Basis for the control of purine biosynthesis by purine ribonucleotides.

An animal model was used to determine the basis for the increase in purine biosynthesis that results from hepatic depletion of purine nucleotides, such as seen in patients with type I glycogen storage disease or following fructose administration. Mice were injected intravenously with glucose or fructose, 2.5 mg/g of body weight, and the animals were killed at 0, 3, and 30 min following carbohydrate infusion. Fructose, but not glucose, administration led to a threefold increase in [14C]glycine incorporation into hepatic purine nucleotides documenting an increase in the rate of purine biosynthesis in the liver of fructose-treated animals. In the fructose, but not the glucose-treated animals, there was a reduction in the hepatic content of purine nucleotides that are inhibitory for amidophosphoribosyltransferase, the enzyme that catalyzes the first reaction unique to the pathway of purine biosynthesis. PP-ribose-P, an important metabolite in the control of purine biosynthesis, was increased 2,3-fold in liver following fructose, but not glucose administration. In conjunction with the decrease in inhibitory nucleotides and increase in PP-ribose-P 29% of amidophosphoribosyltransferase was shifted from the large inactive to the small active form of the enzyme. Results of these studies demonstrate that the end-products of the pathway, purine nucleotides, control the activity of the enzyme that catalyzes the first reaction leading to purine nucleotide synthesis either through a direct effect of purine nucleotides on the enzyme, through an indirect effect of the change in nucleotides on PP-ribose-P synthesis, or a combination of these effects. The resultant changes in amidophosphoribosyltransferase conformation and activity provide a basis for understanding the increase in purine biosynthesis that results from hepatic depletion of purine nucleotides.

Breast implant-associated anaplastic large cell lymphoma: A review and assessment of cutaneous manifestations.

One newly recognized form of T-cell lymphoma is breast implant-associated anaplastic large cell lymphoma (biALCL), which appears in close proximity to breast implants. The number of reported cases of biALCL is increasing and warrants careful attention by clinicians to more effectively diagnose and treat affected individuals. As pertinent to dermatologists, the objective of this paper is to present the associated cutaneous features of this clinical entity along with the pathogenesis, management, and clinical outcomes. biALCL is a T-cell lymphoma in which malignant T-cells are characterized by large pleomorphic and anaplastic morphology and immunoreactivity for CD30, similar to primary cutaneous anaplastic large cell lymphomas (pcALCL). It has a favorable clinical outcome like nonimplant-associated pcALCL and involves the fibrous capsule around the implant, which creates an immunologically privileged site with a peri-implant effusion (seroma). More rare presentations are of a solitary mass. Appropriate management of biALCL is the complete surgical removal of the implant and total capsulectomy. Dermatologists should be aware of the occurrence of this entity in patients who have breast implants because patients may present specifically for breast-related cutaneous findings or have incidental cutaneous changes noted during a skin examination. The recognition and timely diagnosis of biALCL is critical to prevent progression to more advanced disease, ensure adequate treatment with removal of the implant, and avoid unnecessary aggressive systemic chemotherapy.

Stimulation of cutaneous T-cell lymphoma cells with superantigenic staphylococcal toxins.

Stimulation of T cells by superantigenic bacterial toxins is selective for cells bearing particular B chain variable (VB) gene segments of T-cell receptor (TCR). In humans, staphylococcal exfoliating toxin (ExT) and toxic shock syndrome toxin-1 (TSST-1) are known to stimulate VB 2-bearing T cells and staphylococcal enterotoxin B (SEB) does not activate VB 2-bearing T cells. We examined the proliferative response of cutaneous T-cell lymphoma (CTCL) cells to ExT, TSST-1, and SEB. Leukemic VB 2.1-bearing CTCL cells were reactive to ExT and TSST-1, but not SEB. In addition, two leukemia CTCL-VB 2- cell samples (one of which was VB 8) showed no substantial response to ExT. Thus, it was shown that Sezary cells proliferate in response to bacterial superantigens in a manner that is restricted by their VB usage. The addition of interleukin-1 (IL-1) in combination with ExT enhanced the stimulative response of VB 2.1-bearing CTCL cells that were pre-cultured with ExT for 7 d, suggesting that IL-1 can be a co-factor for the stimulation. The present study indicates that the superantigen reaction occurs with CTCL cells and implies a possible involvement of bacterial toxins in the pathogenesis of CTCL.

A novel helix termination mutation in keratin 10 in annular epidermolytic ichthyosis, a variant of bullous congenital ichthyosiform erythroderma.

Annular epidermolytic ichthyosis is a distinct phenotypic variant of bullous congenital ichthyosiform erythroderma that has recently been described in two separate kindreds. Individuals with this variant present with bullous ichthyosis in early childhood and hyperkeratotic lichenified plaques in the flexural areas and extensor surfaces at later ages. Characteristically, they also develop intermittent bouts of annular and polycyclic, erythematous, scaly plaques on the trunk and proximal extremities. We now describe a third kindred with annular epidermolytic ichthyosis. Molecular analysis of this family revealed a novel mutation resulting in an isoleucine to threonine substitution at residue 107 (codon 446) within the highly conserved helix termination motif at the end of the rod domain of keratin 10.

Skin-selective lymphocyte homing mechanisms in the pathogenesis of leukemic cutaneous T-cell lymphoma.

The concept of skin-associated lymphoid tissue embraces those cells and functions that are integrated in the cutaneous host defense. Recently, it has been possible to identify those circulating T-cells that are skin associated. These cells display the cell-surface phenotype of memory T cells (CD45RO+) and express the cutaneous lymphocyte antigen, a tissue-selective homing receptor involved in directing T-cell traffic to inflamed skin. To investigate the participation of this skin-associated T-cell subset in the pathogenesis of cutaneous T-cell lymphoma, we studied 16 patients with erythrodermic cutaneous T-cell lymphoma for the presence of these surface proteins on circulating cells. Results were compared with eight patients in remission and eight with minimal patch-plaque cutaneous T-cell lymphoma. The mean expression of both CD45RO and cutaneous lymphocyte antigen were significantly greater in the erythrodermic patients than in the other two patient groups. Expression of these markers was shown to be on the cells of the malignant clone by two-color flow cytometry. These results demonstrate that the malignant cells of cutaneous T-cell lymphoma express the markers of skin homing lymphocytes and that their levels are increased in the erythrodermic cutaneous T-cell lymphoma patients. Moreover, the findings suggest a critical role for the skin-selective homing receptor cutaneous lymphocyte antigen in the pathogenesis of cutaneous T-cell lymphoma.

BE-2 antigen: appearance in activation and long-term growth of T cells.

The BE-2 lymphocyte surface protein is frequently expressed by the malignant cells of cutaneous T-cell lymphoma (CTCL) but is not detectable on the surface of normal resting peripheral blood lymphocytes. The expression of BE-2 by normal T cells can be induced by lectin stimulation. Membrane expression of BE-2 surpasses that of the membrane receptor for IL-2, another T-cell activation marker, at day 5. The peak expression of BE-2 appears at day 6-8. The appearance of BE-2 could also be demonstrated after anti-CD3 and allogeneic stimulation. Long-term T-cell clones derived from normal donors and maintained in culture with periodic stimulation were also found to express BE-2 continuously. Thus, BE-2 is a late activation marker not expressed on normal peripheral blood lymphocytes and pathologically expressed on circulating malignant cells in the disease CTCL.

Systemic chemotherapy and extracorporeal photochemotherapy for T3 and T4 cutaneous T-cell lymphoma patients who have achieved a complete response to total skin electron beam therapy.

PURPOSE: To evaluate the impact of systemic adjuvant therapies on relapse-free (RFS) and overall survival (OS) of cutaneous T-cell lymphoma (CTCL) patients treated with total skin electron beam therapy (TSEBT). METHODS AND MATERIALS: Between 1974 and 1990, TSEBT (36 Gy at 1 Gy/day; 9 weeks; 6 MeV electrons) was administered with curative intent to a total of 163 CTCL (mycosis fungoides) patients using six fields supplemented by orthovoltage boosts (120 kvp, 1 Gy x 20) to the perineum, soles of feet, and apical scalp (120 kvp, 2 Gy x 3). In this group, all patients who achieved a clinical complete response or a good partial response were offered one of two competing regimens of either adjuvant doxorubicin/cyclophosphamide or adjuvant extracorporeal photochemotherapy (ECP). RESULTS: When the results for the group who achieved a complete response (CR) to TSEBT were analyzed, OS for T1 and T2 patients was excellent (85-90% at 5-10 years) and not improved by either adjuvant regimen. However, T3 and T4 patients who received either adjuvant doxorubicin/cyclophosphamide (75% at 3 years) or adjuvant ECP (100% at 3 years) had better overall survival than those who received neither adjuvant regimen (approximately 50% at 5 years). The difference between the OS curves for those who received ECP vs. those who received no adjuvant therapy approached statistical significance (p < 0.06), while a significant survival benefit from the addition of chemotherapy for TSEBT complete responders was not observed. Neither adjuvant therapy provided benefit with respect to relapse free survival after TSEBT. CONCLUSIONS: These results suggest that an adjuvant nontoxic regimen of extracorporeal photochemotherapy may prolong survival in advanced stage CTCL patients who have achieved a complete remission after TSEBT. The combination of doxorubicin/cyclophosphamide had no significant impact on overall survival in those patients who achieved CR to TSEBT, and neither adjuvant therapy had an impact on relapse free survival for all T-stages. Such results are the basis for the current development of a prospective, randomized trial studying the impact of ECP after TSEBT in patients with advanced stage CTCL.

Total skin electron beam therapy followed by adjuvant psoralen/ultraviolet-A light in the management of patients with T1 and T2 cutaneous T-cell lymphoma (mycosis fungoides).

PURPOSE: Patients with mycosis fungoides [cutaneous T-cell lymphoma (CTCL)] may benefit from adjuvant therapy after completing total skin electron beam therapy (TSEBT). We report the results for T1/T2 CTCL patients treated with adjuvant oral psoralen plus ultraviolet light (PUVA) with respect to overall survival (OS), disease-free survival (DFS), salvage of recurrence, and toxicity. METHODS AND MATERIALS: Between 1974 and 1993, TSEBT was administered to a total of 213 patients with CTCL. Records were reviewed retrospectively, and a total of 114 patients were identified as having T1 or T2 disease. Radiotherapy was provided via a 6-MeV linac to a total of 36 Gy, 1 Gy/day, 4 days/week, for 9 weeks. Beginning in 1988, patients were offered adjuvant PUVA within 2 months of completing TSEBT. This was started at 0.5-2 J/m2, 1-2 treatments/week, with a taper over 3-6 months. Therapy then continued once per month. There were 39 T1 and 75 T2 patients. Six T1 (15%) and eight T2 (11%) patients were treated with adjuvant PUVA. A further 49% of the 114 patients received adjuvant systemic therapy, 3% received spot external beam, 4% received adjuvant ECP, 2% received topical nitrogen mustard, 22% received a combination of therapies exclusive of PUVA, and 9% received no adjuvant therapy. Patients were balanced in all subgroups based on pre-TSEBT therapy. The median age of the cohort was 58 (range 20-88), with a median follow-up time of 62 months (range 3-179). RESULTS: Within 1 month after completing of TSEBT, 97% of T1, and 87% of T2 patients had achieved a complete remission. Stratified by adjuvant therapy, none of six T1 and one of eight T2 patients who received adjuvant PUVA failed within the first 3 years after completion of TSEBT. A total of 43% of the T1 and T2 patients receiving other or no adjuvant treatment failed within the same time course. The 5-year OS for the entire cohort was 85%. Those who received PUVA had a 5-year OS of 100% versus a 5-year OS for the non-PUVA group of 82% (p < 0.10). The 5-year DFS for the entire cohort was 53%. Those who received PUVA had a 5-year DFS of 85% versus a 5-year DFS for the non-PUVA group of 50% (p < 0.02). By T stage, those with T1 receiving PUVA exhibited no relapses, whereas those with T1 not treated with PUVA had a crude relapse rate of 36%. Median DFS was not reached at 103 months for the T1 adjuvant PUVA patients versus 66 months for the non-PUVA patients (p < 0.01). For those with T2, crude relapse rates were 25% and 55%, respectively, with DFS of 60 (median DFS not reached) and 20 months (p < 0.03). The 5-year DFS for patients salvaged with PUVA was 50%. Toxicity of adjuvant and salvage PUVA therapy was acceptable, with only two patients requiring a reduction in PUVA dosage. CONCLUSION: PUVA can maintain remissions in patients with CTCL after TSEBT. There is a significant benefit in DFS but no statistically significant improvement in OS. Prospective, randomized data are needed to confirm these results. PUVA is also effective as a salvage therapy after TSEBT in early-stage patients with recurrence, with acceptable toxicity.

Extracorporeal photochemotherapy in human and murine graft-versus-host disease.

Extracorporeal photochemotherapy (ECP) is an immunotherapy that has found a role in the therapy of cutaneous T cell lymphoma, a disease of mature activated T cells. Graft-versus-host disease (GVHD) is also mediated by activated T cells, and thus often responds to therapies that target T cells. Murine models for both GVHD and ECP can be combined to study the impact of this immunotherapy on GVHD. In this paper we present a patient with GVHD who demonstrated a beneficial therapeutic response to treatment with ECP. The findings of this case are compared with the observations from a murine model for GVHD-ECP. The potential mechanisms of ECP in the treatment of GVHD are discussed. along with the similarities observed with ECP in the treatment of other conditions.

Idiopathic CD4+ lymphocyte deficiency. Report of an unusual case associated with atopic dermatitis and allergic contact dermatitis and review of the literature.

BACKGROUND: Idiopathic CD4+ lymphocyte deficiency is a newly described entity of apparently non-human immunodeficiency virus-associated helper T-cell depletion. The clinical spectrum continues to evolve, but, to date, it has included patients ranging from those with minimal symptoms to those who have died with acute opportunistic infections. Several individual cases have been previously reported, many with distinctive, primarily infectious, cutaneous manifestations. OBSERVATIONS: We describe a patient with idiopathic CD4+ lymphocyte deficiency distinguished by a unique clinical presentation of atopic dermatitis exacerbated by contact urticaria and allergic contact dermatitis. She has a persistent markedly diminished CD4+ lymphocyte count (absolute count less than 50), no serologic evidence of, or risk factors for, human immunodeficiency virus infection, and no history of opportunistic infections. CONCLUSIONS: We present a possible new cutaneous manifestation of idiopathic CD4+ lymphocyte disease and summarize the previously reported cases, with an emphasis on the cutaneous features.

Cell membrane DNA: a new target for psoralen photoadduct formation.

The effects of 8-methoxypsoralen plus long wavelength ultraviolet radiation on cell membrane DNA were examined. Treatment of human lymphocytes with 100 ng/ml 8-methoxypsoralen and 5 J/cm2 UVA led to the formation of 7.1 +/- 3.8 photoadducts per million bases. A monoclonal antibody, specific for 8-methoxypsoralen 4',5'-monoadducts, was used to detect photoadducts in the cell membrane DNA of human lymphocytes and three lymphoblastoid cell lines. Treatment of lymphocytes with 8-MOP and UVA reduced the lymphocyte DNA binding capacity by 56%. Cell membranes of normal lymphocytes were shown to contain three high affinity DNA binding proteins of 28, 59, and 79 kDa, respectively.

Photopheresis for T cell mediated diseases.

Photopheresis is a relatively safe and technically simple modality for immunomodulation. The extracorporeal activation of a drug with UVA constitutes a novel form of drug delivery. The usefulness of this system in erythrodermic CTCL is well established. Immunomodulating therapy can thus be conducted outside the host, where controlled conditions permit cellular manipulations not possible in the intact patient. This system is an excellent paradigm for future immunomodulating therapies in diseases such as pemphigus vulgaris and lupus erythematosus.

Current treatment practice of herpes zoster.

The management of herpes zoster infection has been impacted by the development of oral and iv. antiviral therapies. There are clinical and historical features that help optimise the particular therapy course for a given patient. Additionally, there are common features of management in all patients with herpes zoster. In this review an understanding of the pathogenesis of herpes zoster is utilised as a starting point for the development of a rational approach to therapy. Clinical findings that impact decision making are emphasised and the appropriate goals for therapy are discussed.

Cutaneous T-cell lymphoma and cutaneous graft-versus-host disease. Two indications for photopheresis in dermatology.

Dermatologists are frequently involved in the management of cutaneous T-cell lymphoma (CTCL) and graft-versus-host disease (GVHD). The similarities of these two entities are reviewed in the context of clinical and histologic findings, pathogenesis, and therapy. Photopheresis therapy (extracorporeal photochemotherapy) is used in the treatment of both entities, and the mechanisms underlying the responses represent yet another striking similarity of these two crippling dermatologic diseases.

T-cell technology in the diagnosis & management of cutaneous T-cell lymphoma.

Cutaneous T-cell lymphoma (CTCL) is a malignancy of mature, clonal, helper (CD4+) T-cells that have a propensity for localizing in the skin. This article discusses the new immunologic and molecular advances and their practical application in the management of CTCL.