Interferon alfa-2a maintenance after salvage autologous stem cell transplantation in atypical mycosis fungoides with central nervous system involvement.

Mycosis fungoides (MF) is a primary cutaneous T-cell lymphoma with unfavourable prognosis for patients with advanced stages of the disease. Refractory disease and advanced-stage disease require systemic therapy. We report on a rare case of an atypical predominantly CD8+ folliculotropic MF, a subtype of MF with poorer prognosis, in a 59-year-old woman. She was initially diagnosed with MF restricted to the skin, of T3N0M0B0/stage IIB according to the current World Health Organization-European Organisation for Research and Treatment of Cancer classification. First-line treatment with local percutaneous radiotherapy in combination with systemic interferon alfa-2a resulted in complete remission. However, 21 months later the disease progressed to T3N0M1B0/stage IVB with development of cerebral manifestation and thus very poor prognosis. Allogeneic stem cell transplantation (SCT) was not a therapeutic option due to the lack of a suitable donor. We initiated methotrexate and cytarabine chemotherapy, followed by high-dose chemotherapy with thiotepa and carmustine with autologous SCT. Despite rapid response and complete remission of the cerebral lesions, disease recurrence of the skin occurred soon after. Interestingly, readministration of interferon alfa-2a as a maintenance treatment after the salvage autologous SCT resulted in a durable complete remission during the follow-up period of currently 17 months after autologous SCT. What's already known about this topic? Mycosis fungoides is a primary cutaneous T-cell lymphoma with unfavourable prognosis for the advanced stages of the disease. A refractory course of disease requires systemic therapy. What does this study add? We report on an unusual case of a patient with mycosis fungoides with cerebral involvement, in which a durable complete remission was achieved upon autologous stem cell therapy and interferon alfa-2a maintenance therapy.

Adverse Reactions of Antibody-Therapy for Primary Cutaneous Lymphomas: Rituximab, Brentuximab Vedotin, Alemtuzumab, and Mogamulizumab.

Treatment of advanced PCLs is limited and rarely reaches complete remission despite aggressive treatment modalities, such as polychemotherapy with various adverse effects. However, several monoclonal antibodies drug agents in patients with advanced primary cutaneous lymphomas demonstrate promising efficacy and manageable safety profiles. The monoclonal antibodies drug agents have favourable tolerability compared with multi-agent cytotoxic chemotherapy. However, adverse effects manifest with a broad clinical spectrum, hence the markers of targeted therapies are not limited to tumour cells but found on tumour cells and also on benign T and/or B cells. Moreover, the safety profile and direct causal association of drug and adverse effects should be interpreted with caution because many of the patients in clinical studies have received multiple treatments. Here, we focus on the safety profile of mAbs therapies that have recently been approved or are currently under preclinical or clinical investigation for CBCLs (rituximab) and CTCLs (brentuximab, mogamulizumab, and alemtuzumab). Further studies to define clinical safety profile in the patient cohort with cutaneous lymphomas are needed.

Systemic corticosteroids for subcutaneous panniculitis-like T-cell lymphoma.

BACKGROUND: Primary cutaneous γ/δ T-cell lymphoma (PCGD-TCL) is aggressive and has a poor prognosis. In contrast, subcutaneous panniculitis-like T-cell lymphoma (SPTCL) of the α/ß T-cell receptor phenotype is known to follow an indolent course and have a more favourable prognosis. In the past, PCGD-TCL and SPTCL were often considered to be a manifestation of the same disease, and aggressive systemic polychemotherapy has commonly been the first-line therapy for both. Given the understanding that SPTCL is a separate and less aggressive entity, clinical data exclusively evaluating the efficacy of conservative treatment in SPTCL are needed. OBJECTIVES: To assess the overall clinical response to systemic corticosteroids in the treatment of SPTCL. METHODS: This was a retrospective cross-sectional study based on a patient data repository from two tertiary care university hospitals in Zürich (Switzerland) and Tübingen (Germany). The repository spanned 13 years. RESULTS: In four of the five patients (80%) with SPTCL, treatment with systemic corticosteroids induced a complete remission. CONCLUSIONS: Systemic corticosteroids may be an excellent first-line single-agent therapy for SPTCL.

Incidental finding of lamellar calcification of the falx cerebri leading to the diagnosis of gorlin-goltz syndrome.

Here, we report the case of an incidental finding of lamellar calcification of the falx cerebri in a routine computed tomography scan of the head after an accidental trauma. This lamellar calcification led to the diagnosis of Gorlin-Goltz syndrome (GGS) in the patient and her daughter. Lamellar calcification of the falx cerebri is a pathognomonic feature of GGS. Our case report highlights the importance of a multidisciplinary diagnostic approach to GGS.

Basal serum tryptase as risk assessment for severe Hymenoptera sting reactions in elderly.

BACKGROUND: Epidemiologic studies suggest that elderly people are more prone to develop severe anaphylactic reactions. However, the exact cause for this phenomenon remains unclear. AIMS OF THE STUDY: To study the role of the serum tryptase as a diagnostic parameter for individual risk evaluation and its impact on the severity of allergic reactions in elderly people. METHODS: Two hundred and seventy-four consecutive patients visiting the Department of Dermatology, Tübingen, Germany, who were diagnosed with honeybee or wasp venom allergy, were included in the study. RESULTS: Sting reaction severity increased with increased age and tryptase levels (P = 0.001 and P = 0.0003, respectively). Furthermore, we find not only a general increment in tryptase levels in elderly people (P = 0.0001) but also a continuous increase in tryptase concentrations even below the cut-off (11.4 microg/l) with increasing age (P = 0.0026). CONCLUSIONS: Our data confirm serum tryptase as a risk factor for severe anaphylactic reaction to hymenoptera stings. Furthermore, we give first evidence that basal serum tryptase levels increase continuously with age and being an indicator for either increased mast cell load or reactivity this can at least partly be responsible for the observed aggravated allergic reactions in elderly people. As those patients are at increased risk for life-threatening anaphylactic reactions, it should be considered to adjust VIT especially in elderly patients with elevated tryptase levels as recommended for patients with mastocytosis by increasing venom doses during VIT and by considering its life-long continuation.

Vitamin D receptor ablation alters skin architecture and homeostasis of dendritic epidermal T cells.

BACKGROUND: 1alpha,25-dihydroxyvitamin D(3)[1,25(OH)(2)D(3)], the active metabolite of vitamin D, exerts its activities by binding to the vitamin D receptor (VDR) with subsequent function as a transcription factor. Targeted ablation of the VDR in mice results in rickets and alopecia. OBJECTIVES: To study the consequences of VDR deficiency for skin physiology, and to investigate the mechanisms of the immunosuppressive effect of 1,25(OH)(2)D(3) on LC. METHODS: We studied the structural, phenotypic and functional properties of skin and individual skin leucocyte populations in VDR(-/-) mice. RESULTS: The lack of VDR induced a wide spectrum of pathologies including dermal deposition of collagen, enlargement of sebaceous glands, dilation of the hair follicles, development of epidermal cysts, increased numbers of dendritic epidermal T cells (DETC) and hyperkeratosis. Ageing aggravated these changes. Intriguingly, Langerhans cells (LC) were indistinguishable in distribution, morphology and number compared with controls. In vitro, LC underwent a maturation/migration process similar to LC from control mice. Pretreatment of epidermal cells or LC-enriched epidermal cell suspensions with 1,25(OH)(2)D(3) impaired LC maturation and T-cell stimulatory capacity from VDR(+/+) but not VDR(-/-) mice, demonstrating that LC are targets of vitamin D(3) and that interaction between vitamin D(3) and LC results in a suppression of LC activity. CONCLUSIONS: Our data imply that VDR expression controls dermal collagen production, hair development and growth, proliferation of sebaceous glands and the homeostasis of DETC. Surprisingly, VDR deficiency does not influence LC phenotype and function.

Alpha-Gal on bioprostheses: xenograft immune response in cardiac surgery.

BACKGROUND: The alpha-Gal (Galalpha1,3-Galbeta1-4GlcNAc-R) epitope is the major xenoantigen causing hyperacute rejection of pig organs transplanted into primates. Porcine bioprostheses are utilized in cardiac surgery. However, premature degeneration of bioprostheses has limited utilization in younger patients and the immune response remains elusive. We sought to investigate whether a specific alpha-Gal immune response may play a role in this clinical scenario. MATERIALS AND METHODS: We investigated the presence of alpha-Gal-epitope on native and fixed porcine valves by means of confocal laser scanning microscope (CLSM). ELISA was utilized to evidence whether implantation of bioprostheses elicits augmentation of pre-existing cytotoxic anti alpha-Gal IgM antibodies within 10 days of surgery. Patients who underwent coronary artery bypass grafting (CABG) or mechanical valve replacement served as controls (each group, n = 12). To corroborate the clinical relevance of the alpha-Gal immune response in vivo, we studied serum obtained before and after implantation of bioprostheses and its potency to lyse porcine alpha-Gal-bearing PK15 cells. RESULTS: We found the immunogenic alpha-Gal-epitope on fibrocytes interspersed in the connective tissue of porcine valves as determined by vimentin/IB4 lectin binding. Moreover, patients who were provided with a bioprostheses had developed a significant increase of naturally occurring cytotoxic IgM antibodies directed towards alpha-Gal after surgical intervention as compared with control patients (P < 0.0001, respectively). Sera obtained from the patients after the implantation of bioprostheses demonstrated an increased cytotoxicity against alpha-Gal-bearing PK-15 cells as compared with preoperative sera (P < 0.001). The specificity of the cytotoxic effects was proven as soluble Galalpha1-3Galbeta1-4GlcNAc markedly inhibited cell death of alpha-Gal-bearing PK15 cells (P < 0.001). CONCLUSION: Our data suggest that implantation of bioprostheses in cardiac surgery induces a xenograft-specific immune response. Procedures diminishing the presence of alpha-Gal on bioprostheses, such as utilization of genetically manipulated alpha-Gal-deficient xenograft or pretreatment with alpha-Galactosidase, might diminuate the immune response against bioprostheses and extend durability.

Fetal and neonatal murine skin harbors Langerhans cell precursors.

Resident epidermal Langerhans cells (LC) in adult mice express ADPase, major histocompatibility complex (MHC) class II, and CD205 and CD207 molecules, while the first dendritic leukocytes that colonize the fetal and newborn epidermis are only ADPase(+). In this study, we tested whether dendritic epidermal leukocytes (DEL) are end-stage cells or represent LC precursors. In epidermal sheets of fetal and neonatal mice, we found no apoptotic leukocytes, suggesting that these cells do not die in situ. To address whether DEL can give rise to LC, sorted DEL from murine newborn skin were cultured with cytokines used to generate LC from human CD34(+) precursors. After 7-14 days, DEL proliferated and acquired the morphology and phenotype of cells reminiscent of LC. In concordance with this finding, we show that neonatal epidermis harbors 10-20 times the number of cycling MHC class II(+) leukocytes as adult tissue. To test whether LC can differentiate from skin precursors in vivo, we developed a transplantation model. As it was impossible to transplant fetal epidermis, whole fetal skin was grafted onto adult severe combined immunodeficient mice. As opposed to the uniform absence of donor LC at the time of transplantation, examination of the epidermis from the grafts after 2-4 weeks revealed MHC class II(+) donor cells, which had acquired CD205 and CD207, thus qualifying them as LC. Finally, we present evidence that endogenous LC persist in skin grafts for the observation period of 45 days. These studies show that hematopoietic precursors seed the skin during embryonic life and can give rise to LC.