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In patients up to 70 years of age with colon carcinoma stage III adjuvant chemotherapy with infusions of fluorouracil (5-FU) or oral capecitabine combined with oxaliplatin should be the standard method. A new standard for the palliative treatment of Her2/newly positive advanced gastric cancer and cancer at the gastro-esophageal junction is the administration of trastuzumab combined with chemotherapy. Patients with high-risk soft tissue sarcoma can be helped, in addition to surgical resection and subsequent radiotherapy, by neoadjuvant chemotherapy combined with regional deep hyperthermia. For patients with lung cancer additional individualized treatment is about to become routine. In addition to the EGFR mutation status, all non-smokers should in future be tested for aberration in the anaplastic lymphoma kinase (ALK) gene.

Despite the fact that soft tissue sarcomas are representing a rare tumor entity with a low incidence rate of about 2-4 per 100,000 per year, they highly require a multimodality therapeutic approach. Based on a reference pathology a complete surgical resection is the first treatment goal. After accomplished R0 resection the local relapse rate can be further decreased by an adjuvant radiotherapy. For primarily irresectable or only partially respectable tumors a neoadjuvant chemotherapy combined with regional hyperthermia should be considered. Patients with metastasized soft tissue sarcomas should receive an anthracyclin-based chemotherapy in a palliative intention. Prognostically more favorable are gastrointestinal stroma tumor, also in advanced stages with metastases, since the tyrosine kinase inhibitors imatinib and sunitinib can induce durable remissions.

Recombinant adeno-associated virus (rAAV) is a promising vector for somatic gene therapy due to the ability to transduce terminally-differentiated and non-dividing cells, the lack of any apparent pathogenicity, a low immunogenicity, a relatively high stability of transgene expression, and the potential for targeted integration. Improved methods of rAAV packaging allow the generation of concentrated and highly purified rAAV for clinical trials. Preclinical studies with rAAV are currently in progress for the treatment of a variety of inherited monogenic defects, but also for acquired diseases like HIV infection and cancer. Because of the broad host range of wild type AAV, rAAV is able to transduce a variety of human tissues, preferentially those of epitheloid origin, with high efficiency and therefore may be used for various clinical applications. Whilst several issues including safety, tissue tropism and methods to achieve site-specific integration need further improvement, rAAV certainly has a sufficient number of advantages to be seriously considered as a gene therapy vector.

The efficacy and toxicity of a combination of fludarabine and cyclophosphamide (FC) was evaluated in patients with B-cell chronic lymphocytic leukaemia (CLL). Between April 1997 and July 1998, 36 patients with CLL (median age 59 years) received a regimen that consisted of fludarabine 30 mg/m(2) in a 30-min IV infusion, d 1-3, and cyclophosphamide 250 mg/m(2) in a 30-min IV infusion on d 1-3. Cycles were repeated every 28 d. Twenty-one patients had received between one and three different treatment regimens prior to the study, while 15 patients had received no prior therapy. The median Eastern Cooperative Oncology Group performance score was 1. One patient was at Binet stage A, 18 were stage B and 17 patients were stage C. Objective responses, assessed according to the revised guidelines of the National Cancer Institute-sponsored Working Group, were recorded in 29 out of 32 assessable patients (90.6%). Twenty-four partial remissions and five complete remissions were observed. Two patients showed no change and one patient showed disease progression. At February 2000, three of the responders had relapsed. Severe neutropenia, anaemia and thrombocytopenia (Common Toxicity Criteria grade 3 and 4) were observed in 25, six and six patients (69.4%, 16.7% and 16.7%) respectively. Other side-effects were uncommon. No treatment-related deaths and no grade 3 or 4 infections occurred. We conclude that the combination of fludarabine and cyclophosphamide showed significant activity in patients with CLL. Myelosuppression was the major side-effect. These results warrant further study on the FC combination in randomized trials.

Primary malignant melanoma of the lung (PMML) is a rare neoplasm that may be misdiagnosed as one of the more common types of lung cancer. Most cases are characterized by a very poor prognosis, ultimately leading to the patient's death. Since an optimal systemic treatment schedule is not established so far, early detection of lymph node metastases may be important for surgical interventions. We report on a 55-year-old male patient with a primary bronchial malignant melanoma of his left lower lobe that was treated by pneumonectomy. 11 and 17 months after removal of the PMML, suspicious lymph nodes in the patient's left axilla were identified by 7.5 MHz-ultrasound examinations. Again surgical treatment was performed and histopathology showed lymph node metastases of malignant melanoma. During adjuvant therapy with interferon alpha (3 x 6 Mio IE per week) no further relapse has been observed with a follow-up of 8 months after the last operation. An overview of primary melanoma of the lung is given and diagnostic options are discussed. The 7.5 MHz-ultrasound examination appears to be especially helpful in the early detection of lymph node metastases leading to early initiation of surgical treatment possibly associated with a prolonged survival in our patient.

Adeno-associated virus (AAV) is a single-stranded DNA dependovirus of the family of Parvoviridae which has promising features as a vector for somatic gene therapy. Different recombinant (r) AAV vectors have been generated which seem to have some advantages in comparison with other vectors, like the ability to transduce terminally differentiated and non-dividing cells, the lack of any apparent pathogenicity, a low immunogenicity, a relatively high stability of transgene expression and the potential of targeted integration. Recent improvements of rAAV packaging now allow the generation of sufficient quantities of rAAV for clinical trials. Pre-clinical studies with rAAV are currently performed not only for the treatment of a variety of inherited, monogenic defects such as s-thalassemia, sickle cell anemia, Fanconi anemia, chronic granulomatous disease, Gaucher disease, metachromatic leukodystrophy, or cystic fibrosis, but also for acquired diseases like infection with HIV and non-Hodgkin’s lymphoma. The diversity of these studies indicates that rAAV might have a broad range of clinical applications. A first clinical trial with rAAV vectors has been started for cystic fibrosis. While several important issues including safety, tissue tropism and methods to achieve site-specific integration need further clarification, rAAV seems to have a sufficient number of advantages to be considered seriously as a future gene therapy vector.

A 64-year-old woman with an 11-year history of systemic lupus erythematosus and amputation of her left lower leg as a consequence of arterial embolism, presented with two large, non-healing ulcers on her right shank. Pyoderma gangrenosum associated with secondary antiphospholipid syndrome was diagnosed based upon the typical clinical features and increased antibodies to cardiolipin. Although an aggressive therapy with corticosteroids and cyclosporine was started, her condition continued to worsen. She finally died as a result of sepsis. We discuss the difficulties in diagnosis and therapy of SLE combined with the antiphospholipid syndrome and pyoderma gangrenosum.

Adeno-associated virus (AAV) is a single-stranded DNA dependovirus of the family of Parvoviridae that has promising features as a vector for somatic gene therapy. Different recombinant (r) AAV vectors have been generated that seem to have some advantages compared with other vector systems, such as the transduction of terminally differentiated and non-dividing cells, the lack of any apparent pathogenicity, low immunogenicity, relatively high stability of transgene expression, and the potential of targeted integration. Recent improvements in rAAV packaging should allow the generation of sufficient quantities of rAAV for clinical trials. Preclinical studies with rAAV are currently being performed for the treatment of a variety of inherited monogenic defects, such as beta-thalassemia, sickle cell anemia. Fanconi anemia, chronic granulomatous disease, Gaucher disease, metachromatic leukodystrophy and cystic fibrosis, and of acquired diseases, such as HIV infection and non-Hodgkin lymphoma. The diversity of these studies indicates that rAAV might have a broad range of clinical applications. A first clinical trial with rAAV vectors has been started for cystic fibrosis. While several important issues, including safety, tissue tropism and methods to achieve site-specific integration, need further clarification, rAAV seems to have a sufficient number of advantages to be seriously considered as a future gene therapy vector.

CD30 is a transmembrane receptor of the nerve growth factor/tumor necrosis factor receptor superfamily. Its expression associated with Hodgkin's lymphoma and a subset of non-Hodgkin's lymphoma. Recently, its ligand (CD30L) has been cloned. CD30L enhances the proliferation of peripheral T cells and the Hodgkin's cell line HDLM-2 but seems to exert antiproliferative effects on large cell anaplastic lymphoma cell lines. Since tyrosine kinases are critical regulators of cell growth, we investigated whether CD30L induced changes in cellular tyrosine phosphorylation in CD30-positive lymphoma cell lines. Stimulation with CD30L or with an agonistic mAb against CD30, M44, induced a rapid, transient, and concentration-dependent tyrosine phosphorylation of a cytosolic protein of M(r) 42,000 (p42) in the Hodgkin's lymphomas cell line HDLM-2 but not in other CD30-positive lymphomas. In HDLM-2 cells, the phrobol ester phorbol 12-myristate 13-acetate also stimulated tyrosine phosphorylation of p42, and this effect was enhanced by M44. In marked contrast, agents stimulating the protein kinase A pathway, like forskolin or dibutyryl cAMP, did not affect tyrosine phosphorylation of P42. By immunoprecipitation with mAbs against mitogen-activated protein kinase (MAPK; p42ERKII), a M(r) 42,000 protein was identified which comigrated with p42 on SDS gels and which was phosphorylated on tyrosine residues in response to stimulation of CD30. Immune complex kinase assays showed that M44 mAb induced the activation of MAPK (p42ERKII) and the phosphorylation of a MAPK substrate, myelin basic protein. Taken together, the results suggest that CD30L induces the tyrosine phosphorylation and activation of the MAPK p42ERKII isoform in HDLM-2 cells. These findings may have implications for the understanding of the pathogenesis of Hodgkin's disease.

One approach for a rational postremission therapy of acute leukemia is based on detection of residual leukemic blasts. Immunophenotyping with monoclonal antibodies, quantitative DNA analysis for aneuploidy, PCR analysis of clonal immunoglobulin and TCR gene rearrangements as well as studies regarding growth of progenitor cells in clonogenic assays are only a selection of approaches for diagnosis of minimal residual disease (MRD) [1–4]. In this study leukemic cells were examined for aberrant transcripts of two differentiation-associated genes, the protooncogene ETS 1 and the gene for the enzyme marker terminal deoxynucleotidyl transferase (TdT).

The genes of the ets family are thought to code for a novel class of transcriptional factors. These proteins have a specific DNA-binding domain different from the basic domain of both the helix-loop-helix and leucine zipper families of DNA-binding proteins. The ets-1 gene product has been shown to bind to the enhancer region of the human T-cell receptor alpha gene during thymocyte ontogeny. This finding explains the high expression of ets-1 observed in T cells and the correlation between ets-1 expression and the expression of the T-cell receptor gene during fetal development. The ets-1 gene is also possibly biologically active in neural cells. By using RNA in situ hybridization analysis, we demonstrate the presence of ets-1 transcripts in cells of peripheral embryonal neuroectodermal tumors, specifically neuroepithelioma and neuroblastoma. In addition, the gene is found transcribed in Ewing's sarcoma, postulated to be ontogenetically related to tumors derived from the neural crest.