Biomedical subjects
Publications and source records attributed to G Burg.
Melanoma is still the most frequent cause of death for diseases arising in the skin. The mortality rate is approximately 25%, tumor thickness, sex and localization being the most important prognostic factors. It is still unclear whether the margin of excision, type of anaesthesia and the pattern of follow-up should be taken into consideration in relation to the individual prognostic groups.
A great deal of new immunological, biochemical, and cell biological information has been published on the pathogenesis of psoriasis. Many of these findings must be considered to be epi-phenomena of the inflammatory reaction (clinical correlate--erythema) and hyperproliferation of keratinocytes (scaling). The mechanisms of the psoriatic inflammatory reaction and of the specific neutrophil infiltration can now be more readily understood following the discovery of adhesion molecules, and the identification of new mediators--in particular NAP-1/IL-8. Proliferation-promoting factors for keratinocytes in vitro, that is, possible mediators of psoriatic scaling, are listed, and currently known changes in expression and concentration in psoriatic lesions are discussed.
Modern aspects of treatment for malignant melanoma, basalioma and cutaneous lymphomas are reviewed. Cytokines have been proposed as immunostimulants in adjuvant therapy (destruction of residual tumor) for malignant melanoma or at high doses for treatment of metastatic melanoma. Basalioma is the most common tumor of the skin, prone to recurrence because of its iceberg-like subclinical growth-pattern. Micrographic surgery is best adapted to this growth behaviour by following the extent of the tumor in all directions by special histopathologic techniques thus permitting radical excision. Primary lymphomas of the skin although rare (1 in 100,000 per year) prevail and cumulate because of the long course over years and decades. New treatment avenues have opened by topical use of phospholipids and cytostatic drugs i. e. carmustine (BCNU).
Activated neutrophil granulocytes are an important source of oxygen free radicals in acute skin grafts. Lipid peroxidation and immigration of PMNs, indicating inflammatory mechanisms, affect each other to a variable extent. The effect of the scavengers allopurinol and alpha-D-tocopherol on both lipid peroxidation and neutrophilic infiltration was investigated. A possible mechanism for the superior effect of allopurinol compared to vitamin E was discussed.
The interleukin-2 receptor (IL-2R) is mainly expressed on activated T cells. Depending on its rate of synthesis, a portion is released from the cell surface as soluble IL-2R (sIL-2R). Since the role of mononuclear cells in the pathology of bullous pemphigoid (BP) is not well understood, we determined the sIL-2R in both blister fluid and serum of 15 BP patients with generalized disease before initiating systemic treatment. In addition, we obtained both lesional and perilesional skin biopsies and examined the mononuclear infiltrate with a panel of monoclonal antibodies. In BP blisters, sIL-2R levels were significantly increased (2070 +/- 350 U/ml), (+/- SEM) compared with serum samples taken at the time of blister puncture (1340 +/- 290 U/ml). In six patients with blisters due to second-degree burns or friction and in five suction blister volunteers, sIL-2R levels were normal in both blisters and serum. In BP, elevated serum levels decreased to normal during therapy, correlating with disease activity. The immunohistology showed that 30% of mononuclear cells in the dermal infiltrate of lesional skin expressed the IL-2R, whereas only 15% were positive in perilesional skin. IL-2R-positive cells are the most likely source of the shed receptor in BP blisters. Our results indicate the presence of activated T cells in lesions and peripheral blood of BP and thus underline the importance of cell-mediated immune mechanisms in the pathology of this disease.
Recently we described a cutaneous T-cell lymphoma expressing the gamma/delta T-cell receptor [5]. The patient suffering from this lymphoma showed low numbers of myeloid and T cells in peripheral blood, while B and NK cells were relatively increased. In vitro culture of the patient's bone marrow (BM) cells revealed a significant suppression of myeloid/monocyte colony formation (GM-CFU) compared with normal controls. This was not due to infiltration of the BM with lymphoma cells. We speculated that a soluble factor either secreted or induced by the lymphoma cells might be responsible for the marked suppression of hematopoiesis in this patient. From a skin biopsy with infiltrating gamma/delta T-lymphoma cells we established T-cell clones bearing the gamma/delta T-cell receptor and resembling the phenotype of the lymphoma cells. The supernatant (SN) of these gamma/delta T-cell clones reduced the number of colonies in a CFU-GM assay (using normal control BM) in comparison to SN of alpha/beta T-cell clones established from the same biopsy. This suppression was seen mainly on day 7 of culture and was not neutralized by the addition of placenta-CM. The main mediator of this suppression seems to be IFN-gamma, since it was detectable in high amounts in the SN of these gamma/delta T-cell tumor clones as well as in the serum of the patient. In addition, anti-IFN-gamma antibodies can reverse the T-cell SN-mediated suppression of CFU-GM. We conclude that high serum levels of interferon-gamma, which is secreted in high amounts from gamma/delta T-cells grown from a biopsy of a cutaneous lymphoma, can suppress hematopoiesis.
The prognostic value of the TNM classifications of the UICC dated 1978 and 1987, was investigated in a population of 2,495 patients who were followed up over the long term. In the case of primary melanoma, Breslow's tumour thickness proved to be the most powerful predictor of patient survival in multivariate analysis, while the significance of Clark's level ranged after that of both localisation of the primary tumour and the sex of the patient. The continuous proportional relationship between tumour thickness and risk of death makes it possible to regrade thickness groups. Grading cutoffs at 1, 2 and 4 millimetres, with no account being taken of depth of invasion, proved to be particularly favourable for a classification in accordance with prognostic criteria. In advanced stages of the disease, the outcome of locoregional and distant metastasis is significantly different; and furthermore in the case of locoregional metastasis, in-transit and satellite metastases exert a significantly better prognosis than regional lymph node involvement. Isolated juxtaregional lymph node metastases occurred primarily or during the course of the observation period in only 19 patients of our group, and, in comparison with visceral metastases, proved to have only an insignificantly better prognosis. For this reason, it would appear meaningful to assign them to a common stage. On the basis of these results, proposals are made for modifications of the TNM classification.
To our knowledge, necrotizing lid tumors occurring in the context of a necrotizing lobular panniculitis have not yet been described in the literature. Our patient, a 75-year-old male, presented with indolent, nonmoveable subcutaneous lumps that were centrally ulcerating. They appeared first on his upper lid, then on his lower lid and thereafter on the neck, back, upper extremity and abdomen, especially in the area of his cholecystectomy scar. A thorough work-up, which included repeated histopathological examinations performed by several laboratories, led to the diagnosis of an idiopathic necrotizing lobular panniculitis. A serum level determination performed later revealed no alpha 1-antitrypsin deficiency. As the eye-lid's subcutaneous tissue lacks fat, the association between the necrotizing lid tumors and the necrotizing panniculitis appears to be a paradox. In spite of the normal alpha 1-antitrypsin serum levels--determined when the patient's lesions had long ago healed--we think in retrospect that the differential diagnosis should have included the possibility of a decreased alpha 1-antitrypsin serum level (e.g. heterozygous MZ-phenotype). An alpha 1-antitrypsin level deficiency--with resulting decreased inhibition of collagenase and elastase--could account for the necrotizing process that also occurred in the eyelid's subcutaneous tissue. In the Van Gieson stain of this patient's eyelid biopsy, fragmentation of all visible collagen and elastic fibers was noted. In our opinion, the differential diagnosis does include lid involvement with secondary panniculitis caused by partially decreased alpha 1-antitrypsin serum levels and--by exclusion--idiopathic necrotizing lobular panniculitis. Therapeutic possibilities are briefly discussed.
Intercellular adhesion molecule-1 (ICAM-1, CD54), a molecule bound to the cell surface membrane, mediates various cell-cell interactions in inflammation and immunosurveillance. By means of a new specific enzyme-linked immunosorbent assay (ELISA) for soluble ICAM-1, free circulating ICAM-1 was measured in serum from five healthy volunteers, 10 melanoma patients at different stages of their disease, and eight patients receiving high-dose interleukin-2 (IL-2) for metastatic melanoma. No correlation between the concentration of circulating ICAM-1 and the tumor burden could be detected. In melanoma patients receiving high-dose IL-2, we observed an increase of circulating ICAM-1 of up to 200%, compared to the concentration prior to therapy, ranging between 4 and 13 ng/ml. The increase in circulating ICAM-1 was associated with the induction of tumor necrosis factor-alpha and interferon-gamma.
In patients with cutaneous T-cell lymphomas (CTCL), soluble interleukin-2 receptor serum levels (sIL-2R) were determined by ELISA technique, and natural killer cell (NK) activity, by a 4-h chromium-51 release assay. Decrease of NK activity correlated with the augmentation of serum sIL-2R. After a 4-d stimulation with interleukin 2 CTCL patients' peripheral mononuclear cells (PMC) showed an increase of cytotoxic activity similar to that in healthy donors' PMC. Normal donors' PMC demonstrated a diminished IL-2-induced cytotoxic activity in 25% CTCL serum (sIL-2R of 3000, 7330, and 10700 U/ml, respectively) compared to control serum (sIL-2R of 400, 340, and 420 U/ml, respectively). IL-2-dependent proliferation of 2-d phytohemagglutinin (PHA) blasts was lower in CTCL serum than in control serum. sIL-2R was enriched from one CTCL patient's serum by IL-2 affinity chromatography. Transfection of the Tac gene into NIH/3T3 fibroblasts resulted in the production of a recombinant sIL-2R. The presence of enriched native or recombinant sIL-2R inhibited interleukin-2-dependent generation of cytotoxic activity and PHA blast proliferation. We suggest that elevated sIL-2R levels account for diminished NK activity by neutralizing interleukin 2 in CTCL patients.
Explore the source record for details and available documents.
Non-specific antibody production usually accompanies the T-cell-regulated B-cell response. In this paper the mechanisms involved in non-MHC-restricted T-B-cell interaction were studied. As previously shown for NK cells, activated B cells induce IFN-gamma and TNF alpha production in non-MHC-restricted cytotoxic T lymphocytes (NrCTL). Using an in vitro model system, we demonstrate that direct cell-cell interactions are required to induce these cytokines in NrCTL. Receptor ligand systems involved are leucocyte function antigen-1/intercellular adhesion molecule-1 (LFA-1/ICAM-1)(CD11a, CD18/CD54), T11/LFA-3 (CD2/CD58), and the clonotypic T-cell receptor (TCR) structure NKTa of JT9/JT10 with its non-MHC-related target antigen TNKtar (4F2). Cytokine production can be induced by activating monoclonal antibodies against CD2R. Antibodies against the clonotypic TCR (NKTa) or CD3 had no cytokine-inducing effect on NrCTL cultured alone, but were able to retrieve the effect of blocking the target antigen on co-cultured B cells. We could further demonstrate that the inhibition of the TCR/target antigen interaction could be overcome by close cell-cell contact culture conditions. From these findings it is concluded that the role of the TCR in non-MHC-restricted cell-cell interaction is to facilitate LFA-1/ICAM-1-mediated effector target adhesion in a specific way rather than to mediate direct activating signals upon lymphokine production or cytotoxicity.
We have evaluated a subchronic model of contact hypersensitivity in the guinea pig to mimic human chronic/recurrent eczema. Repeated challenges of the ears of previously sensitized guinea pigs with 0.1% dinitrochlorobenzene (once a week for 4 weeks) induced a typical oedema response, which increased during the first 48 h after each challenge. Crusts were detectable (48 h after challenge) and histological observations (72 h after challenge) revealed hyperplasia, papillomatosis, hyperkeratosis and some mononuclear cell infiltrates in the dermis. In agreement with clinical observations in humans, topical treatment of challenged animals with corticosteroid (1% hydrocortisone) reduced the oedema, hyperplasia, papillomatosis, and leucocyte infiltrates, while application of 5% bufexamac (a non-steroidal drug) was associated with a slight enhancement of the inflammatory response. Thus, this model presents clinical and histological similarities with human eczema. Its pharmacological relevance is also suggested, although further investigations are required to better define its selectivity.
Explore the source record for details and available documents.
Report on a 44-year-old male patient who developed a solitary plaque on the trunk. Histologically there is hypertrophy of adnexal duct structures and a lymphoid infiltrate with a T helper phenotype. The term 'syringotropic variant of mycosis fungoides' is proposed for this distinct disorder.
Topical use fo vitamin E (E-Mulsin) is recommended as an alternative treatment modality in otherwise recalcitrant granuloma anulare.
Explore the source record for details and available documents.
Explore the source record for details and available documents.