among the 244 interferon α-2a-treated patients compared with 119 relapses and 76 deaths among the 245 controls. The estimated 3-year-relapse rates were 32% in the interferon α-2a group and 44% in controls; the 3-year death rates were 15% and 21%, respectively. Only 10% of patients experienced WHO grade 3 or 4 adverse events. Treatment was compatible with normal daily life. Interpretation Adjuvant therapy of high-risk melanoma with low doses of interferon α-2a for 18 months is safe and is beneficial when started before clinically detectable node metastases develop.

Delays in diagnosis and melanoma prognosis (I): The role of patients

A prospective survey was conducted to assess the role of patients in the melanoma prognosis. Consecutive patients with primary melanoma were interviewed and examined using a comprehensive questionnaire including a psychological instrument. Main outcome measures were the delay before medical intervention and the tumor thickness. Of 590 melanomas, 70.8% were detected by patients and this proportion was higher in females. Relatives were involved in the detection of half of the cases. Median delays before the patient realized he had a suspicious lesion, before this lesion was seen by a doctor, and before the melanoma was removed were 4 months, 2 months, and 1 week, respectively. Delays up to several years were observed in some cases. The rate of self‐detection tended to be lower, the delays before seeking medical advice to be longer, and the tumor thickness to be higher in old people, in males, in lower‐educated individuals, in those living out of towns, and in people with a low awareness about melanocytic tumors than in other cases. Conversely, individuals with a high number of atypical nevi, those who were aware to be at risk, and those who regularly visited a dermatologist tended to detect their melanoma more rapidly. No specific psychological traits were associated with a late reaction, although negligence and anxiety tended to prolong the delays. Knowledge about melanoma was poor in many patients, especially in males, and wrong beliefs were widespread. This study provides the targets of future education programs. Int. J. Cancer 89:271–279, 2000.

Delays in diagnosis and melanoma prognosis (II): The role of doctors

A prospective survey was conducted to assess physician responsibility in melanoma prognosis. Consecutive patients with primary melanoma were interviewed and examined using a standardized questionnaire. Main outcome measures were medical components of the delay before tumor resection and tumor thickness. Of 590 melanomas, 29.1% were coincidentally detected by physicians and their tumor depth was lower than in melanomas detected by patients (p < 0.001). Physician sensitivity for melanoma diagnosis was evaluated at 86%. Median time intervals to propose resection and to perform removal of melanoma were short: 0 (mean 103) and 7 (mean 68) days, respectively. Melanomas were managed in an inappropriate way in 14.2% of cases. Location on acral areas and absence of pigmentation were associated with longer medical delays and more frequent inappropriate medical attitudes. Melanomas located on hardly visible areas were less frequently detected by physicians than those on visible areas. Medical delays were shorter, doctors attitude was more frequently appropriate, and melanoma thickness was lower (p < 0.001) when the patient visited a dermatologist (54.7%) than when he or she visited a general practitioner (33.4%). Our study shows that doctor responsibility accounts for only a small part of the total delay before melanoma removal. However, systematic total examination and better training of doctors, especially about unusual forms of melanoma, could still improve melanoma detection. Int. J. Cancer 89:280–285, 2000.

Neurological disorders in patients with bullous pemphigoid.

Background: Unexpected cases of bullous pemphigoid (BP) have been reported in adult patients with various neurological disorders suggesting a possible relationship between these diseases. Objectives: (1) To determine the prevalence and types of neurological disorders in patients with BP, (2) to assess patients’ functional impairment, and (3) to compare the clinical and biological findings as well as prognosis of BP patients presenting with or without neurological disorders. Methods: BP patients with neurological disorders were selected in a series of 341 consecutive BP patients treated in 20 French Dermatology Departments. Functional impairment was prospectively assessed using the Karnofsky score which is a measure of patients’ general condition. Results: At least one neurological disorder was present in 123 of the 341 BP patients (36%). They primarily consisted of dementia (n = 68; 20%; 95% CI: 16–25%), cerebral stroke (n = 52; 15%; 95% CI: 4–19%), and/or Parkinson’s disease or parkinsonism (n = 32; 9%; 95% CI: 7–13%). BP patients with neurological disease were older than patients without neurological disease (83.8 ± 7.5 years vs. 79.3 ± 10.3 years, p < 10–4). They also had a lower Karnofsky score (47 ± 19% vs. 74 ± 20%, p < 10–4). One-year overall survival rates of the two groups were 50.8% (95% CI: 41.8–59.7) and 78.7% (95% CI: 73.0–84.2), respectively (p < 10–4). In contrast, the number of bullae and main biological features at baseline were not different between the two groups of patients. Conclusion: This study demonstrated a high frequency of neurological disorders, particularly dementia, in BP patients. Most of these patients had a severe functional impairment and a poor prognosis.

Risk Factors for Relapse in Patients With Bullous Pemphigoid in Clinical Remission: A Multicenter, Prospective, Cohort Study

OBJECTIVE To identify prognostic factors for relapse in the first year after cessation of therapy in bullous pemphigoid (BP). DESIGN Prospective, multicenter, cohort study (January 1, 2000, through December 31, 2006). SETTING Fifteen French dermatology departments. Patients Patients with BP in remission under low doses of topical or systemic corticosteroids. Interventions Cessation of corticosteroid treatment (day 0) followed by a systematic clinical and immunologic follow-up. MAIN OUTCOME MEASURES The end point was clinical relapse within the first year after cessation of therapy. Associations of clinical, biological, and immunologic (including direct immunofluorescence, serum anti-basement membrane zone autoantibodies, and serum BP180 autoantibodies by enzyme-linked immunosorbent assay [ELISA] on day 0) variables with clinical relapse were assessed by means of univariate and multivariate analyses. RESULTS On day 0, 30 of 114 patients (26.3%) still had a positive result of direct immunofluorescence, 63 of 112 (56.3%) had circulating anti-basement membrane zone autoantibodies, and 34 of 57 (60%) had anti-BP180 antibodies by ELISA. At month 12, 22 patients were dead (n = 11) or lost to follow-up (n = 11), 51 were in remission, and 45 had had relapses (mean interval to relapse, 3.2 months). Factors predictive of relapse within 12 months after cessation of therapy were a positive result of direct immunofluorescence microscopy (P = .02), a greater age (P = .01), and high-titer ELISA scores (P = .02) on day 0. In multivariate analysis, the only factor independently predictive of relapse was a high-titer ELISA score on day 0 (odds ratio, 11.00; 95% confidence interval, 1.29-93.76). CONCLUSIONS High-titer anti-BP180 ELISA score and, to a lesser degree, a positive direct immunofluorescence finding are good indicators of further relapse of BP. At least 1 of these tests should be performed before therapy is discontinued.

Impact of protein deficiency on venous ulcer healing

OBJECTIVE The prevalence of protein deficiency and its impact on wound healing is not known for leg ulcers. The aim of this study was to determine the prevalence of protein deficiency in outpatients presenting with leg ulcers and the parameters prognostic value for wound outcome. DESIGN OF STUDY Prospective controlled observational study. SETTING Ambulatory patients referred for chronic wounds to four university hospitals. METHODS Consecutive out-patients with a leg ulcer present for at least 2 months, related to venous insufficiency, associated or not with moderate peripheral arterial disease (ankle-brachial pressure index > 0.7), were included in a prospective study. Wound evaluation (area and occurrence of complications) was performed at baseline and at 12 weeks of follow-up. Biologic nutrition assessment (serum albumin, transthyretin, c-reactive protein) was performed at baseline. The control group consisted of consecutive patients free of leg ulceration and attending the dermatology outpatient clinic for remissive skin cancer or miscellaneous skin disorders. RESULTS Forty one patients and 43 controls were included. Serum albumin level was under 35 g/L (normal values: 36-44 g/L) in 27% of the patients and 2% of the controls (P < .001). At 12 weeks, 34% of the patients had an increase in wound area. Wound infections occurred in 12% (n = 5) of the patients. Protein deficiency was independently associated with an increase in wound area at 12 weeks (P = .034) and the presence of an inflammatory syndrome was associated with the occurrence of wound complications (wound infection or hospitalization) during follow-up (P < .001). CONCLUSION The prevalence of protein deficiency in out-patients with leg ulcers is high and significantly associated with a poor healing prognosis.

EMLA cream as a topical anesthetic for the repeated mechanical debridement of venous leg ulcers: A double-blind, placebo-controlled study

BACKGROUND A granulating surface is important for skin grafting and healing of leg ulcers. Mechanical debridement to remove necrotic tissue often must be stopped before completion because of pain. OBJECTIVE Our purpose was to assess the effect of EMLA cream on the number of debridements required to obtain a clean ulcer and on pain during debridement and to determine its safety after repeated doses. METHODS In this randomized double-blind, placebo-controlled study, 69 patients with venous leg ulcers received cream before debridement until a clean ulcer was obtained (or a maximum of 15 debridements). RESULTS EMLA decreased the median number of debridements required for a clean ulcer (EMLA 11.5, placebo >15; P = .019) and decreased pain by 50% (P = .003). Plasma levels of lidocaine, prilocaine, and their main metabolites were low without any apparent accumulation. CONCLUSION EMLA produces effective pain relief for the debridement of leg ulcers and shortens the time to a clean ulcer.

Cutaneous Sarcoidosis Occurring during Anti-TNF-Alpha Treatment: Report of Two Cases

We report two cases of cutaneous granuloma induced by anti-TNF-α therapy: a 47-year-old man suffering from psoriatic arthritis treated with infliximab and a 56-year-old woman treated with adalimumab for polyarticular juvenile rheumatoid arthritis. The biospies confirmed the diagnosis of a ‘sarcoidosis-like’ reaction. No systemic involvement was observed. Such cases of noninfectious granulomatous diseases occurring during anti-TNF-α therapy are becoming increasingly frequent.

Brain magnetic resonance imaging in patients with Cowden syndrome.

Abstract: Cowden syndrome (CS) is a rare autosomal dominant genodermatosis, characterized by multiple hamartomas, particularly of the skin, associated with high frequencies of breast, thyroid, and genitourinary malignancies. Although Lhermitte-Duclos disease (LDD) or dysplastic gangliocytoma of the cerebellum, a slowly progressive unilateral tumor, is a major criterion of CS, its frequency in patients with CS is unknown. Other cerebral abnormalities, especially meningioma and vascular malformations, have also been described, albeit rarely, in these patients. The aim of the current study was to use cerebral magnetic resonance imaging (MRI) to evaluate LDD frequency and to investigate other brain abnormalities in CS patients recruited by dermatologists. A multicenter study was conducted in 8 hospital dermatology departments between January 2000 and December 2003. Twenty patients with CS were included; specific cerebral MRI abnormalities were found in 35% (7/20) of them. Cerebral MRI revealed LDD in 3 patients, a meningioma in 1, and numerous vascular malformations in 6 patients. Five patients had venous angiomas (3 associated with LDD) and 2 patients had cavernous angiomas (1 associated with LDD and a venous angioma). The discovery of asymptomatic LDD in 3 patients and a cavernous angioma in another prompted us to perform neurologic examinations regularly and MRI to estimate the size and the extension of the tumor, and to assess the need for surgery. CS similarities with Bannayan-Riley-Ruvalcaba (BRR) are discussed because some patients could also have the BRR phenotype (for example, genital lentigines, macrocephaly, multiple lipomas) and because BRR seems to have more central nervous system vascular anomalies. Because CS signs can involve numerous systems, all physicians who might encounter this disease should be aware of its neurologic manifestations. Our findings confirm the contribution of brain MRI to detecting asymptomatic LDD, vascular malformations, and meningiomas in patients with CS. Abbreviations: BRR = Bannayan-Riley-Ruvalcaba, CNS = central nervous system, CS = Cowden syndrome, CT = computed tomography, LDD = Lhermitte-Duclos disease, MRI = magnetic resonance imaging, PTEN = phosphatase and tensin homolog deleted on chromosome 10.

The kinetics of the visible growth of a primary melanoma reflects the tumor aggressiveness and is an independent prognostic marker: a prospective study.

Primary melanoma (MM) could be a good model to test an intuitive concept: a cancer that is growing fast in its early phase is likely to have a high aggressiveness. Since MMs are visible tumors, many patients can provide information to indirectly assess the kinetics of their lesion. A prospective study was designed to assess if the kinetics of the visible growth of a primary MM, as described by the patient, could be a noninvasive prognostic marker. The ratio of MM thickness to delay between MM appearance and MM removal was used as a surrogate value for the kinetics of the MM growth. To assess the delay between MM appearance and removal, 362 patients with self‐detected invasive MM fulfilled a detailed questionnaire, which provided 2 types of estimations of this delay and thus 2 melanoma kinetics indexes (MKI and MKI*). After a median follow‐up of 4 years, univariate and multivariate analyses assessed whether relapse‐free survival was linked to MKI or MKI*. MKI was significantly predictive of relapse‐free survival (HR = 1.84 [1.51–2.25]) and relapse at 1 year (RR = 2.93 [1.84–4.69]), independently from Breslow thickness. MKI was retained in multivariate prognostic models, just after thickness and before other usual markers. MKI* was also a significant independent risk marker, although less predictive. In this model, the initial growth kinetics of a cancer reflects its aggressiveness and a high index predicts a short‐term relapse. The “subjective” data obtained from patients about their MM history, although usually neglected, can thus provide a better prognostic marker than many “objective” tests.