The purpose of this article is to provide an overview on the current clinical application of hyperthermia combined with conventional treatment modalities (e.g. ionizing radiation, chemotherapy) in the treatment of malignant disease. The clinical application of hyperthermia with increase of tissue temperatures (range 40-44 degrees C) has been integrated in multimodal anti-cancer strategies. This review describes selected phase I or II (n = 17) and phase III trials (n = 16) investigating the effect of hyperthermia combined with radiotherapy (n = 10 trials), chemotherapy (n = 15 trials), or both (n = 8 trials) in a total of more than 2200 patients. The trials were performed in a variety of solid tumours (e.g. melanoma, head and neck cancer, breast cancer, cancer of the gastrointestinal or urogenital tract, glioblastoma, sarcoma) in paediatric or adult patients. Profound research has produced a scientific basis for the simultaneous application of hyperthermia in combination with ionizing radiation and/or systemic chemotherapy. Hyperthermia is becoming more accepted clinically, due to the substantial technical improvements made in achieving selected increase of temperatures in superficial and deep-seated tumours. At present, the combination of hyperthermia and chemotherapy or radiochemotherapy is further tested within clinical protocols (phase II/III) in order to improve local tumour control and relapse-free survival in patients with high-risk or advanced tumours of different entities.
Two genetic events contribute to the development of endemic Burkitt lymphoma (BL) infection of B lymphocytes with Epstein-Barr virus (EBV) and the activation of the protooncogene c-myc through chromosomal translocation. The viral genes EBV nuclear antigen 2 (EBNA2) and latent membrane protein 1 (LMP1) are essential for transformation of primary human B cells by EBV in vitro; however, these genes are not expressed in BL cells in vivo. To address the question whether c-myc activation might abrogate the requirement of the EBNA2 and LMP1 function, we have introduced an activated c-myc gene into an EBV-transformed cell line in which EBNA2 was rendered estrogen-dependent through fusion with the hormone binding domain of the estrogen receptor. The c-myc gene was placed under the control of regulatory elements of the immunoglobulin K locus composed of a matrix attachment region, the intron enhancer, and the 3' enhancer. We show here that transfection of a c-myc expression plasmid followed by selection for high MYC expression is capable of inducing continuous proliferation of these cells in the absence of functional EBNA2 and LMP1. c-myc-induced hormone-independent proliferation was associated with a dramatic change in the growth behavior as well as cell surface marker expression of these cells. The typical lymphoblastoid morphology and phenotype ofEBV-transformed cells completely changed into that of BL cells in vivo. We conclude that the phenotype of BL cells reflects the expression pattern ofviral and cellular genes rather than its germinal center origin.
Confirming the initial results, further follow-up continues to show that survival time for patients with stage IIIB/IV NSCLC was longer with L-BLP25 plus BSC compared with BSC alone, with the greatest difference seen in patients with stage IIIB LR disease.
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