维A酸类药物治疗皮肤T细胞淋巴瘤的研究进展

维A酸类药物是一类维生素A衍生物,具有调节细胞增殖、分化,促进凋亡的作用并能影响人体免疫应答,其应用于皮肤T细胞淋巴瘤的治疗已有多年,疗效确切.维A酸类药物生物学作用机制主要是通过与维A酸受体和维A酸X受体结合,转录辅助活化因子和转录抑制因子参与,诱导基因转录.维A酸受体选择剂和维A酸X受体选择剂治疗皮肤T细胞淋巴瘤均有效,但联合治疗疗效更明显.维A酸类药物常与光疗、干扰素及其他免疫抑制剂联合,其联合疗法已成为其在皮肤T细胞淋巴瘤中应用的主要方式.维A酸类药物的不良反应主要表现在对肝功能、血脂、甲状腺激素水平、白细胞及生殖系统的影响,外用主要表现为皮肤刺激反应.     

Retinoids: therapeutic applications and mechanisms of action in cutaneous T-cell lymphoma

Retinoids, natural and synthetic derivatives of vitamin A, are biological regulators of differentiation, proliferation, apoptosis, and immune response. Retinoic-acid-receptor-selective retinoids (all-trans retinoic acid, 13-cis-retinoic acid, and the synthetic analogs isotretinoin, etretinate and acitretin) have been used for years as monotherapy and/or in combination for treatment of cutaneous T-cell lymphoma (CTCL). Orally administered bexarotene, the first synthetic highly selective retinoid-X-receptor retinoid to be approved by the FDA for CTCL, was shown to be active against the cutaneous manifestations of all stages of CTCL. The topical gel formulation was also effective for early cutaneous manifestations of CTCL or as an adjunct to systemic or phototherapy. Bexarotene treatment induces apoptosis of CTCL cells with down-regulation of its receptors and of survivin, an inhibitor of apoptosis. Identification of new receptor subtype-selective retinoids, combination of various receptor-selective retinoids or other agents, and a new drug delivery system may improve the clinical efficacy of retinoids in the future.     

Retinoids for prevention and treatment of actinic keratosis

Actinic keratosis is a common cause of dermatological consultations and it presents astrong association with squamous cell carcinoma. Many substances are used fortreatment and prevention, such as retinoids. Nevertheless, many studies on retinoidsemphasize their application in treating and preventing non melanoma skin cancers. Inthis article, we reviewed studies about systemic and topical retinoids used withimmunocompetent patients and organ transplant recipients with actinic keratosis, asprimary or secondary outcomes. The majority of these papers pointed to a reduction inactinic keratosis count after treatment with retinoids. However, studies need to bebetter-defined in order to address the lack of a standardized dose, the absence ofcontrol groups, the low number of patients and short follow-up periods. Blind,randomized and controlled clinical trials with adequate sample sizes, specificallyfocused on actinic keratosis, are needed to clarify the real benefit of topicaland/or oral retinoids. Comparison of efficacy and safety between oral and topicalretinoids in the prevention and treatment of non-melanoma skin cancers and actinickeratosis is an essential pre requisite to establish new strategies to control theseconditions.     

Multiple synchronous cutaneous melanomas: implications for prevention

BACKGROUND: A subset of about 3-5% of melanoma patients present a second primary melanoma. OBSERVATIONS: We describe two cases of primary multiple synchronous melanomas consecutively observed in the last 6 months in our department in two male patients presenting multiple atypical nevi. In both patients, the second melanoma was diagnosed by the clinician who had identified the first one, but at the time of the first follow-up consultation, 3 months later. The delayed discovery of the second melanoma required another referral for surgery with additional discomfort for the patients. Concern about the first lesion (the thickest in both cases) probably rendered the second one less evident to both patients and clinician, until the first follow-up examination after excision of the first lesion. CONCLUSION: We stress the need for careful and thorough examination of the whole body surface at the time of detection of a cutaneous melanoma in subjects with multiple atypical moles because the finding of synchronous multiple melanomas is not uncommon.     

Retinoids and the eye.

Systemic retinoids are being used more frequently to treat various disorders of the skin, particularly disorders of keratinization. They are promising agents for chemoprevention of cancer and as such may be widely used in the future. Both natural and synthetic retinoids may affect the eye, both on the surface epithelium and the visual metabolism. Three basic effects of pharmacologic doses of synthetic retinoids have been seen. Blepharoconjunctivitis has been particularly prominent with isotretinoin use. Pseudotumor cerebri has been reported sporadically. Recently, night blindness has been reported with both isotretinoin and fenretinide. The greater use of isotretinoin may be more important in explaining the increased incidence of these side effects than is the individual metabolism of the different available synthetic retinoids. These three major side effects of the eye will be carefully evaluated as newer synthetic retinoids are proposed for further trials. Fortunately, it seems that all of these ocular manifestations are dose dependent and reversible, giving the clinician several alternatives to adjust the treatment regimen.     

Beta-carotene in prevention of cutaneous carcinogenesis.

Beta-carotene, administered orally to mice, caused a decrease in angiogenesis evoked by HPV-transformed tumorigenic cell lines (SKv-t, HeLa). It did not affect angiogenesis induced by the non-tumorigenic SKv (not-t) cell line, and increased lymphocyte-induced immune angiogenesis. We suggest that the anti-cancerogenic effect of beta-carotene may be due, at least in part, to its inhibitory effect on formation of new blood vessels within the tumour mass.     

Randomized clinical trials for psoriasis 1977-2000: the EDEN survey

This study aims to describe the range of treatment comparisons, study designs and quality of reporting of randomized clinical trials (RCTs) in psoriasis published in a variety of medical and dermatological journals, and to analyze time trends with quality items. Hand-searching of clinical trials of psoriasis published from 1977 to 2000 in 13 medical or dermatological journals, selected as relevant to a European readership, was performed. A total of 249 trials published in 226 papers were classified as RCTs. Of these, 139 (55.8%) employed a parallel control group design, 107 (43.0%) studies adopted a self-control design and 3 (1.2%) a cross-over design. The median number of patients recruited per study was 40 (range 6-699). Overall, 55 different treatment modalities, including topical, ultraviolet-based, systemic, and other miscellaneous therapies were assessed. Only 31 (12.5%) RCTs were comparative studies of treatment modalities in different therapeutic classes. Most of the studies were short-term with a median study duration of 7 weeks (range 1-104), with only 18 studies (7.2%) lasting for more than four months. A variety of outcome measures including 44 different score systems were employed. According to the conclusions of the authors, 196 (78.7%) studies were judged to provide striking or definite observations in favor of one of the treatments examined. No important variations over time were documented for quality items. Based on our survey we have identified an enormous range of treatments that have been evaluated for psoriasis over the examined period. Most studies were short-term, and only a handful compared treatment options in different therapeutic classes. Since we did not examine all the relevant journals, the number of treatment options may be even greater than we have documented. There is an urgent need to reset the research agenda focusing on long-term comparative RCTs. Editors of major medical and dermatological journals are urged to take a role in improving the quality of RCT reporting.     

Vaccines and immunotherapies for the prevention of infectious diseases having cutaneous manifestations

Although the development of antimicrobial drugs has advanced rapidly in the past several years, such agents act against only certain groups of microbes and are associated with increasing rates of resistance. These limitations of treatment force physicians to continue to rely on prevention, which is more effective and cost-effective than therapy. From the use of the smallpox vaccine by Jenner in the 1700s to the current concerns about biologic warfare, the technology for vaccine development has seen numerous advances. The currently available vaccines for viral illnesses include Dryvax for smallpox; the combination measles, mumps, and rubella vaccine; inactivated vaccine for hepatitis A; plasma-derived vaccine for hepatitis B; and the live attenuated Oka strain vaccine for varicella zoster. Vaccines available against bacterial illnesses include those for anthrax, Haemophilus influenzae, and Neisseria meningitidis. Currently in development for both prophylactic and therapeutic purposes are vaccines for HIV, herpes simplex virus, and human papillomavirus. Other vaccines being investigated for prevention are those for cytomegalovirus, respiratory syncytial virus, parainfluenza virus, hepatitis C, and dengue fever, among many others. Fungal and protozoan diseases are also subjects of vaccine research. Among immunoglobulins approved for prophylactic and therapeutic use are those against cytomegalovirus, hepatitis A and B, measles, rabies, and tetanus. With this progress, it is hoped that effective vaccines soon will be developed for many more infectious diseases with cutaneous manifestations.