Biomedical subjects
Publications and source records attributed to H Lenk.
This is an overview of modern aspects concerning diagnostics and therapy in in children with septic bursitis. A close cooperation of pediatricians, pediatric surgeons, microbiologists and radiologists in this field is essential.
Fourteen patients with metastatic breast cancer previously treated with one chemotherapy regimen received Pirarubicin at a dose of 70 mg/m2 at 3-week intervals. In 7 patients the dose had to be reduced, in 1 patient to 40 mg/m2 and in 6 patients to 50-60 mg/m2. There were 1 complete and 2 partial remissions. These objective responses were observed in soft tissue, lung and pleural areas and lasted 1+; 4+ and 5+ months. Grade 3 and 4 leukopenia was found in 42%, grade 3 thrombocytopenia in 2%, grade 3 nausea/vomiting in 29% of the cycles. Grade 1 and 2 alopecia occurred in 64% of the patients, the remaining 36% of the patients did not suffer from any alopecia. No cardiotoxic side effects were observed in 13 patients. In 1 patient with severe coronary heart disease extrasystoles and reduction in left ventricular ejection fraction occurred. Pirarubicin has antitumor activity in previously treated metastatic breast cancer patients.
A 12-year-old boy with severe hemophilia A fell ill with high fever and painful swelling of joints. There was a delay of four days in the diagnosis of septic arthritis. The course of the disease shows some important distinguishing criteria, speaking in favour of septic arthritis: 1. longlasting temperature above 39 degree C; 2. an elevated peripheral leukocyte count; 3. increasing complaints despite normalisation of the coagulation defect.
Based on a phase I study in 1986, 22 patients have been entered in a phase II study of high-dose human tumor necrosis factor (rH-TNF) since May 1987. Of these patients, 18 are evaluable at present, 2 are still under investigation, and 2 have dropped out. All had advanced stages of cancer (9 soft-tissue sarcomas, 3 melanomas, 5 hypernephromas) and inclusion in the study was ethically acceptable (informed consent). The daily dose of rH-TNF was 15 x 10(5) units/m2, escalated to 21 x 10(5) units/m2 (683-956 micrograms/m2 every week; range 1-6 cycles). Additional prophylactic ketoprofen administration was carried out. Of the 18 evaluable patients, 4 responded with no change (2/4, clinical improvement) and 14 showed progressive disease. The main toxicities observed were hypotension (decrease in systolic blood pressure, 21-60 Torr), leukocytosis, increases in ALAT/ASAT (WHO grade 0-4), fever (WHO grade 1-2), chills (mild to moderate), neurotoxicity (WHO grade 0-2), and nausea/vomiting (WHO grade 0-3).
An organ culture assay for in vitro chemosensitivity testing was used to predict clinical responses of various tumors to antineoplastic chemotherapy. 9 patients with advanced mammary carcinomas, 7 patients with metastatic malignant melanomas, 1 patient with advanced ovarian cancer, 1 with bronchogenic carcinoma, 1 with metastatic leiomyosarcoma and 1 patient with a metastatic carcinoma of the sweat gland were included in the study. 20 in vitro-in vivo correlations were evaluable. 5/9 of the mammary carcinomas showed an objective response, 0/7 malignant melanomas were sensitive in vivo. Further investigations have to assess the value of chemosensitivity assays to predict clinical response for patients with solid tumors.
Because of its severe side effects, initial clinical trials of the antineoplastic compound mitoguazone (Methyl-GAG, M-G) were ceased in the middle of 1960s. One decade later pharmacokinetically guided dose schedules as well as new experimental data on the antiproliferative mechanism of action stimulated new clinical studies. First results indicated that M-G had single-agent activity against various tumors such as acute leukemia and malignant lymphoma connected with acceptable tolerance. M-G seems to be effective especially in combination with other antineoplastic drugs. Its final evaluation may be reserved to further randomized trials. Recently, the psoriasis vulgaris is expected to be an additional field of the application of M-G. In this minireview data on synthesis, preclinical pharmacology, pharmacokinetics, biochemical effects and toxicology of M-G are given. Furthermore, clinical findings on M-G concerning its pharmacokinetic behaviour, antitumor and antipsoriatic activities are described.
The frequency of different types of von Willebrand's disease (vWD) was studied in the southern part of the GDR and during investigations of relatives of already diagnosed patients. Among 111 patients diagnosed, vWD was found to be type I in 85 cases, type II in 13 cases and severe recessive type in 13 cases. The patients with type I belonged to 46 different families. Two families with type II had the II A variant and another a variant similar to II C. No patients with type II B were diagnosed. The incidence of severe recessive vWD was estimated to be lower than in Sweden but higher than in Italy and France.
Out of 113 patients with vWD 15 were of type II. The basic test programme included F VIII:C, vWF-Ag, RCF and BT (Ivy). All type II patients had relatively high vWF-Ag and low RCF values. CIEP proved increased anodal migration velocity. IRMA testing of vWF:Ag was showing narrow correlation with RCF. Thrombocyte count was unchanged after DDAVP infusion and RIPA was always diminished. Finally multimeric sizing was done in 6 patients. From the completely diagnosed patients 5 are of type IIA and one seems to have type IIC. Nobody of the 15 had the characteristics of type IIB.
15 patients aged between 24 and 66 years with 10 different malignant tumor diseases were treated with a recombinant human tumor necrosis factor preparation PAC-4D in a phase-I trial. The starting dose was 10(5) U PAC-4D as an intravenous short infusion. The maximally tolerable dose is around 18 X 10(5) U/m2. As the main clinical side effects were observed: fever, chills, hypertension with subsequent hypotension, lethargy, transient somnolence, headache, neurological deficiency symptoms, nausea and vomiting. Important laboratory-chemical parameters were the increase in transaminases and, in higher dose levels, leukocytosis with the left shift and lymphopenia in the differential blood picture. As dose-limiting toxicity are estimated hypotension, and neurological side effects and hepatotoxicity. In one female patient who received 27 X 10(5) U PAC-4D there appeared pronounced, histologically verified necroses in the metastases of a malignant fibrous histiocytoma.
The treatment of testicular tumors is among the most impressive examples of progress in tumor chemotherapy. At present, a complete remission can be achieved with the world-wide adopted standard therapy Cisplatinum/Vinblastine/Bleomycin in 50-80% of the cases. Whether these remissions are equivalent to healing remains to be established in long-term studies; at any rate, they are long-term palliations. Main problems of further research are the high-risk patients. Approaches to reach complete remissions and thus long-term palliations or healing, consist in increase of combination, dose escalation with Cisplatinum, introduction of novel substances (Etoposide, Ifosfamide etc.). The latter field is scientifically underdeveloped, as is the field of second- and third-order therapy. After all, chemotherapy of testicular tumors--similarly as treatment of leukemia--is an oncological intensive therapy that should be restricted to specialized centers.
Sixty-nine children with hemophilia were treated in our center between 1968 and 1983. About 1 per cent of hemorrhagic complications were bleedings localized in the iliopsoas muscle of 12 patients ranging in age from 9 to 15 years. The typical sign of the bleeding is a tight, palpable tumour above the inguinal fold. Today mass bleedings of the muscle with retroperitoneal localization are diagnosed safely by help of computer tomography or sonography. Psoas muscle bleedings in children are characterized by a high recurrence rate (41.5%) and often by an associated damage of the femoral nerve. Surgery was necessary only in 1 patient where a huge psoas hematoma with cystic transformations had to be removed. High substitution doses led to a complete recovery within 3 weeks in all other children.
In five hemophilic children an attempt was made to eradicate inhibitors by continuous treatment with low doses of cryoprecipitate. All patients were high responders with maximum titers of 25 and 600 U. In four patients the anamnestic response was prevented or diminished by simultaneous treatment with cyclophosphamide. In these patients the inhibitor did not return during the continuous replacement therapy, even not after cessation of cyclophosphamide administration and in three of them not after intensive substitution. In the other child the titer decreased continuously in the beginning, but only to values unsuitable for replacement effects. Attempts to exterminate the inhibitor should be occasionally made by continuous low dose substitution therapy. The importance of the combination with cyclophosphamide cannot be decided until now because of the small number of observations.
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The preliminary results of a prospective controlled study for a first-line-therapy in women with hormone-resistant advanced breast cancer are reported. Two therapy-regimens were compared: 1) cyclophosphamide, methotrexate and ftorafur (CMFt) and 2) cyclophosphamide and ftorafur (CFt). The overall objective response rate for both treatment groups was 30%, the duration of remission was 10 months in the CMFt-regimen and 5 months in the CFt-regimen. 21 patients were subsequently treated with the non-cross-resistant combination adriamycin and vincristine (AV) after either relapse or failure of the firstline modalities. 33% of the AV-group obtained further palliation with a median duration of 7 months, objective response was not seen.
Haemophilia A and B are X-chromosomally recessively inherited. In the GDR the frequency of these genuine haemophilias is 1 to 6,500 male births. The frequency of sporadic haemophilias is still in dispute and certainly depends on the intensity of genealogic examinations. The mutation rate for haemophilia A is estimated to 1.3 to 3.6 x 10(-5). In secure female conductors the lyonisation evokes a considerable dispersion of the factor VIII coagulation activity, wherefore this is able to prove also only a small proportion, about 20-50%. The lyonisation apparently takes place in a critical anlage of less than 32 cells. Bleeding female conductors are in the first place the sequel of extreme lyonisation, more infrequently homozygotes or such ones with anomalies of the X-chromosomes. The state of female conductors is best characterized by th discrepancy between decreased factor VIII coagulation activity and the normal factor VIII associated antigen. At present numerous variants of this female conductor test are used, particularly concerning its calculatory evaluation. In many places only quotients from the two parameters are formed. Discriminancy-analytical methods brings without doubt better results. They allow to coordinate a certain probability to each result, which with the help of genealogic criteria may be combined to an evidence. Immunochemical determinations of the factor IX are certainly not of value for the proof of the state of female conductors of haemophilia B. The prenatal diagnostics of sex is recommended for pregnant conductors by amniocentesis in the 14th week of pregnancy. Only in few countries the prenatal diagnostics of haemophilia is possible. In blood tests taken by means of fetoscopy beginning with the 18th week of pregnancy the factor VIII coagulation property is determined by immunoradiometrical methods or recently even by means of a coagulation method. Though for the genetic consultation only female conductors in the reproductive phase are of importance, for the search of female conductors the whole lineage must be worked up genealogically, at least over four generations and with the help of archives material. The genetic consultation of haemophils and female conductors should be performed early and directedly, for important reasons also repeatedly.
Disturbances of haemostasis caused immunologically and non-immunologically were observed after transfusion of blood and blood derivatives. Transfusion of heparin blood increased the bleeding susceptibility only in case of pre-existing high-degree defects of haemostasis or if they were performed as massive or exchange transfusions. Massive transfusions with blood stored for a long time will induce complex defects. Under intensive substitution therapy of haemophilia A the so-called paradoxical bleeding will occur in spite of a high factor VIII level. These bleedings are supposed to be disturbances of the thrombocyte function and are caused by fibrin(ogen) derivatives. Post-transfusional thrombocytopenias may be brought to remission by repeated plasmapheresis. Factor specific inhibitory bodies will appear after substitution in a small percentage of haemophilic patients. 5 to 7 days after the onset of therapy an anamnestic reaction can be observed as a titre increase by leaps. Usually, the inhibitory titre will decrease to a mostly low basal value in the course of three to five months. The therapy with cyclophosphamide simultaneously started with the substitution will more frequently prevent the anamnestic reaction or reduce it. Titres with more than 5 units cannot be overcome at the beginning even by higher concentrations of preparations. The substitution therapy should be preceded by exchange transfusions or plasmapheresis of up to 25 units. With still higher titres only procedures of inhibitor-bypassing are possible with factor VIII preparations of animal origin or better with activated prothrombin complex preparations, such as FEIBA. Recent reports give evidence that permanent substitution with factor VIII concentrates at a highest dosage can eliminate the production of inhibitors completely.
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