Search

Viruses can escape destruction by the immune system by exploitation of the chemokine-chemokine receptor system. It is less established whether human cancers can adopt similar strategies to evade immunologic control. In this study, we show that advanced cutaneous T cell lymphoma (CTCL) is associated with selective and efficient inactivation of CXCR3-dependent T cell migration. Our studies demonstrate that this alteration is at least in part due to CXCR3 down-regulation in vivo by elevated serum levels of CXCR3 ligands. The T cell population most affected by this down-regulatory mechanism are CD8+ cytotoxic effector T cells. In CTCL patients, cytotoxic effector T cells have strongly reduced surface CXCR3 expression, accumulate in peripheral blood, but are virtually absent from CTCL tumor lesions, indicating an inability to extravasate into lymphoma tissue. CTCL-associated inactivation of effector cell recruitment may be a paradigmatic example of a new type of immune escape mechanisms shielding the neoplasm from a tumoricidal attack.

The ISCL/EORTC recommends revisions to the Mycosis Fungoides Cooperative Group classification and staging system for cutaneous T-cell lymphoma (CTCL). These revisions are made to incorporate advances related to tumor cell biology and diagnostic techniques as pertains to mycosis fungoides (MF) and Sézary syndrome (SS) since the 1979 publication of the original guidelines, to clarify certain variables that currently impede effective interinstitution and interinvestigator communication and/or the development of standardized clinical trials in MF and SS, and to provide a platform for tracking other variables of potential prognostic significance. Moreover, given the difference in prognosis and clinical characteristics of the non-MF/non-SS subtypes of cutaneous lymphoma, this revision pertains specifically to MF and SS. The evidence supporting the revisions is discussed as well as recommendations for evaluation and staging procedures based on these revisions.

Several reviews and guidelines on the management of mycosis fungoides and Sézary syndrome (MF/SS) have been published; however, treatment strategies for patients with MF/SS vary from institution to institution and no European consensus has yet been established. There are few phase III trials to support treatment decisions for MF/SS and treatment is often determined by institutional experience. In order to summarise the available evidence and review 'best practices' from each national group, the European Organisation for Research and Treatment of Cancer (EORTC) Cutaneous Lymphoma Task Force met in September 2004 to establish European guidelines for the treatment of MF/SS. This article reviews the treatment regimens selected for inclusion in the guidelines and summarises the clinical data for treatments appropriate for each stage of MF/SS. Guideline recommendations are presented according to the quality of supporting data, as defined by the Oxford Centre for Evidence-Based Medicine. Skin-directed therapies are the most appropriate option for early-stage MF/SS and most patients can look forward to a normal life expectancy. Patients with advanced disease should be encouraged to participate in clinical trials and maintenance of quality of life should be paramount.

Background: Systemic sclerosis is a multisystemic connective tissue disease with marked involvement of the skin and joints for which few effective evidence based therapies are available. To further investigate the efficacy of extracorporeal photochemotherapy on early aggressive cutaneous disease, a randomized, double-blind, placebo-controlled trial was performed., Objective: Our aim was to evaluate the efficacy of photopheresis in the treatment of patients with systemic sclerosis (scleroderma)., Methods: This randomized, double-blind, placebo-controlled clinical trial was conducted at 16 investigational sites in the United States, Canada, and Europe. Sixty-four patients with typical clinical and histologic findings of scleroderma, of less than 2 years' duration, were studied. Patients did not receive any other concomitant treatment for scleroderma. Patients were randomized to receive either active or sham photopheresis treatment on two consecutive days monthly for 12 months. Severity of skin (skin scores assessed in 22 body regions) and joint involvement (60 joints examined for contractures) were assessed on a monthly basis., Results: A statistically significant improvement in skin scores as compared with baseline was observed at 6 months (P = .0024) and 12 months (P = .008) among those who received active photopheresis, but not among those who received sham photopheresis. Comparison of skin scores between the two study arms did not achieve statistical significance because of the small sample size of the study arms. Joint involvement was also significantly improved after 6 months (P = .002) and 12 months (P = .001) of active photopheresis when compared with baseline., Limitations: The study lacks sufficient statistical power to reveal a significant difference in skin and joint manifestations between the active and sham photopheresis arms., Conclusion: Photopheresis induced significant improvement of skin and joint involvement in patients with scleroderma of recent onset; however, any effect when compared with sham treatment and a possible placebo effect may be modest.

The lack of standardized criteria for quantitative measurement of therapeutic response in clinical trials poses a major obstacle for the development of new agents in chronic graft-versus-host disease (GVHD). This consensus document was developed to address several objectives for response criteria to be used in chronic GVHD-related clinical trials. The proposed measures should be practical for use both by transplantation and nontransplantation medical providers, adaptable for use in adults and in children, and focused on the most important chronic GVHD manifestations. The measures should also give preference to quantitative, rather than semiquantitative, measures; capture information regarding signs, symptoms, and function separately from each other; and use validated scales whenever possible to demonstrate improved patient outcomes and meet requirements for regulatory approval of novel agents. Based on these criteria, we propose a set of measures to be considered for use in clinical trials, and forms for data collection are provided (). Measures should be made at 3-month intervals and whenever major changes are made in treatment. Provisional definitions of complete response, partial response, and progression are proposed for each organ and for overall outcomes. The proposed response criteria are based on current expert consensus opinion and are intended to improve consistency in the conduct and reporting of chronic GVHD trials, but their use remains to be demonstrated in practice.

Acute graft-versus-host disease (GVHD) is a major cause of mortality after allogeneic hematopoietic stem cell transplantation. We performed a phase II study on patients with acute steroid-refractory GVHD grades II to IV given extracorporeal photochemotherapy (ECP) weekly and analyzed response and long-term survival. Complete resolution of GVHD was achieved in 82% of patients with cutaneous involvement, 61% with liver involvement, and 61% with gut involvement. The probability of survival was 59% among patients who responded completely to ECP compared to 11% in patients not responding completely. We conclude that intensified ECP is highly effective in acute GVHD and that sustained responses are associated with over 50% long-term survival.

This editorial review summarizes the results of 5 meetings sponsored by the International Society for Cutaneous Lymphoma at which the clinicopathologic and ancillary features of early mycosis fungoides were critically examined. Based on this analysis, an algorithm was developed for the diagnosis of early mycosis fungoides involving a holistic integration of clinical, histopathologic, immunopathologic, and molecular biological characteristics. A novel aspect of this algorithm is that it relies on multiple types of criteria rather than just one, for example, histopathology. Before its finalization, the proposed diagnostic algorithm will require validation and possibly further refinement at multiple centers during the next several years. It is anticipated that a more standardized approach to the diagnosis of early mycosis fungoides will have a beneficial impact on the epidemiology, prognostication, treatment, and analysis of clinical trials pertaining to this most common type of cutaneous lymphoma.

There is evidence that regulation of inflammatory cytokines is among the immunomodulatory effects of photochemotherapy with 8-MOP and UVA. We have recently demonstrated that in the monocytoid cell line U937 incubation with 8-MOP and subsequent exposure to UVA is able to efficiently downregulate the release of TNF-alpha into the culture supernatant. Chlorpromazine, a well known photosensitising drug, was even more potent with regard to this effect. Based on these observations, in this study we further investigate the mechanisms of TNF-alpha inhibition by 8-MOP and CPZ photosensitization. For this purpose we determined intracellular protein levels and gene expression of TNF-alpha by western blot and quantitative real-time PCR, respectively. Our results indicate that the observed inhibition of TNF-alpha secretion after photochemotherapy is not due to downregulation of gene transcription but rather to a post-transcriptional mechanism. The observed decrease of intracellular TNF-alpha with CPZ and 8-MOP points to decreased protein synthesis or enhanced degradation. These findings demonstrate that posttranscriptional regulation of cytokine expression is a possible mechanism of action of photochemotherapy.

ECP's extensive clinical record, as well as a considerable improvement in the understanding of the mechanism that underlies its efficacy, opens potential novel strategies for the treatment of cancer, GVHD, transplant rejection, and autoimmunity. The low side effect profile of this therapy has made it a more attractive treatment consideration than current conventional chemotherapeutic and immunosuppressive medications. As the mechanism of action of ECP is more fully elucidated and clinical studies are completed, the role of ECP in modern therapeutics of CTCL and other malignancies, as well as in the treatment of other T-cell mediated diseases, will be become clearer.

Therapeutic vaccination against cutaneous T cell lymphoma (CTCL) requires the characterization of cancer cell-specific CTL epitopes. Despite reported evidence for tumor-reactive cytotoxicity in CTCL patients, the nature of the recognized determinants remains elusive. The clonotypic TCR of CTCL cells is a promising candidate tumor-specific Ag. In this study, we report that the clonotypic and framework regions of the TCRs expressed in the malignant T cell clones of six CTCL patients contain multiple peptides with anchor residues fitting the patients' MHC class I molecules. We demonstrate that TCR peptide-specific T cells from the blood of healthy donors and patients can be induced to become cytotoxic effectors after repeated stimulation with 6 of 11 selected peptides with experimentally proven affinity for HLA-A*0201. Importantly, 4 of these 6 CTL lines reproducibly recognize and lyse autologous primary CTCL cells in MHC class I/CD8-dependent fashion. These tumoricidal CTL lines are directed against epitopes from V, hypervariable, and C regions of TCRalpha. We therefore conclude that recombined as well as V framework regions of the tumor cell TCRs contain predictable epitopes for CTL-mediated attack of CTCL cells. Our data further suggest that such peptides represent valuable tools for future anti-CTCL vaccination approaches.

We describe a patient with therapy-resistant cutaneous T-cell lymphoma, Sézary syndrome variant, in association with concurrent polyarthritis and vitiligo, who was successfully treated with extracorporeal photochemotherapy (ECP). The combination of Sézary syndrome with seronegative rheumatoid arthritis is rare. In our patient the T-cell lymphoma was refractory to standard treatments that included psoralen-UVA, lymph node irradiation, and polychemotherapy. ECP has been shown to be effective in the treatment of selected cases of Sézary syndrome. There is a strong suggestion that ECP as a monotherapy can provide a significant benefit for other T-cell-mediated diseases including rheumatoid arthritis. In spite of a disease duration of 10 years, a very low CD8 cell count (2% of lymphocytes), a very high CD4 cell count (94%), and multiple unsuccessful chemotherapeutic trials before initiation of ECP, our patient achieved a long-lasting complete remission of both diseases with normalization of the CD4+ and CD8+ T-lymphocyte subsets. Concurrent developing vitiligo was unaffected by ECP.

Radiotherapy has been successfully implemented in the treatment of mycosis fungoides (MF) for almost a century. With the development of the modern linear accelerator, it has become possible to treat extended areas of the skin with accelerated electrons. Total skin electron beam radiation (TSEB) has been in use for several decades, and a number of technical modifications have been made with the goals of optimizing dose distribution and improving clinical outcome. Emerging evidence from recent studies suggests an association between TSEB techniques and efficacy in the treatment of MF. Based on this evidence, the European Organization for Research and Treatment of Cancer Cutaneous Lymphoma Project Group, in association with experts from radiotherapy centers in North America, has reached a consensus on acceptable methods and clinical indications for TSEB in the treatment of MF. The aims of this report are to enhance accessibility of this highly efficacious treatment modality to patients with MF and to provide a point of reference for further clinical research.