Correlation of cytogenetic findings with clinical features in 18 patients with inv(3)(q21q26) or t(3;3)(q21;q26).

An inversion in the long arm of chromosome 3--inv(3)(q21q26)--or a translocation between both homologous chromosomes 3--t(3;3)(q21;q26)--is found specifically in myeloid neoplasias characterized by disturbances of thrombopoiesis and megakaryocyte development. Cytogenetic findings were correlated with clinical and hematological data in altogether 18 patients with acute nonlymphocytic leukemia (ANLL) and with inv(3) (13 patients) or t(3;3) (five patients), six of whom were male and 12 who were female. Chromosomal changes in addition to the 3q anomalies were demonstrated in 14 out of 18 patients, predominantly numerical and structural aberrations of chromosome 7 (12 cases) and/or abnormalities of 5q (five cases). Complex karyotype abnormalities were observed in six of 13 patients with inv(3), but in only one of five patients with t(3;3). In ten out of our 18 patients a preceding myelodysplastic syndrome (MDS) and/or exposure to mutagenic/carcinogenic agents had been established. In eight patients the morphology of ANLL blasts was immature (FAB subtype M1); in three patients ANLL-M4, and in two patients each ANLL-M5, M6, and M7 was diagnosed; in one patient with antecedent MDS the leukemic blasts were not classifiable according to the FAB criteria. A disturbed megakaryocyte development, characterized by an excess of micromegakaryocytes was observed in 14 patients, seven of them showed normal or elevated platelet counts as an unusual feature in patients with ANLL. The clinical course and outcome was extremely poor: 15 of 18 patients died within 10 months after the diagnosis of ANLL. Because of their missing response to conventional chemotherapy, patients with inv(3) or t(3;3) have to be estimated as at high risk. The characterization of genes affected by inv(3) or t(3;3) could help to elucidate molecular changes leading to impaired proliferation and differentiation of hematopoietic cells, also of the megakaryocytic lineage. Based on molecular genetic findings new therapeutical approaches could be designed.

Intermittent regional therapy with rt-PA is not superior to systemic thrombolysis in deep vein thrombosis (DVT)--a German multicenter trial.

In a prospective and randomized multicenter trial the efficacy of intermittent regional and systemic thrombolytic therapy for DVT was evaluated. 137 patients with phlebographically confirmed acute DVT above the calf region were treated with 20 mg of rt-PA for 4 h each day. Thrombolysis was applied either locally via a dorsal pedal vein of the firmly bandaged affected leg or systemically using a cubital vein. Treatment lasted for 4-7 days, and during this time unfractionated heparin was applied continuously with the dosage adjusted according to aPTT (1.5-2.0 times the normal value). A second phlebography was performed within 24 h after the end of treatment. Results were evaluated by an independent radiologist who was unaware of the treatment given. Significant thrombolytic results (e.g. lysis of more than 50% of the original thrombus and complete recanalization of all affected veins) were reached in only 1/3 of all patients. Rates of recanalization did not differ in both groups and bleeding complications occurred in 26.5%. We conclude that intermittent local or systemic application of 20 mg rt-PA seems to be ineffective in the treatment of DVT.

Influence of mesna and cysteine on the systemic toxicity and therapeutic efficacy of activated cyclophosphamide.

Presumably the coadministration of the uroprotector mesna in cyclophosphamide treatment does not influence the systemic activity of its activated metabolite. This was newly investigated in a mouse model. The LD50 values of i.p. administered mafosfamide, a derivative of act. CP, were increased by the simultaneous i.p. administration of mesna (mafosfamide: mesna 1:2 on a molar weight basis) from 590 mg/kg to 750 mg/kg, and after i.v. injection of cytostatic and thiol from 505 mg/kg to 810 mg/kg. Administration of 2 X molar cysteine i.v. or i.p. to mafosfamide-treated animals was even more effective against its lethal toxicity (LD50 i.p. 1800 mg/kg and i.v. 1130 mg/kg). Bone marrow toxicity (severe leukocytopenia) was partially abolished by both thiols. Also the therapeutic efficacy of act. CP against L1210 leukemia in DBA2 mice was reduced by 50% in the presence of cysteine and of mesna. Compared with mesna the higher detoxification effect of cysteine is attributed to its longer half-life (t1/2 20 min vs 12 min of mesna) and presumably an accumulation of cysteine in some cell systems (distribution coefficient 1.20 ml/g vs 0.68 ml/g of mesna). Nevertheless, our study clearly demonstrates a distinct systemic deactivation of act. CP by mesna, which might be of clinical relevance.

Effects of fosfomycin, mesna, and sodium thiosulfate on the toxicity and antitumor activity of cisplatin.

Fosfomycin and mesna were investigated in rats and mice concerning their detoxifying effects on cisplatin toxicity in comparison to sodium thiosulfate, a known protector against cisplatin nephrotoxicity. After separate i.p. injection of cisplatin and fosfomycin (500 mg/kg) or mesna (800 mg/kg) a slight increase in the 50% lethal dose of cisplatin was found in all animals. In mice sodium thiosulfate proved to be far more effective in preventing lethal toxicity and nephrotoxicity as measured by blood urea nitrogen increase. Fosfomycin and mesna were almost without influence on cisplatin treatment of L-1210 leukemia whereas their inhibition of the antitumor effect against S-180 ascites sarcoma (increase of in cisplatin dose to cure 50% of animals from 2.0 mg/kg to 3.5/4.7 mg/kg cisplatin) was similar to thiosulfate, which showed a strong inhibiting effect in the treatment of both tumors. In rats fosfomycin distinctively reduced the antitumor efficacy of cisplatin against Yoshida ascites sarcoma. Thus the concurrent injection of fosfomycin and mesna reduced both the toxicity and the antitumor activity of cisplatin. Therefore their simultaneous administration in addition to cisplatin via the same injection route should be avoided. Due to the weak detoxifying efficacy of fosfomycin and mesna they cannot be used instead of sodium thiosulfate for renal protection against cisplatin toxicity in local i.p. treatment modalities.

[First experiences with temporary vena cava filters]. / Erste Erfahrungen mit temporären Vena-cava-Filtern.

AIM: For prophylactic measures we used 3 different temporarily insertable vena cava filters. MATERIAL AND METHODS: In 49 patients we inserted 12 Cook-filters (6 transjugular, 6 transfemoral), 11 Angio-cor-filters (1 transjugular, 10 transbrachial), 26 Antheor-filters (1 transjugular, 1 transfemoral, 24 transbrachial). 35 patients underwent a lysis therapy, 11 a major operation of the pelvis, and 3 patients a Caesarean section. RESULTS: No patient suffered from a clinically significant pulmonary embolism after filter insertion, but complications occurred caused by the basic therapy (1 lethal abdominal aortic aneurysm operation, 1 cerebral bleeding, 2 retroperitoneal haematomas, 2 streptokinase fever reactions, 1 compartment syndrome, 1 macro-haematuria) or by therapy joined with the filters insertion (2 groin haematomas, 2 haematomas of the bend of the elbow, 2 subclavian vein thrombosis, 1 catheter dislocation, 1 infection, 1 air embolism, 1 break of a leg of the filter basket). CONCLUSION: Temporary vena cava filters are highly efficient in preventing pulmonary embolism, but the side-effects show that they should only be inserted in patients with known deep vein thrombosis and a high risk treatment of the underlying disease.

Nocardial infection in a renal transplant recipient--a case report.

Report is given about a 50 year old renal transplant recipient who developed signs of a severe pneumonia 37 days post transplantation. The diagnosis following chest X-ray and physical examination was multifocal nodular pneumonia of unknown origin in an immunosuppressed patient. Although a varying antibiotic chemotherapy was administered at high doses he died 4 weeks later without identification of the infective agent. Post-mortem and microbiological examinations revealed a systemic suppurative infection caused by Nocardia asteroides. Percutaneous or open lung biopsy within the first 10 days after onset of clinical symptoms has to be recommended to secure the diagnosis and treatment with sulphonamides.

[Fatal pulmonary embolism in venous thrombosis of the leg and pelvis during lysis therapy]. / Tödliche Lungenembolie bei Bein-Beckenvenenthrombose unter Lysetherapie.

A 19-year-old girl had for four weeks the clinical signs of recurrent pulmonary emboli and deep-vein thrombosis (tachycardia, dyspnoea, right inguinal pain), which had been misdiagnosed. The correct diagnosis was made only after drastic deterioration in her condition following appendicectomy for falsely diagnosed appendicitis. Urokinase infusion (80,000-160,000 IU/h for 11 days) having failed to bring about improvement, much greater than ultra-high much less than thrombolysis with streptokinase was begun (250,000 IU streptokinase over 30 min, followed by 9 million IU over 6 hours). Fatal pulmonary embolism occurred seven hours after the end of the infusion. Autopsy revealed extensive separation of thrombotic material in the pelvic veins. This observation and other reports should serve as a warning against using streptokinase in ultra-high doses if large veins, as those in the pelvis, are involved.

[Congenital protein C deficiency and thromboembolic diseases]. / Kongenitaler Protein-C-Mangel und thromboembolische Erkankungen.

Besides its cofactor protein S and antithrombin III, protein C is one of the most important inhibitors of plasma coagulation. In seven members of a family as well as in three further unrelated patients, a congenital protein C deficiency with thromboembolic diseases including a coumarin necrosis was observed in two cases. Deficiency of protein C predisposes to the occurrence of thromboembolism, but the severity of the underlying heterozygotic genetic defect can also vary within the family. Long-term oral anticoagulation with phenprocoumon is the therapy of choice. Genetic counselling should always be carried out.

Translocation of c-abl oncogene and PDGFB (c-sis) gene in a case of CML with 46,XY, t(22;22).

In a case of CML with a variant Philadelphia translocation (Ph1 or Ph) t(22;22) (q11;q13) in bone marrow cells and unstimulated peripheral blood cells, no cytogenetically detectable involvement of chromosome 9 was observed. Southern blot experiments using probes specific for bcr and c-sis however revealed rearrangement of the bcr, but not of PDGFB (c-sis) gene. Northern blot analysis of bone marrow RNA showed a very weak signal with the c-sis probe, while in a lymph-node biopsy PDGFB m-RNA could not be detected. Chromosomal in situ hybridization gave evidence for translocation of c-abl from chromosome 9 to Ph and of PDGFB from chromosome 22 to chromosome 9, as the result of a threefold translocation t(9;22;22).

[Indications and results of surgically treated, with temporary vena cava filter managed patients]. / Indikation und Ergebnisse bei operierten, mit temporären Vena-cava-Filtern versorgten Patienten.

Heavily injured patients, patients who underwent operations on pelvis, hips, abdomen or malignoma surgery, as well as gynaecology patients suffering from malignoma or previous deep femoral vein thrombosis in connection with pregnancy or obesity are at risk to suffer from pulmonary embolism with potentially lethal course. In a retrospective study we evaluated the advantage of the prophylactic use of temporary vena cava filters and their side effects. The indications were 18 cases of surgery, with known iliacal vein or cava thrombosis, 3 cases of pregnancy thromboses, and 1 high-dose heparinisation after acute pulmonary embolism without lysis. Additionally a postoperative lysis therapy was performed due to a life-threatening pulmonary embolism in 1 patient. 1 Cook filter (transfemoral), 3 Angiocor filters (transbrachial), and 19 Antheor filters (3 transjugular, 5 transfemoral, 11 transbrachial) were implanted. In these patients no clinically visible pulmonary embolism occurred under therapy, 3 thrombi were detected in the filter. Complications were caused either by the underlying therapy alone (1 lethal outcome of abdominal aortic aneurysm surgery), by the combination of therapy and cava filter implantation (1 case of arm haematoma, 1 ascending thrombosis) or by filter implantation alone (2 cases of v. subclavia thrombosis, 1 dislocation, 1 basket rupture). Since temporary cava filters have no secondary complications per se, their use seems justified as long as there is strict indication including presence of iliacal vein or cava thrombosis and risk of thrombi mobilisation.

Moderate dose escalation for advanced stage Hodgkin's disease using the bleomycin, etoposide, adriamycin, cyclophosphamide, vincristine, procarbazine, and prednisone scheme and adjuvant radiotherapy: a study of the German Hodgkin's Lymphoma Study Group.

The BEACOPP (bleomycin, etoposide, adriamycin, cyclophosphamide, vincristine, procarbazine, and prednisone) regimen, a rearranged and accelerated version of the standard COPP/adriamycin, bleomycin, vinblastine, and dacarbazine (ABVD) chemotherapy, has been shown to be effective and safe in a previous pilot study for advanced stage Hodgkin's disease (HD). The present study aimed to determine a maximum practicable dose of three drugs, ie, etoposide, adriamycin, and cyclophosphamide, for which acute toxicities were acceptable and to assess the feasibility of the escalated scheme. Sixty untreated patients with advanced stage HD were enrolled in this study. Radiotherapy was given in 44 patients (73%) after chemotherapy to initial bulk lesions and residual disease. Granulocyte-colony stimulating factor (G-CSF) was given from day 8 to prevent prolonged neutrocytopenia and severe infections. The intended doses of adriamycin, etoposide, and cyclophosphamide in the BEACOPP schedule could be substantially escalated: adriamycin from 25 to 35, cyclophosphamide from 650 to 1,200, and etoposide from 100 to 200 mg/m2. The major toxicities were leukocytopenia and thrombocytopenia with considerable heterogeneity between individual patients. Of 60 patients, 56 (93%) achieved a complete remission (CR). At a median observation of 32 months, the rates of survival and freedom from treatment failure (FFTF) were estimated to be 91% (95% confidence interval 83% to 99%) and 90% (82% to 98%). These results show that a moderate dose escalation of adriamycin, cyclophosphamide, and etoposide of the baseline BEACOPP regimen is feasible. The escalated BEACOPP regimen shows very encouraging results in advanced stage HD and is now being compared in a randomized phase III study with BEACOPP at baseline dose level.