Harald Wagner

A multimodal treatment approach including high-dose chemotherapy in very advanced gastric cancer: evidence for control of metastatic disease

Summary:The present multimodal treatment approach was designed to achieve prolonged tumor control in advanced gastric cancer. A total of 26 patients with stage IV gastric cancer (metastatic disease n=25), ECOG performance status 0–3 and laparoscopically evaluated peritoneal status received a modified EAP schedule to prove chemosensitivity and to mobilize autologous peripheral blood stem cells (aPBSC). Patients without progressive disease proceeded to tandem high-dose chemotherapy (HD-CT) and aPBSCT. Patients with >50% reduction of the target lesion received a second cycle of HD-CT. Responders were selected for local R0 resections (D2 resection) according clinical criteria. Of 26 patients, 20(77%) achieved partial remission after dose-intensive chemotherapy: local R0 resection was achieved in 12 out of 14 patients selected for surgery (46% of all patients). Eight of these R0-resected patients initially had peritoneal carcinomatosis. With a median follow-up of 3.2 years, four patients are still alive. The median overall survival was 8.4 months (CI 2.5–14.4 months), for histologic regression grade 3 (seven out of 25 patients, 28%) 29 months (CI 12–46 months). The combined treatment approach is tolerable and feasible in advanced disease and opens a therapeutic window for a significant proportion of patients, even in cases with histologically proven peritoneal carcinomatosis.

An Alternative Transcript of the Human GM-CSF Receptor Alpha Chain Lacking the Signal Sequence Is Found in AML Blasts and Normal Controls

Blast cells from 70% of patients with acute myeloid leukaemia (AML) show autonomous growth characteristics. One of the autocrine growth factors involved is granulocytemacrophage colony-stimulating factor (GMCSF). The receptor for GM-CSF (GM-CSFR) is composed of at least 2 chains. The alpha chain binds GM-CSF specifically but with low affinity. The beta chain confers high affinity binding when associated with the alpha chain. So far at least 6 alternative transcripts of the alpha chain have been described which differ from each other in the 3′ end of the coding sequence. Using RT-PCR of RNA from normal bone marrow mononuclear cells and blast cells from patients with AML we have found an mRNA transcript with a deletion of 102 nucleotides (nt) between nt 123 and 226 of the published sequence. This deletion removes the original initiation codon and the signal peptide sequence. Translation would still be possible starting from ATG (nt 282-284), creating an alpha chain lacking the signal peptide and the first 22 amino acids of the extracellular protein sequence. In RNAse protection assays transcripts carrying the 102 nt deletion were expressed at levels of about 20% of the total alpha chain message in normal bone marrow cells. In blasts from AML patients expression varied between 5 and 60%. Full length GM-CSFR alpha RT-PCR products from a patient with AML showed that transcripts carrying the 102 nt deletion also lack the sequence coding for the transmembrane domain. Translation of this mRNA transcript would therefore produce a signal peptide deficient, soluble GM-CSFR alpha isoform that might be confined to the cytosol. It is possible that such a cytosolic receptor chain could be involved in intracellular autocrine loops.