Cutaneous T cell lymphoma: translating immunobiology into therapeutic opportunities.

Cutaneous T cell lymphoma (CTCL) has always served as a proving ground where conceptual advances in immunology can be tested and the results translated into clinical practice. From the earliest studies that used sheep red blood cells to identify the malignant cell as a T lymphocyte to molecular demonstration of the clonalilty of the disease, basic science techniques have provided sign posts that allow us to understand the clinical features seen in the patients. We continue to apply this paradigm to develop new insights into the role of the immune system in CTCL with the goal of using this knowledge to enhance the therapeutic options available to the patient. This article will review the studies that have led to our current understanding of the immunobiology of CTCL and the new therapeutic approaches that are being tested in this disease.

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.

Uterine chromatin template activity during the early stages of pregnancy in the rat.

1. The template activity of chromatin prepared from rat uterine nuclei during dioestrus, oestrus and the first 7 days of pregnancy has been examined. 2. The DNA, RNA, histone and non-histone protein contents of uterine chromatin remained constant during early pregnancy. 3. The rate of RNA synthesis on Day 1 uterine chromatin was 8.61 +/- 0.59 (mean +/- S.E.) pmol of UMP incorporated/mg DNA per 10 min. When compared with DNA prepared from rat liver nuclei, 13.20 +/- 0.27% (mean +/- S.E.) of the Day 1 chromatin DNA was available for transcription by Escherichia coli RNA polymerase. 4. Uterine chromatin from rats in early dioestrus had significantly less template activity than during oestrus. 5. Chromatin prepared from whole uterus on Day 5 and from implantation sites on Days 6 and 7 of pregnancy had a significantly higher template activity than chromatin obtained from uteri on Day 1. Chromatin from interimplantation tissue on Day 6 had a lower template activity than that from uteri on Day 1. 6. RNA - DNA hybridisation of RNA transcribed from chromatin obtained on Days 2, 5 and 7 of pregnancy showed that RNA transcribed from Day 5 chromatin obtained species not present (or present in very small amounts) in RNA transcribed by chromatin from uteri on Day 2 and from implantation tissue on Day 7 of pregnancy. 7. The results are discussed in relation to the cellular changes occurring in the stroma immediately before implantation and it is postulated that the appearance of a new species of RNA on Day 5 is related to the preparation of the stromal cells for decidualisation.

Bexarotene is effective and safe for treatment of refractory advanced-stage cutaneous T-cell lymphoma: multinational phase II-III trial results.

PURPOSE: Cutaneous T-cell lymphomas (CTCL) are malignancies of T cells appearing as skin lesions and are responsive to retinoid therapy. Safety and efficacy of a novel RXR-selective retinoid (rexinoid) bexarotene (Targretin, LGD1069; Ligand Pharmaceuticals Inc, San Diego, CA) was evaluated as a single-agent oral therapy administered once daily in an open-label study in patients with refractory advanced-stage CTCL. PATIENTS AND METHODS: Ninety-four patients with biopsy-confirmed CTCL in advanced stages (IIB-IVB) were enrolled at 26 centers. Fifty-six patients received an initial dose of 300 mg/m2/d oral bexarotene and 38 started at more than 300 mg/m2/d. RESULTS: Clinical complete and partial responses were reported by Primary End point Classification for the study in 45% (25 of 56) of patients enrolled at 300 mg/m2/d dosing. At more than 300 mg/m2/d, 55% (21 of 38) of patients responded, including 13% (five of 38) clinical complete. For the 300 mg/m2/d initial dose group, the rate of relapse after response was 36% and the projected median duration of response was 299 days. Improvements were also seen in overall body-surface area involvement, median index lesion surface area, adenopathy, cutaneous tumors, pruritus, and CTCL-specific quality of life. The most frequent drug-related adverse events included hypertriglyceridemia (associated rarely with pancreatitis), hypercholesterolemia, hypothyroidism, and headache. CONCLUSION: Bexarotene is the first in a novel class of pharmacologic agents, the RXR-selective retinoids, or rexinoids. Bexarotene is orally administered, safe, and generally well tolerated with reversible side effects, and is effective for the treatment of advanced, refractory CTCL.

Pivotal phase III trial of two dose levels of denileukin diftitox for the treatment of cutaneous T-cell lymphoma.

PURPOSE: The objective of this phase III study was to determine the efficacy, safety, and pharmacokinetics of denileukin diftitox (DAB389IL-2, Ontak [Ligand Pharmaceuticals Inc, San Diego, CA]) in patients with stage Ib to IVa cutaneous T-cell lymphoma (CTCL) who have previously received other therapeutic interventions. PATIENTS AND METHODS: Patients with biopsy-proven CTCL that expressed CD25 on > or = 20% of lymphocytes were assigned to one of two dose levels (9 or 18 microg/kg/d) of denileukin diftitox administered 5 consecutive days every 3 weeks for up to 8 cycles. Patients were monitored for toxicity and clinical efficacy, the latter assessed by changes in disease burden and quality of life measurements. Antibody levels of antidenileukin diftitox and anti-interleukin-2 and serum concentrations of denileukin diftitox were also measured. RESULTS: Overall, 30% of the 71 patients with CTCL treated with denileukin diftitox had an objective response (20% partial response; 10% complete response). The response rate and duration of response based on the time of the first dose of study drug for all responders (median of 6.9 months with a range of 2.7 to more than 46.1 months) were not statistically different between the two doses. Adverse events consisted of flu-like symptoms (fever/chills, nausea/vomiting, and myalgias/arthralgias), acute infusion-related events (hypotension, dyspnea, chest pain, and back pain), and a vascular leak syndrome (hypotension, hypoalbuminemia, edema). In addition, 61% of the patients experienced transient elevations of hepatic transaminase levels with 17% grade 3 or 4. Hypoalbuminemia occurred in 79%, including 15% with grade 3 or 4 changes. Tolerability at 9 and 18 microg/kg/d was similar, and there was no evidence of cumulative toxicity. CONCLUSION: Denileukin diftitox has been shown to be a useful and important agent in the treatment of patients whose CTCL is persistent or recurrent despite other therapeutic interventions.

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.

The immune response to class I-associated tumor-specific cutaneous T-cell lymphoma antigens.

In order to determine whether the neoplastic T cells from patients with cutaneous T-cell lymphoma express tumor-specific antigens that can serve as the targets of an immune response, we took advantage of family-specific monoclonal antibodies, magnetic bead technology, and recombinant cytokines, which provided the previously precluded ability to isolate and expand populations of purified tumor and autologous CD8 cytotoxic T cells. Four patients with advanced cutaneous T-cell lymphoma had CD8 cells that specifically killed autologous tumor in a class I limited fashion. Tumor cell cytolysis could be specifically enhanced by pre-culture with autologous gamma-irradiated tumor. The cytolytic T cells produced tumor necrosis factor-alpha in response to stimulation with autologous tumor. The presence of tumor-specific cytotoxic T cells recognizing distinctive class I associated molecules on cutaneous T-cell lymphoma tumor cells suggests that infiltration of early lesions by CD8 cells reflects host immunity to the neoplasm. These studies provide the foundation for the development of tumor vaccines through the use of cytotoxic T cells to isolate and characterize tumor-associated cutaneous T-cell lymphoma peptides.

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.

Detection of clonal T-cell receptor gamma gene rearrangements in early mycosis fungoides/Sezary syndrome by polymerase chain reaction and denaturing gradient gel electrophoresis (PCR/DGGE).

We used a gene amplification strategy to analyze T-cell receptor (TCR) gene rearrangements in 185 specimens, including mycosis fungoides/Sezary syndrome (MF/SS), other cutaneous neoplasms, inflammatory dermatoses, reactive lymphoid tissues, and normal skin. Genomic DNA was extracted from lesional tissues and rearrangements of the TCR-gamma chain gene were amplified using the polymerase chain reaction (PCR) with primers specific for rearrangements involving V gamma 1-8 or V gamma 9 gene segments. The resulting PCR products were then separated according to their nucleotide sequence as well as size by denaturing gradient gel electrophoresis (DGGE). Dominant clonal TCR-gamma gene rearrangements were detected in 61 of 68 MF/SS cases by PCR/DGGE. This sensitivity of 90% compared to a sensitivity of only 59% when dominant clonality was sought in 17 of these same cases by Southern blot analysis of TCR-beta gene rearrangements. This difference in sensitivity was greatest in early, minimally infiltrated skin lesions. PCR/DGGE was also more sensitive than Southern blot analysis for detecting peripheral blood involvement in two cases of early MF. Among 12 additional specimens of suspected MF/SS, nine (75%) showed clonal TCR-gamma gene rearrangements by PCR/DGGE including six of eight cases with a previously confirmed diagnosis of MF/SS and three of four cases without prior known MF/SS. Among 105 non-MF/SS specimens, dominant TCR-gamma gene rearrangements were detected in only six cases (6%). Four were diagnosed as chronic dermatitis and two were diagnosed as cutaneous lymphoid hyperplasia. We conclude that the large majority of MF/SS cases, including patch phase disease, possess dominant clonal TCR-gamma gene rearrangements. PCR/DGGE is more sensitive than Southern blot analysis for detecting dominant clonality and staging disease in patients with a confirmed diagnosis of MF/SS. However, because PCR/DGGE is sensitive enough to detect dominant TCR-gamma gene rearrangements in a subset of patients with chronic dermatitis, it cannot be used as the sole criterion for establishing a diagnosis of T-cell lymphoma. As with other molecular biologic clonality assays, clinicopathologic correlation is essential. Nevertheless, the detection of dominant clonality in some cases of histologically nonspecific dermatitis allows the identification of a previously unrecognized subset of patients, i.e., those with "clonal dermatitis." It will be important to determine the long-term risk of MF/SS among these patients because our study indicated that MF/SS can sometimes present with lesions indistinguishable from clonal dermatitis.

Malignant and normal T cells show random use of T-cell receptor alpha chain variable regions in patients with cutaneous T-cell lymphoma.

Cutaneous T-cell lymphoma (CTCL) is a malignancy of mature T lymphocytes, most of which express alpha/beta type T-cell receptors (TCRs). The cause of CTCL is unknown, but hypotheses postulating chronic stimulation of TCRs by superantigen or by a leukemogenic virus have been proposed. Either mechanism might produce bias in the TCR variable (V) region types used by the malignant cells. To determine if TCR alpha use is restricted in CTCL, we used reverse transcription and the polymerase chain reaction to determine V alpha and V beta usage by malignant cells purified from the peripheral blood of leukemic patients with CTCL. Usage of alpha chain V region segments appeared totally random; malignant lymphocytes isolated from each of six patients used different V alpha regions. As has been previously reported, no bias was found in beta chain V region usage either. In addition to productive (in frame) TCR V region mRNAs in malignant cells from each patient, we detected non-productive (out of frame) beta chain transcripts in these cells in two of six patients, and non-productive alpha chain transcripts in five of six. Residual normal peripheral blood lymphocytes from these patients showed a random, polyclonal or oligoclonal pattern of V region usage. We conclude that there is no bias in V region usage in CTCL, making it unlikely that interactions between superantigen or virus and the TCR V regions play a role in the pathogenesis of CTCL.

Future directions for pentostatin (Nipent) usage in dermatology.

Cutaneous T-cell lymphoma (CTCL) is a dynamic disease with several distinct components that make it unique from other lymphomas. The components of CTCL are reviewed to provide a background for understanding the role of pentostatin (Nipent; SuperGen, San Ramon, CA) in CTCL. In CTCL the malignant T cells mimic and eventually replace their nonmalignant counterparts. This enhances the need for targeting T cells with therapy that preferentially eliminates CTCL cells while sparing nonmalignant cells. Given the similarities of CTCL with T-cell mediated chronic inflammatory diseases, therapies used for this lymphoma also may play a role in nonmalignant disease management.

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.

Interactions of oestradiol-17beta and tamoxifen in the uterus of the pregnant rat.

Measurement of the uptake and retention of a radioactive post-coital antifertility agent tamioxifen, by reproductive tissues of the rat have shown that the ovary retained more radioactivity than did any other reproductive organ. Studies have also been made of the uptake and distribution of [3H]tamoxifen and [3H]oestradiol-17beta in the uterus of the pregnant rat on days 2-6 post coitum. Twenty-four hours after administration of tamoxifen, either i.v. or orally, 40-50% of the radioactivity was in the high speed pellet, 10-20% in the nuclear fraction, and 15-30% in the cytosol. An equivalent dose of [3H]oestradiol-17beta yielded distributions of 5%, 5% and 82% respectively. Fractionation of uteri from animals given 0-2 mg tamoxifen/kg on Day 2 of pregnancy followed by [3H]oestradiol 60 min before death showed little difference in total uptake of oestradiol or distribution in the subcellular fraction on Days 4,5 and 6. Although uptake of oestradiol by uterine nuclei was reduced on Day 3 by previous administration of tamoxifen on Day 2, appreciable quantities were still bound to the nuclear receptors. Treatment of ovariectomized animals with tamoxifen at doses up to 40 mug/rat (i.e. 0-2 mg/kg) led to the accumulation of oestrogen-receptor complex in the nucleus. It is concluded that the antifertility properties of tamoxifen (under the conditions of these experiments) cannot be ascribed to the suppression of uptake and binding of oestradiol by the uterus.

Plasma hormones and pituitary luteinizing hormone in the rat during the early stages of pregnancy and after post-coital treatment with tamoxifen (ICI 46,474).

Plasma levels of oestradiol-17beta, progesterone and luteinizing hormone (LH) and pituitary levels of LH have been measured during the first 6 days of pregnancy, in normal rats and in rats receiving two doses of Tamoxifen (trans-1-(rho-beta dimethylamino-ethoxyphenyl)-1-2-diphenylbut-1-ene) on day 2 of pregnancy. In normal rats oestradiol rose strongly from early on day 3 to reach a peak concentration between 22.00 h on day 3 and 08.00 h on day 4. Progesterone concentrations rose from day 2 to reach peak values on day 3-4. In animals in which implantation was delayed 20-24 h by administration of Tamoxifen (0.1 mg/kg) orally on day 2 the increased level of plasma oestrogen was also delayed by 20 h. A higher dose of Tamoxifen (0.2 mg/kg) on day 2, which prevented implantation, completely eliminated the increase in plasma oestradiol. Neither dose of Tamoxifen affected the levels of progesterone. In both normal rats and rats treated with 0.1 mg Tamoxifen/kg, plasma LH levels declined by day 3 while pituitary levels rose steadily. There was no detectable change in either plasma or pituitary LH levels, accompanying the increase in plasma oestradiol in the normal rats. In animals receiving Tamoxifen (0.2 mg/kg), plasma LH increased to a maximum by day 4 while levels of pituitary LH decreased. The results show that the oestrogen "surge" of early pregnancy, occurs normally about midnight on day 3 and not late on day 4 as previously thought. It is considered that the plasma oestradiol peak in early pregnancy results from an increased release of FSH rather than an increased release of LH. Tamoxifen may owe part of its antifertility action to a capacity to inhibit the synthesis of oestradiol from progesterone.

PIP: The plasma levels of estradiol-17beta, progesterone, and luteinizing hormone (LH) and pituitary levels of LH were studied in normal rats during the first 6 days of pregnancy, and in rats receiving 2 postcoital doses of Tamoxifen (trans-1-(rho-beta dimethylamino-ethoxyphenyl)-1-2 diphenylbut-1-ene) on Day 2 of pregnancy. Plasma levels of estradiol in untreated animals began to rise on Day 3 of pregnancy and reached a maximum at 20.00 hours on Day 3, before declining early on Day 4. Progesterone levels showed a similar pattern. Although progesterone levels did not vary significantly in treated animals compared to untreated animals, the highest dose of Tamoxifen eliminated the estrogen peak late on Day 3 and levels remained low up to the end of the study period. Lower doses did retard the estrogen peak, but an increase in estrogen was observed on Day 4, which was maintained until Day 6. The high dose of Tamoxifen reduced levels of pituitary LH to extremely low values, while plasma LH concentrations increased 2-3 times the concentrations found in the normal pregnant rat at Day 4. It is suggested that the plasma estradiol peak in early pregnancy is induced by a release of pituitary follicle-stimulating hormone. The antiimplantation effect of Tamoxifen may be due to its ability to inhibit the synthesis of estradiol from progesterone.

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.

An outbreak of mupirocin-resistant Staphylococcus aureus on a dermatology ward associated with an environmental reservoir.

OBJECTIVE: To investigate a cluster of mupirocin-resistant Staphylococcus aureus on a dermatology ward. DESIGN: An outbreak of mupirocin-resistant S aureus was noted on the dermatology ward during a prospective epidemiologic study of methicillin-resistant S aureus (MRSA) and borderline methicillin-susceptible S aureus (BMSSA). Pulsed-field gel electrophoresis (PFGE) of whole-cell DNA digested with Sma I was used as a marker of strain identity. SETTING AND PATIENTS: An 850-bed university hospital with a 12-bed inpatient dermatology ward. Most patients have severe, exfoliating dermatologic disorders. RESULTS: MRSA or BMSSA were isolated from 13 patients on the dermatology ward over a 14-month period. Eleven of these isolates (84.6%) were mupirocin-resistant. Nine isolates were present on admission (81.8%); 8 of these patients had been hospitalized on the same ward within the last two months. Nasal and hand cultures from 36 personnel were negative for mupirocin-resistant MRSA or BMSSA. Extensive environmental culturing revealed that a blood pressure cuff and the patients' communal shower were positive for mupirocin-resistant BMSSA. PFGE of all mupirocin-resistant isolates demonstrated that the nine patients and both environmental sources had identical DNA typing patterns. INTERVENTIONS: Changing of blood pressure cuffs between patients and more stringent cleaning of communal areas was initiated. Repeat environmental cultures were negative. CONCLUSIONS: S aureus is not usually associated with an environmental reservoir; however, these patients all had severe desquamation, which may have prolonged environmental contamination.