Dendritic cell-based cancer immunotherapy targeting MUC-1.

Vaccination therapy using dendritic cells (DC) as antigen presenting cells (APC) has shown significant promise in laboratory and animal studies as a potential treatment for malignant diseases. Pulsing of autologous DCs with tumor-associated antigens (TAA) is a method often used for antigen delivery and choice of suitable antigens plays an important role in designing an effective vaccine. We identified two HLA-A2 binding novel 9-mer peptides of the TAA MUC1, which is overexpressed on various hematological and epithelial malignancies. Cytotoxic T cells generated after pulsing DC with these peptides were able to induce lysis of tumor cells expressing MUC1 in an antigen-specific and HLA-restricted fashion. Within two clinical studies, we demonstrated that vaccination of patients with advanced cancer using DCs pulsed with MUC1 derived peptides is well tolerated without serious side effects and can induce immunological responses. Of 20 patients with metastatic renal cell carcinoma, 6 patients showed regression of metastases with 3 objective responses (1 CR, 2 PR). Furthermore, we found that in patients responding to treatment T cell responses for antigens not used for treatment occurred suggesting that antigen spreading in vivo might be a possible mechanism of mediating antitumor effects. These results demonstrate that immunotherapy in patients with advanced malignancies using autologous DCs pulsed with MUC1 derived peptides can induce immunological and clinical responses. However, further clinical studies are needed to identify the most potent treatment regimen that can consistently mediate an antitumor immune response in vivo.

Secondary leukemia after first-line high-dose chemotherapy for patients with advanced germ cell cancer.

PURPOSE: We investigated the incidence of secondary leukemia in patients treated with first-line high-dose chemotherapy (HDCT) plus autologous stem cell transplantation (PBSCT) for advanced testicular cancer. METHODS: Three hundred and twenty-three patients who were entered into two consecutive prospective Phase-II studies of the German Testicular Cancer Study Group were analyzed. A total of 221 patients had received HD-VIP containing cisplatin, ifosfamide, and etoposide and 102 patients were treated with Tax-HD-VIP containing cisplatin, ifosfamide, etoposide, and paclitaxel, each cycle supported by autologous PBSCT. RESULTS: Patients had received a median cumulative etoposide dose of 4.9 g/m(2) (range, 2.2-9.4 g/m(2)). The median follow-up duration for all patients was 36 months (range, 0-128) with a median follow up time of 50 months (range, 0-128) for patients surviving at least 1 year after therapy. One patient developed a secondary acute myeloid leukemia (s-AML) involving a chromosomal translocation t(11;19)(q23;p13.3) 24 months after the start of chemotherapy resulting in a cumulative incidence of 0.48% [95% confidence interval (CI) 0-1.42]. Additionally, two patients with primary mediastinal germ cell cancer developed a myelodysplastic syndrome. No solid tumors had occurred. CONCLUSIONS: HDCT including high-dose etoposide with autologous PBSCT as first-line therapy for advanced testicular cancer was associated with an acceptably low risk of developing secondary leukemia.

[Compression syndromes]. / Kompressionssyndrome.

Superior vena cava syndrome is a medical condition determined by the mechanisms of extrinsic compression, invasion or thrombosis of the superior vena cava. The most common underlying cause is a malignant process, especially lung cancer and lymphoma. Typical symptoms include progressive dyspnea, head and upper body edema and cyanosis. Most patients can be treated with appropriately directed chemotherapy or radiotherapy. Accurate diagnosis of the underlying etiology needs to be established before treatment. Only under extreme emergency conditions such as laryngeal or cerebral edema irradiation should be initiated without a histological diagnosis. With the refinement of endovascular stents, percutaneous stenting is being increasingly used as primary treatment modality. Metastatic spinal cord compression is one of the most dreadful complications of cancer. In most patients the initial symptom is progressive back pain with an axial or radicular distribution. MRI should be preferred in the diagnostic work-up, corticosteroids be administered promptly after biopsy. Radiation therapy or surgical treatment should be started as soon as possible.

Human skin mast cells rapidly release preformed and newly generated TNF-alpha and IL-8 following stimulation with anti-IgE and other secretagogues.

Several groups have previously reported that rodent or human leukemic mast cells produce inflammatory cytokines such as TNF-alpha and IL-8 as well as the pro-allergic cytokines IL-4, IL-5 and IL-13. Comparatively little is known, however, regarding the ability of normal human skin mast cells to secrete these factors following either IgE-dependent or IgE-independent modes of activation. We therefore investigated whether normal human skin mast cells produce these cytokines following stimulation by a variety of secretagogues. Enriched isolated skin mast cells released both TNF-alpha and IL-8 following activation with either anti-IgE, SCF, substance P, compound 48/80 or A23187. This release was dose- and time-dependent, with maximal levels being reached within 4 h of stimulation involving, in part, the secretion of preformed stores of both cytokines. In accordance with this, using lysates of highly purified (>90%) skin mast cells, we could demonstrate that both TNF-alpha and IL-8 mRNA and protein were present in both unstimulated as well as stimulated mast cells. In stark contrast to these results, no significant levels of either IL-4, IL-5 or IL-13 were detected, regardless of the secretagogue used or the period of stimulation. These results show that human skin mast cells are capable of rapidly secreting pro-inflammatory cytokines like TNF-alpha and IL-8 following IgE-dependent activation and stimulation by the neuropeptide substance P, SCF and the basic polypeptide analogue compound 48/80. In contrast to other types of human mast cells however, human skin mast cells were incapable of secreting IL-4, IL-5 or IL-13 in these settings.