Manfred Goos

Randomized, controlled phase II trial of subcutaneous interleukin-2 in combination with highly active antiretroviral therapy (HAART) in HIV patients

Objective:To determine the immunological, virological and clinical effects of subcutaneous IL-2 in 44 HIV-patients in conjunction with pre-existing tri-therapy (zidovudine, 3TC, saquinavir). Design:Partially randomized, controlled, prospective trial. Setting:Single center study at tertiary care center. Patients:Sixty four patients (CD4 count 200–500 × 106/l). Intervention:Fourty four patients were randomized to receive 5-day cycles of IL-2 (9 Mio IU/d) every 6 weeks (Group A) or whenever the CD4 cell count dropped below the 1.25-fold of baseline (Group B), whereas 20 control patients received the same HAART without IL-2. Outcome measures:The optimal individual treatment interval and the immunological and virological effects of subcutaneously administered IL-2 were analysed. Importantly, the level of cellular in vivo immunity and the frequency of dermatological marker diseases and infectious complications were assessed. Results:IL-2 was well tolerated although fever, influenza-like symptoms and indurated injection sites were commonly encountered. After 1 year of IL-2, there was a median increase of more than 100 × 106/l CD4 cells in both IL-2 groups in contrast to the controls (P < 0.01, 0.01 and not significant). The median HIV load did not increase either in plasma or in lymph nodes. Lymphocyte activation decreased as assessed by MHC class II (P < 0.001), CD25 (P < 0.001) and CD38 expression (P < 0.005). Although delayed type hypersensitivity against common recall antigens increased in both IL-2 groups, it did not reach statistical significance. However, it is of note, that in 7 of 11 (63.6%) patients delayed type hypersensitivity against recombinant HIV antigens improved significantly. Whereas there was no opportunistic infection in either IL-2 group, three cases of Kaposis sarcoma occurred in the controls. Dermatological indicator diseases (thrush, condyloma, herpes simplex) were found to occur more frequently in the control group. Conclusions:Subcutaneous IL-2 in addition to HAART was safe and led to sustained qualitative and quantitative immunological improvements in the majority of patients. Individualisation of therapy intervals further improved the efficacy and tolerance of IL-2.

Expression analysis of classic and non-classic HLA molecules before interferon alfa-2b treatment of melanoma

Individual predictive clinical, immunological, or molecular features for definition of patients with lymph-node-positive melanoma who do not benefit from adjuvant postsurgery high-dose interferon alpha treatment are lacking. Expression analysis of classic and non-classic HLA molecules on melanoma cells metastatic to the locoregional lymph node may help select these patients before treatment.

Oxymetholone promotes weight gain in patients with advanced human immunodeficiency virus (HIV-1) infection

The effect of the testosterone derivative oxymetholone alone or in combination with the H1-receptor antagonist ketotifen, which has recently been shown to block tumour necrosis factor alpha (TNF alpha), on weight gain and performance status in human immunodeficiency virus (HIV) patients with chronic cachexia was evaluated in a 30-week prospective pilot study. Thirty patients were randomly assigned to either oxymetholone monotherapy (n 14) or oxymetholone plus ketotifen (n 16). Patients receiving treatment were compared with a group of thirty untreated matched controls, who met the same inclusion criteria. Body weight and the Karnofsky index, which assesses the ability to perform activities of daily life, and several quality-of-life variables were measured to evaluate response to therapy. The average weight gain at peak was 8.2 (SD 6.2) kg (+ 14.5% of body weight at study entry) in the oxymetholone group (P < 0.001), and 6.1 (SD 4.6) kg (+10.9%) in the combination group (P < 0.005), compared with an average weight loss of 1.8 (SD 0.7) kg in the untreated controls. The mean time to peak weight was 19.6 weeks in the monotherapy group and 20.8 weeks in the combination group. The Karnofsky index improved equally in both groups from 56% before to 67% after 20 weeks of treatment (P < 0.05). The quality of life variables (activities of daily life, and appetite/nutrition) improved in 68% (P < 0.05) and 91% (P < 0.01) of the treated patients respectively. Oxymetholone was safe and promoted weight gain in cachectic patients with advanced HIV-1 infection. The addition of ketotifen did not further support weight gain. These results suggest the need for a randomized, double-blind, placebo-controlled multicentre trial.

Die Bedeutung von oxidativem Stress in der Genese und Therapie chronischer Wunden

ZusammenfassungMolekularer Sauerstoff spielt sowohl in der Genese als auch in der Therapie chronischer Wunden eine entscheidende Rolle. Durch die übermäßige Generierung von reaktiven Sauerstoffspezies kann es zur Ausbildung von oxidativem Stress kommen, der unter anderem durch zytotoxische Effekte zu einer verzögerten Wundheilung führt. Die Elimination von reaktiven Sauerstoffspezies könnte somit einen wesentlichen Bestandteil der Therapie insbesondere von chronischen Wunden darstellen. Aktuell werden erste spezifische therapeutische Optionen mit Antioxidanzien zur Therapie chronischer Wunden in die Klinik eingeführt.AbstractMolecular oxygen plays a central role in the pathogenesis and therapy of chronic wounds. When reactive oxygen species are overproduced, oxidative stress results, with detrimental cytotoxic effects causing delayed wound healing. Therefore, elimination of reactive oxygen species could be an important strategy to improve healing of chronic wounds. Currently first therapeutic strategies targeting reactive oxygen species by antioxidants are being introduced into the treatment of chronic wounds.

Liposomal doxorubicin in AIDS-related Kaposi's sarcoma

taneous KS, progression under interferon alfa (6), Karnofsky index over 70%, constitutional symptoms, and CD4 counts under 100/pL. Complete response was defined as the absence of clinically and histologically detectable disease for more than a month. Partial remission was defined as at least a 50,,o decrease in the sum of the product of the perpendicular diameters of the indicator lesions without the occurrence of

Optionen des Debridements in der Therapie chronischer Wunden

Das Debridement ist definiert als Entfernung von nicht‐vitalem Gewebe aus einer Wunde. In chronischen Wunden wird mit dem Debridement die Elimination von Nekrosen, aber auch die Abtragung von Verbandresten, Fremdkörpern oder anderen avitalen Bestandteilen bezeichnet. Das sachgerechte Debridement stellt eine grundlegende Voraussetzung für den Ablauf eines nicht verzögerten Wundheilungsprozesses dar. Eingebunden in Überlegungen zur Therapie der zugrunde liegenden Ursachen einer verzögerten Wundheilung sollte das Debridement den ersten Schritt in einer adäquaten Phasen‐adaptierten Wundgrund‐Konditionierung chronischer Wunden darstellen.

Lithium and psoriasis : cytokine modulation of cultured lymphocytes and psoriatic keratinocytes by lithium

The predominant cutaneous side effect of lithium is the exacerbation or aggravation of psoriasis, but the pathogenesis is still unclear. The hyperproliferation of keratinocytes and a dense lesional infiltrate of mononuclear cells are the hallmarks of psoriatic skin lesions. Interactions between keratinocytes and T cells are thought to be one reason for an incrased secretion of proinflammatory cytokines and growth factors. To investigate whether lithium influences cytokines of the ‘psoriatic cytokine network’, we established a coculture model with keratinocytes from psoriatic patients and from healthy controls cultured with HUT 78 lymphocytes and measured the cytokine levels of Il-2, Il-6, Il-8, IFNγ and TGFα in the culture supernatants after treatment with lithium. Il-6 levels were slightly elevated in the supernatants obtained from psoriatic and control keratinocyte cultures after lithium treatment, but IFNγ and Il-2 levels were elevated only in the lithium-treated cocultures with psoriatic keratinocytes. In contrast, these two cytokines were not affected by lithium in HUT 78 monocultures or in cocultures with normal epidermal cells. We also found slightly elevated TGFα levels in lithium-treated psoriatic cocultures but not in control cultures. We therefore demonstrated that lithium influences the cell communication of psoriatic keratinocytes with HUT 78 lymphocytes by triggering the secretion of TGFα, Il-2 and, massively, IFNγ. It seems possible that lithium also influences similar parts of the psoriatic cytokine network in vivo.

Expression of Stromelysin 3 in the Stromal Elements of Human Basal Cell Carcinoma

In basal cell carcinoma, release of proteolytic activity is implicated in extracellular matrix degradation and tumor infiltration. The stromelysin metalloproteinase family is a major candidate for the matrix proteolytic activity in infiltrative tumors. However, in murine models of basal cell carcinoma, neither stromelysin 1 nor 2 appears to play a role in tumor infiltration. We have analyzed the expression of the newly described stromelysin 3 in human basal cell carcinoma using Northern blot analysis and in situ hybridization. In 12 of 14 cases, levels of stromelysin 3 expression were more than tenfold above those observed in normal skin. In one of five cases of squamous cell carcinoma, stromelysin 3 expression was tenfold above levels seen in normal skin. Stromelysin 3 expression was either undetectable or extremely weak in all five cases of infiltrative malignant melanoma. In basal cell carcinoma, stromelysin 3 transcripts were localized by in situ hybridization to the stromal tissue immediately adjacent to basal cell carcinoma, the tumor cells themselves being negative. Therefore, expression of stromelysin 3 in stromal cells may be expected to play a significant role in destruction of the basal membrane zone and extracellular matrix in basal cell carcinoma invasion.

Lymphocytes proliferate in blood and lymph nodes following interleukin-2 therapy in addition to highly active antiretroviral therapy

Background Substantial redistribution of lymphocytes occurs upon the initiation of highly active antiretroviral therapy (HAART) and immune-based HIV therapies. Objective To evaluate the relative contribution of apoptosis and proliferation to changes in lymphocyte populations in peripheral blood and lymph node resulting from interleukin-2 (IL-2) therapy in patients receiving stable HAART. Methods Lymphocyte apoptosis was analyzed on various subtypes using fluorescence activated cell sorting with an annexin-V antibody in peripheral blood and by the TUNEL (terminal uridine nucleotide end labelling) method in corresponding lymph node sections. Lymphocyte proliferation was evaluated using an antibody against the cell cycle-associated marker Ki-67 (MIB-1) in peripheral blood and lymph nodes. Results A transient increase in apoptosis was seen in peripheral blood and lymph nodes during a cycle of subcutaneous IL-2. A pronounced proliferative effect of IL-2 (from 6.4% of total lymphocytes in patients only treated with HAART to 23.4% in those treated with HAART + IL-2) was detected in peripheral blood, affecting the CD4, CD8 and CD16/56 subsets to a similar extent. Remarkably, the proliferative effect also occurred in lymphoid tissues. While the lymph node structure gradually disintegrated over 24 months in some individuals, the amount of proliferating lymphocytes, including CD4 cells, B cells and follicular dendritic cells, greatly increased upon IL-2, while HIV RNA load in lymph nodes remained unaffected. Conclusion These results show that IL-2 leads to lymphocyte proliferation in peripheral blood and lymph nodes without an impact on viral load in lymphoid tissue. These results have important implications for attempts to reconstitute the immune system in HIV disease.

Analysis of Pmel17/gp100 expression in primary human tissue specimens: implications for melanoma immuno- and gene-therapy

Abstract Pmel17/gp100-encoded tumor-associated antigens are recognized by cytotoxic T lymphocytes in melanoma patients and may represent attractive target antigens for immuno- and gene-therapeutic strategies. An important prerequisite for identifcation and monitoring of melanoma pateints that could potentially benefit from Pmel17/gpl00-based immuno- and gene-therapies is the detailed knowledge of Pmel17/gpl00 expression in vivo. Immunophenotyping is considerably hampered by the different immunoreactivities of Pmel17/gpl00-reactive antibodies. Therefore, we analyzed an extended series of different primary normal and malignant human tumor specimens for Pmel17/gpl00 expression at the mRNA level. Transcripts were detectable in all malignant melanoma tissue specimens representing all stages of tumor progression, with significant levels even in early and amelanotic melanoma lesions. In contrast, normal melanocytes exhibited significantly less Pmel17/gpl00 mRNA in vivo, as determined by comparative in situ hybridization. Tissue specimens from the retina and substantia nigra also contained Pmel17/gpl00 mRNA, whereas other normal and malignant human tissues were negative. As determined by comparative in situ hybridisation and HMB-45 immunostaining, even tumor tissue lacking Pmel17/gpl00 immunoreactivity contained Pmel17/gp100 transcripts. Our results indicate a melanocytic-cell-lineage-restricted expression of Pmel17/gpl00 with significant transcript levels in all stages of melanoma progression, including early and amelanotic melanoma lesions, and a significantly differential expression between melanoma cells and normal melanocytes in vivo. Owing to its higher sensitivity, phenotyping of individual tumor specimens by mRNA expression analysis seems to be more valuable than phenotyping by immunostaining.