SummaryExtramedullary disease in patients with multiple myeloma is a rare event, occurring mostly in advanced disease or relapse. Outcome is poor and prognostic factors predicting the development of extramedullary disease have not been defined. We investigated cytogenetic alterations of myeloma cells in different extramedullary manifestations by adapting the fluorescence in situ hybridization (FISH) technique in combination with cytoplasmic immunoglobulin staining to study the cytogenetics of plasma cell tumours on paraffin embedded material. Thirty six patients were investigated: 19 with extramedullary disease, 11 with skeletal extramedullary disease and six with solitary extramedullary plasmacytoma. The first two groups showed the following results: del(17p13) 32% vs. 27%, del(13q14) 35% vs. 27%, MYC-overrepresentation 28% vs. 18% and t(4;14) 37% vs. 18%. We detected an overall higher incidence of del(17p13) in both groups compared to data from bone marrow samples of multiple myeloma reported to date (range 7-16%). The solitary extramedullary plasmacytomas presented overall less cytogenetic aberrations than the other groups. Most important, three patients with extramedullary disease and one with skeletal extramedullary disease presented different FISH findings in the extramedullary tumour compared to their bone marrow plasma cells. del(17p13), occurring additional in three of four cases, seems a strong marker for extramedullary progression of myeloma.

We investigated the ability of human lung cancer cells of different histological subtypes to cause platelet aggregation. Tumor-cell-induced platelet aggregation (TCIPA) was studied in vitro in 13 human lung cancer cell lines [small-cell lung cancer (SCLC), squamous-cell lung cancer, large-cell lung cancer, adenocarcinoma and alveolar-cell lung cancer]. Three tumor cell lines failed to aggregate platelets in platelet-rich plasma, whereas platelet aggregation was induced by 12 cell lines when added to washed platelets and minimal amounts of platelet-poor plasma (0.5% v/v). The thrombin antagonist hirudin inhibited TCIPA in non-small-cell lung cancer cell lines (NSCLC). In SCLC, TCIPA was fully abolished only when the ADP scavenger apyrase was added to hirudin. Thus ADP and thrombin generation by these tumor cell lines are responsible for platelet aggregation. The ability to activate platelets independently of coagulation factors VII and X was demonstrated for 8 cell lines. Electron-microscopically, direct tumor-cell/platelet contact was found to be the initiating mechanism of TCIPA in SCLC, whereas tumor-cell/platelet contacts in NSCLC could only be observed at the peak of the aggregation curve. Lung cancer cells activate platelets in vitro by generation of thrombin and/or ADP.

The activation markers (means +/- SEM) were lower in the 33 responders (RSP; complete or partial remission) than in the 66 non-responders (NRSP): TAT 3.96 +/- 0.48 vs. 9.69 +/- 1.57 micrograms/l (P < 0.001), and F1 + 2 1.09 +/- 0.09 vs. 1.64 +/- 0.25 nmol/l (P < 0.05). TAT levels were > 6 micrograms/l in 30 of 66 (45%) NRSP, but only 4 of 33 (12%) RSP. 88% of patients with TAT < or = 6 micrograms/l achieved remission, and 45% with TAT > 6 micrograms/l (P = 0.0014). In the subgroup of 46 patients with advanced disease, the six RSP showed lower TAT than the 40 NRSP: 4.65 +/- 0.94 vs. 11.92 +/- 2.49 micrograms/l (P < 0.01); one of six (17%) RSP, but 21 of 40 (53%) NRSP showed TAT > 6 micrograms/l. These data suggest that in lung cancer the activation of coagulation is an independent prognostic factor, since TAT levels were different between RSP and NRSP, also within the homogeneously unfavourable metastatic subgroup. It should be further studied, whether TAT can identify patients, whose prognosis could be improved by anticoagulation as an adjunct to standard antineoplastic therapy.

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Patients with polycythemia vera (PV) have a high risk of thrombosis. However, thrombosis is not sufficiently predictable with standard diagnostic procedures. We report on a patient with PV and recurrent thrombosis who nevertheless had a low platelet count while under therapy with hydroxyurea. As a result of duodenal ulcer and gastrointestinal bleeding, treatment with phenprocoumon was stopped years ago. Recently, heterozygosity for the factor V gene defect was diagnosed and anticoagulation therapy was reconsidered. In conclusion, the presence of resistance to activated protein C was an additional thrombotic risk factor that was important for our decision to change the treatment strategy in our patient.