No abstract

It is assumed that detoxification enzymes are functionally redundant and only the simultaneous deficiency of several detoxification enzymes increase the risk for HNSCC in alcohol- and tobacco-exposed individuals.

The prodrug bivatuzumab mertansine (BIWI 1) is a novel CD44v6-targeting humanized monoclonal antibody coupled to the toxin mertansine. In a phase I dose escalation trial 31 patients with squamous cell carcinomas of the head and neck were treated with doses of 25-325 mg/m 2 as a 30-min infusion. Thirteen patients received a second infusion after 3 weeks. Serial serum samples were collected to determine the pharmacokinetic parameters of the prodrug BIWI 1 and of deconjugated BIWI 1 as well as the occurrence of anti-BIWI 1 antibodies. The maximum tolerated dose was reached at 300 mg/m 2 attributable to skin toxicity. No immune response was observed in any patient. For BIWI 1 and deconjugated BIWI 1, clearance values were low and distribution was limited resulting in half-lives of ~3-3.5 days and ~6-7 days, respectively, for single and repeated dosing after three weeks. Overall, interindividual variability of the pharmacokinetic parameters was low. In general, the pharmacokinetics of both compounds after single and repeated dosing was comparable across the entire dose range and no significant accumulation took place. Over the dose range investigated, a dose proportional increase in the exposure of BIWI 1 and deconjugated BIWI 1 was observed. Dose individualization according to body size (weight or body surface area) was found to be appropriate and is recommended for the novel immunoconjugate.

BAC in concentrations used in nasal preparations is ciliotoxic. In healthy individuals, the ciliotoxic effect of BAC is neutralized, probably by components of nasal secretions. No BAC-related proinflammatory effects have been observed. At higher doses than normally used therapeutically, BAC caused significant nasal irritation.

Carcinosarcomas of the urinary bladder are malignant biphasic tumors with an epithelial and a spindle cell component. For the histogenesis of the two components, a biclonal and a monoclonal origin are discussed. We present the immunomorphology and molecular cytogenetics of such a case. The immunohistology of biopsies of the urinary bladder revealed a poorly differentiated urothelial carcinoma (GIII) and a co-existing pleomorphic, spindle cell leiomyosarcoma (GIII). The two components were microdissected and further analyzed for gains and losses of chromosomal material using comparative genomic hybridization. In addition, loss of heterozygosity analyses were included. The tumor components revealed as overlapping core aberrations losses on the short arm of chromosome 9 and on the long arm of chromosome 11. However, both components showed additional aberrations exclusively detected in one of the components. The occurrence of overlapping aberrations strongly argues for a monoclonal origin of this tumor with a common ancestor. The additional aberrations of the components point to an independent and divergent course of tumor progression in both components.

Abstract. Despite advances in surgery, radio-and chemotherapy, therapeutic approaches for patients with head and neck squamous carcinoma (HNSCC) need to be improved. Immunotherapies eliciting tumor specific immune responses might constitute novel treatment options. We therefore investigated the expression and immunogenicity of two tumor-associated antigens (TAA) the receptor for hyaluronic acid mediated motility (RHAMM) and carboanhydrase IX (G250/CAIX) in HNSCC patients. Twenty-two HNSCC samples were examined for the expression of RHAMM and G250 by Western blotting and immunohistochemistry, 14/22 samples were tested for HLA-A2 expression by flow cytometry. For 8/22 samples single tumor-cell suspensions were generated, and mixed lymphocyte peptide cultures (MLPC) were performed to evaluate the frequencies of cytotoxic T cells specifically recognizing RHAMM and G250 using Tetramer staining/multi-color flow cytometry and enzyme linked immunosorbent spot (ELISPOT) assays. RHAMM and G250 were expressed in 73 and 80% of the HNSCC samples at the protein level. A co-expression of both TAAs could be detected in 60% of the patients. In 4/8 HLA-A2 + patients, 0.06-0.13% of CD8 + effector T cells recognized Tetramers for RHAMM or G250 and secreted IFNÁ and granzyme B in ELISPOT assays. RHAMM and G250 are expressed at high frequency and high protein level in HNSCCs and are recognized by cytotoxic CD8 + effector T cells. Therefore both TAAs constitute interesting targets for T cell based immunotherapies for HNSCC.

We assume that detoxification enzymes are functionally redundant and that only the simultaneous deficiency of several detoxification enzymes increases the risk for oral cancer.

Ex vivo opsonization of PBMNC with catumaxomab provided biologically active, tumor targeting cells. Extracorporeal PBMNC coating may be an option to control intravascular cytokine release induced by therapeutic antibodies.