Biomedical subjects
Publications and source records attributed to R Dopfer.
In a one year old female infant BCG-vaccinated as a neonate, a large mediastinal mass was found after routine examination. X-ray and CT scan suggested a teratoma. Histology and microbiology, however, revealed the diagnosis of an active tuberculosis. Thus, the tumor was caused by mediastinal BCGitis. To our knowledge this complication of BCG-vaccination has not yet been described.
Cryptosporidium has been found to be a common cause of gastroenteritis during the last years. The natural course of the disease in immunocompromised patients is often met by serious complications. A general therapy recommendation has not been reported so far. We report of a two-year-old boy, who was immunocompromised by a multidrug cytostatic chemotherapy. The patient suffered from a long lasting most severe gastroenteritis, caused by cryptosporidium. There was a good clinical response to spiramycin, a treatment suggested in the literature.
Nine patients with neuroblastoma stage IV were treated with the murine monoclonal antibody 14.G2a, directed against disialoganglioside GD2. The antibody was injected daily for 5-10 days and the total applied dosage ranged between 100 mg/m2 and 400 mg/m2. The peak serum levels of mAb 14.G2a ranged from 28 micrograms/ml to 61 micrograms/ml. Pharmacokinetic data obtained in three patients indicated that the serum elimination of mAb 14.G2a fits a two-compartment model, with an alpha-half-time (t1/2 alpha) between 0.66 h and 1.98 h and a beta-half-time (t1/2 beta) between 30.13 h and 53.33 h. All patients presented with a human anti-(mouse IgG) antibody response either during or shortly after therapy. Eight patients showed a continuous decrease in complement component C4 during therapy, as well as an initial decrease in C3c and an initial increase in C3a, all suggesting an activation of the complement cascade. Side-effects consisted of allergic reactions like pruritus, exanthema, urticaria and of severe pain, predominantly located in the abdomen and lower extremities, which required the use of continuous intravenous morphine. Four patients additionally developed a transient hypertension and one patient experienced a transient nephrotic syndrome. Three patients were treated in an adjuvant setting and are not evaluable for tumor response. Of the remaining six patients, two had a complete remission, two showed a partial remission, and two patients did not respond to treatment.
In a variety of adult and childhood leukaemia cell samples collected at different states of the disease, we analysed in a series of sequentially performed slot-blot or Northern-blot hybridisation experiments the expression of genes possibly involved in multiple drug resistance (MDR) (mdr1/P-glycoprotein, DNA topoisomerase II, glutathione-S-transferase pi), and the expression of the DNA topoisomerase I and histone 3.1 genes. Occasionally, P-glycoprotein gene expression was additionally examined by indirect immunocytofluorescence using the monoclonal antibody C219. No significant difference in mdr1/P-glycoprotein mRNA levels between primary and relapsed state acute lymphocytic leukaemias (ALL) was seen on average. Second or third relapses, however, showed a distinct tendency to an elevated expression of this multidrug transporter gene (up to 10-fold) in part well beyond the value seen in the moderately cross-resistant T-lymphoblastoid CCRF-CEM subline CCRF VCR 100. Increased mdr1/P-glycoprotein mRNA levels were also found in relapsed state acute myelogenous leukaemias (AML), and in chronic lymphocytic leukaemias (CLL) treated with chlorambucil and/or prednisone for several years. Topoisomerase I and topoisomerase II mRNA levels were found to be very variable. Whereas in all but one case of CLL topoisomerase II mRNA was not detected by slot-blot hybridizations, strong topoisomerase I and topoisomerase II gene expression levels, frequently exceeding the levels monitored in the CCRF-CEM cell line, were seen in many cell samples of acute leukaemia. If topoisomerase II mRNA was undetectable, expression of topoisomerase I was clearly visible throughout. These observations might be valuable considering the possible treatment with specific topoisomerase I or topoisomerase II inhibitors. Significant positive correlations were found (i) for topoisomerase I and histone 3.1 gene expression levels in general (P less than 0.001), and (ii) in the CLL samples additionally for the expression levels of the mdr1 gene, and the histone 3.1, topoisomerase I, and glutathione-S-transferase pi genes, respectively.
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Fifty-one children between 26 and 214 months of age (median, 100 months) with acute lymphoblastic leukemia (ALL) were grafted in second remission from HLA-identical sibling donors (except for two patients who were grafted with a marrow with 1 antigen-mismatch). Initial treatment and relapse therapy were similar in all patients according to the BFM- and CoALL-protocols (front line: 38 patients according to BFM-protocols and 13 patients according to CoALL-protocols; relapse: 12 patients in study ALL-REZ-BFM 83, 17 in ALL-REZ-BFM 85, 20 in ALL-REZ-BFM 87, and two in ALL-REZ-BFM 90). The conditioning regimens were different, consisting of cyclophosphamide (CY) total body irradiation (TBI) plus (n = 27), VP-16-TBI (n = 23), and CY-TBI and ARA-C (n = 1). Three patients had a second graft after conditioning with CY-TBI for the first transplantation. The second ablative regimen consisted of CY plus VP-16 in the first patient and CY plus busulfan in the two other patients, one of whom relapsed again. All patients but three had bone marrow (BM), either isolated or combined, relapses. Twenty-nine of the patients are in continuous complete remission (CCR), ranging from 1 to 67 months after transplantation with a median time of 30 months. One patient was lost to follow-up in continuous remission. Nine patients died from treatment-related complications (infections and graft-versus-host disease) and 12 patients suffered a leukemic relapse; three of them received a second graft and two are in CCR. Kaplan-Meier analysis yields an event-free survival (EFS) of 0.52 +/- 0.08. The probability of a 7-year relapse-free interval (RFI) is 0.68 +/- 0.08. EFS for patients with late relapses is 0.47 +/- 0.12 and for patients with early relapses 0.56 +/- 0.1. The RFI for patients with late relapses is 0.65 +/- 0.12 and for patients with early relapses 0.69 +/- 0.11. There is a nonsignificant trend towards superior results for patients grafted after conditioning with VP-16 plus TBI. When all patients who are not in CCR at day +125 (which is the median interval between relapse diagnosis and BM transplantation [BMT]) are excluded from the chemotherapy results, there is no significant difference between the results of BMT and chemotherapy for late relapses. On the other hand, there is a significant advantage between chemotherapy and BMT for early relapses over chemotherapy (P less than or equal to .01).
The pharmacokinetics of etoposide following a new method of administration was determined. Undiluted etoposide was given at a dose of 30 mg/kg as part an intensified conditioning regimen prior to bone marrow transplantation. A terminal half-life of 3.4 +/- 0.7 h and a volume of distribution of 15.4 +/- 9.6 l were found (n = 8); the AUC was 764 +/- 302 micrograms h ml-1. As compared with those obtained in other pharmacokinetic studies using etoposide diluted in normal saline, our data reflect full systemic bioavailability and unaltered pharmacokinetics. The application of undiluted etoposide makes the therapy easier and less time-consuming and avoids a high fluid volume and a high saline load.
We have tested the sialoganglioside monoclonal antibody Gd-2a for scintigraphic diagnostic and for immunotherapy in children with neuroblastoma stage IV. We could confirm tumor sites with Gd-2a scans in 1/2 children. Doses of 20-60 mg/m2 were administered daily for 5-10 days. 2/2 children with multiple tumor sites showed significant tumor regression. Four children, treated preventively, are still in clinical remission. One child showed tumor progression despite Gd-2a treatment. Adverse effects included itching, rashes, and pain.
Since impaired growth may occur as a long--term consequence in children treated with BMT this aspect of development needs particular attention for various reasons. Primarily, in each affected child parameters relevant for the evaluation of growth need to be documented regularly from the beginning in a prospective mode. In addition, treatment protocols should contain elements of a standardized follow-up for the documentation and evaluation of the endocrine, the nutritional and the emotional situation of the patient. This will eventually allow us to define--and hopefully avoid--adverse elements within complex treatment modalities--including BMT--for various malignant diseases. Thus it will be possible to develop a rational approach for the therapy of persistent adverse events following attempts of treatment primarily directed to ensure survival.
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A largely symptom-free swelling of the right submandibular lymph nodes developed in a 23-year-old woman with hyper-IgE syndrome who had suffered from recurrent staphylococcal abscesses since childhood. Histological examination of the lymph nodes revealed highly malignant non-Hodgkin lymphoma of centroblastic type. Extensive staging tests did not reveal any further tumour manifestations. Because granulocyte chemotaxis is abnormal in hyper-IgE syndrome and the patient also had an infection of an old lung cyst, treatment was restricted to local radiotherapy of the cervical lymph nodes. Since 12 months there has been no recurrence. There is probably no connection between the hyper-IgE syndrome and the development of a malignant non-Hodgkin lymphoma, judging by the results of immunological and immunoelectrophoretic findings.
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The in vitro and in vivo influence of interleukin-2 (IL-2) on 2',5'-oligoadenylate (2-5A) synthetase activity and natural killer (NK) activity of peripheral mononuclear blood cells (PBMCs) was investigated. Incubation of PBMCs in vitro with IL-2 resulted in a considerable secretion of interferon-gamma (IFN-gamma) and in a significant elevation of 2-5A synthetase activity, as well as NK activity. Neutralizing monoclonal anti-IFN-gamma antibodies inhibited the elevation of 2-5A synthetase activity, but not the IL-2-induced augmentation of NK activity. Additionally, 2-5A synthetase and NK activity of PBMCs was measured in a child with neuroblastoma that was treated with recombinant IL-2 by continuous intravenous application. During the treatment, NK activity against the NK-sensitive cell line K 562 and against autologous tumor cells was not augmented. However, a significant increase of 2-5A synthetase activity in PBMCs was observed during IL-2 treatment, whereas there was no detectable serum level of IFN-gamma. We conclude that measuring 2-5A synthetase activity in patients treated with IL-2 may be helpful in monitoring the immunomodulatory effects of IL-2 on immune effector cells.
The potentially beneficial effect of 8-methoxypsoralen and ultraviolet A (PUVA) irradiation for treatment of drug-resistant cutaneous manifestations of graft-versus-host disease led us to investigate the effect of this therapy in a larger series of patients with GvHD. To date, 11 patients with histologically demonstrated cutaneous GvHD (acute GvHD grade III-IV in 4 patients, extensive lichenoid chronic GvHD in 6 patients, sclerodermatous chronic GvHD in 1 patient) have received PUVA treatment for 2-24 weeks. All patients have been on CsA for GvH prophylaxis; 5 with mismatched grafts had additionally received methotrexate or monoclonal antibody campath-1 after bone marrow transplantation. Seven patients were on CsA and prednisolone; 2 patients on CsA, prednisolone, and azathioprine; 1 patient on azathioprine and prednisolone; and 1 patient had no immunosuppressive treatment for the duration of PUVA treatment. The 8-methoxypsoralen (0.6 mg/kg bw) was given as photosensitizer before each ultraviolet A irradiation (0.3-8.5 joules/cm2). The only observed adverse reaction was mild nausea. In all patients improvement of cutaneous lesions could be observed with complete response in 5 patients and partial response in 6 patients. Immunosuppressive drugs could be withdrawn in 2 patients and reduced in 8 patients after initiation of PUVA treatment. These findings suggest that PUVA therapy may be a useful adjunct to conventional therapy for cutaneous GvHD.
This is the first report of a phase I study with n-IL 2. N-IL 2 shows a higher biological activity and different immunomodulatory effects compared to recombinant IL 2. 14 patients (9 male, 5 female) entered our phase I study with continuous i.v. n-IL 2 with a median age of 40 years (range 4-65), including 4 children. The study design was a dose rising continuous iv infusion over 5 days with a starting dose of 1 x 10(6) U n-IL 2 up to 6 x 10(6) n-IL 2 over 24 h. In 2 of 16 regimen with n IL-2 there was a dose reduction and in 6 there was an interruption necessary. In 2 patients there was only a dose reduction necessary because of thrombocytopenia and hypotension. In 6 patients n-IL 2 had to break the continuous infusion. Reasons were an increasing BUN, respiratory insufficiency, thrombocytopenia, neurological symptoms and increasing liver enzymes. The 4 children developed an other side effect profile with edema of the face, abdominal cramps and thrombocytopenia. During the study no intensive care was necessary. The most common side effects were erythema, fever, nausea, dyspnea and hypotension. There was no complete remission, 21.5% of the patients had a partial remission, 7% showed no change and 71.5% had a progression. There were no significant differences in toxicity and response was comparable to studies using continuous r IL-2.
From 1983 to 1988 14 patients under 16 years of age with adult type chronic myelogenous leukemia (CML) in chronic or blastic phase were treated by allogeneic bone marrow transplantation (BMT) in our center. These comprise 54% of all patients under 16 years of age grafted for this disease in FRG. These BMT patients were compared with 24 similar patients treated conventionally with busulfan and/or hydroxyurea in various centers. The probability of an event-free survival 5 1/2 years after BMT was 0.61 (SD 0.16); the estimated probability of survival for 3-8 years after diagnosis in the group treated by GMT was 0.78 (SD 0.14) vs 0.55 (SD 0.12) for the non-BMT group. The difference is not significant. In the BMT group only two patients died of transplant-related complications. The non-BMT patient with the longest survival period died recently 10 years after diagnosis. For children with adult type CML, BMT is a safe and effective treatment, and should be recommended if there is an HLA compatible sibling donor or even a fully compatible unrelated donor. However, for a more conclusive comparison between bone marrow transplantation and conventional treatment a longer observation period and larger patient numbers are necessary.