Stephen K. Richardson

Immunopathogenesis and therapy of cutaneous T cell lymphoma

Cutaneous T cell lymphomas (CTCLs) are a heterogenous group of lymphoproliferative disorders caused by clonally derived, skin-invasive T cells. Mycosis fungoides (MF) and Sezary syndrome (SS) are the most common types of CTCLs and are characterized by malignant CD4(+)/CLA(+)/CCR4(+) T cells that also lack the usual T cell surface markers CD7 and/or CD26. As MF/SS advances, the clonal dominance of the malignant cells results in the expression of predominantly Th2 cytokines, progressive immune dysregulation in patients, and further tumor cell growth. This review summarizes recent insights into the pathogenesis and immunobiology of MF/SS and how these have shaped current therapeutic approaches, in particular the growing emphasis on enhancement of host antitumor immune responses as the key to successful therapy.

Biological Effects of Bexarotene in Cutaneous T-Cell Lymphoma

OBJECTIVES To delineate the natural history of pityriasis rosea in black children and to compare our findings with those of the American, European, and African literature on pityriasis rosea. Textbook and journal article descriptions of pityriasis rosea usually offer information about the presentation and clinical course of this condition in white patients. DESIGN Prospective observational study. SETTING The general pediatric clinic, adolescent clinic, and emergency department of Childrens Hospital of Michigan, Detroit, from June 2003 through May 2005. PATIENTS We followed up 50 black children with pityriasis rosea from the time of diagnosis through follow-up visits at 1, 2, and 4 weeks. Detailed observations were made and digital photographs taken at each visit. MAIN OUTCOME MEASURES Duration of illness and pigmentary sequelae. RESULTS Similarities with the medical literature were found regarding season of onset and prevalence of pruritus and of a herald patch. Our patients had more frequent facial involvement (30%) and more scalp lesions (8%) than usually described in white populations. One third had papular lesions. The disease resolved in nearly one half of patients within 2 weeks. Residual hyperpigmentation was seen in 48% of patients. Hypopigmentation developed in 29% of patients with purely papular or papulovesicular lesions. CONCLUSIONS Pityriasis rosea in black children differs in several ways from textbook descriptions. Physicians may use this information to better counsel patients about the course and potential sequelae of this condition.

The biomechanical responses to tension in a peripheral nerve.

The biomechanical adjustments rat sciatic nerves make to tension were studied 7 weeks after experimental nerve repair. Nerve tissue adjusts to tension by increasing its compliance if stretched within its physiological limits. Anatomical changes observed in the nerve tissue 7 weeks after stretching apparently accounts for the nerves extensibility, a biomechanical adjustment that helps preserve nerve continuity during the joint extension phase of extremity rehabilitation.

Electromechanical properties in human articular cartilage.

This report describes the electromechanical potentials measured from within the matrix of human articular cartilage. The potential is increased with increasing load, increasing load rate, and increasing strain concentration. Cartilage is heterogeneous; numerous artefacts are present and must be carefully excluded. The origin of the potential is complex but probably includes such effects as streaming potentials, Donnan equilibrium, dipole orientation of collagen fibers, and alteration in spatial distribution of hydrogen bonds.

Total skin electron beam therapy may be associated with improvement of peripheral blood disease in Sézary syndrome.

Total skin electron beam radiation is an effective therapy for palliation of the cutaneous symptoms of the most common types of cutaneous T-cell lymphomas, mycosis fungoides and Sézary syndrome. We report 4 cases of patients with Sézary syndrome who had significant improvement in their blood burden of malignant cells in addition to complete cutaneous responses to total skin electron beam therapy. The data from these 4 patients illustrate the potential for total skin electron beam to be used as both a skin and blood tumor debulking agent, and not merely as a palliation for skin symptoms.

Update on the epidemiology and systemic treatment of psoriasis

Recent epidemiological observations reveal that the prevalence of psoriasis increases more rapidly in young women compared with young men, and that the prevalence of psoriasis may decrease in the elderly. Emerging evidence suggests that some potentially modifiable exposures, such as smoking, stress and obesity, may increase a patient’s risk of developing psoriasis. The evolving literature suggests that psoriasis is associated with multiple other diseases, including cancer, cardiovascular disease, diabetes and psychiatric disease, and that psoriasis itself may be an independent risk factor for developing atherosclerosis and myocardial infarction. The treatment of moderate-to-severe psoriasis is undergoing a revolution with the advent of biological therapies that target the immunopathogenesis of psoriasis, such as tumor necrosis factor-α and T-cell function. The pharmacokinetics, pharmacodynamics, efficacy and safety profiles vary among biologicals and, therefore, drug and patient factors are important in selecting the optimum therapy. In this article, we focus on recent developments in the epidemiology and systemic treatment of psoriasis.

Low-Dose Bexarotene and Low-Dose Interferon Alfa-2b for Adult T-Cell Leukemia/Lymphoma Associated With Human T-Lymphotropic Virus 1

OBJECTIVES To delineate the natural history of pityriasis rosea in black children and to compare our findings with those of the American, European, and African literature on pityriasis rosea. Textbook and journal article descriptions of pityriasis rosea usually offer information about the presentation and clinical course of this condition in white patients. DESIGN Prospective observational study. SETTING The general pediatric clinic, adolescent clinic, and emergency department of Childrens Hospital of Michigan, Detroit, from June 2003 through May 2005. PATIENTS We followed up 50 black children with pityriasis rosea from the time of diagnosis through follow-up visits at 1, 2, and 4 weeks. Detailed observations were made and digital photographs taken at each visit. MAIN OUTCOME MEASURES Duration of illness and pigmentary sequelae. RESULTS Similarities with the medical literature were found regarding season of onset and prevalence of pruritus and of a herald patch. Our patients had more frequent facial involvement (30%) and more scalp lesions (8%) than usually described in white populations. One third had papular lesions. The disease resolved in nearly one half of patients within 2 weeks. Residual hyperpigmentation was seen in 48% of patients. Hypopigmentation developed in 29% of patients with purely papular or papulovesicular lesions. CONCLUSIONS Pityriasis rosea in black children differs in several ways from textbook descriptions. Physicians may use this information to better counsel patients about the course and potential sequelae of this condition.

Clinical and in vitro resistance to bexarotene in adult T cell leukemia: loss of RXR-alpha receptor

The oral rexinoid bexarotene (Targretin) is widely used for treatment of cutaneous T-cell lymphomas (CTCL). We recently reported the first case of adult T-cell leukemia/lymphoma (ATLL) that responded rapidly to combination therapy of bexarotene and interferon (IFN)-alpha2b with complete clinical response. We demonstrated that bexarotene induced apoptosis of the patients malignant peripheral blood T-cells in vitro. However, our patient developed skin and nodal relapse 180 days after starting treatment. We now demonstrate that his peripheral blood malignant T cells became resistant to bexarotene-induced apoptosis. We investigated potential mechanisms that may cause aberrations in the retinoid X receptor (RXR) subunits, RXR-alpha and RXR-beta, to account for these findings. Sequence analysis did not reveal acquisition of mutations in the genes encoding RXR-alpha and RXR-beta by resistant cells. We assessed RXR-alpha and RXR-beta expression by Western blot analysis and found that resistant cells had significantly decreased RXR-alpha expression compared with pretherapy bexarotene-sensitive cells. Our findings indicate that reduced expression of the RXR-alpha receptor subunit may represent a mechanism for resistance to bexarotene in T-cell malignancies.

The use of cytokines, fusion proteins and antibodies to treat cutaneous T‐cell lymphoma

ABSTRACT:  It has long been known that certain immune augmenting therapeutics, particularly interferon alpha, can exert profound salutary effects on the clinical progress of patients with cutaneous T‐cell lymphoma. Emerging evidence that the host immune response may play an important role in the control of this disorder has led to the clinical application of other cytokines including interleukin‐12 and interferon gamma. In this review, the authors will summarize current knowledge regarding the use of cytokines, fusion proteins and antibodies for the treatment of cutaneous T‐cell lymphoma.