[Help for the cycle of anxiety and pain].
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Anxiety↗
Biomedical subjects
D Niethammer
Publications and source records attributed to D Niethammer.
Investigations on the interferon-induced 2'-5' oligoadenylate system using analytical capillary isotachophoresis.
The activity of the interferon inducible enzyme 2'-5' oligoadenylate synthetase (2-5A synthetase, E.C. 2.7.7) which converts ATP into a series of 2'-5' oligoadenylates was measured using analytical capillary isotachophoresis. The turnover rate of ATP during the reaction was monitored by determination of its concentration at the beginning and the end of the 2-5A synthetase reaction. The enzyme was analysed in extracts of peripheral blood mononuclear cells either pretreated or not with interferon.
2',5'-Oligoadenylate Synthetase↗
Chemotherapy for bone marrow relapse of childhood acute lymphoblastic leukemia.
Results of the BMF study group trials ALL-REZ 83 and 85 for relapsed acute lymphoblastic leukemia (ALL) are presented. For children with late marrow relapse, remission rates of about 90% were seen in both studies. In children treated for early marrow relapse, the remission rate in study ALL-REZ 85 was superior (86% vs 62%). The probability of event-free survival for all patients and for those with early marrow relapse was also statistically significant (P less than 0.05). Children with T-cell ALL had an extremely unfavourable prognosis in both studies.
Adolescent↗
Combination chemotherapy in malignant non-seminomatous germ-cell tumors: results of a cooperative study of the German Society of Pediatric Oncology (MAKEI 83).
In January 1983, the German Society of Pediatric Oncology started a cooperative trial (MAKEI 83) for non-testicular germ-cell tumors. The pilot phase closed in December 1985. The treatment regimen was stratified according to histology, tumor site and tumor stage. In malignant non-seminomatous germ-cell tumors (mNSGCTs), chemotherapy consisted of four courses of 3 mg/m2 vinblastine, on days 1 and 2 and 15 mg/m2 bleomycin on days 1-3, given by continuous infusion, and 20 mg/m2 cisplatin on days 4-8 with mannitol diuresis. Courses were repeated every 3 weeks. In mNSGCT patients with ovarian FIGO stages III-IV or extragonadal primaries, second-look surgery was carried out, followed by four additional courses of chemotherapy with 100 mg/m2 VP-16 on days 1-3, 1.5 g/m2 ifosfamide on days 1-5 with mesna uroprotection and 20 mg/m2 cisplatin on days 1-5 with mannitol diuresis. In patients with sacrococcygeal germ-cell tumors, en bloc resection of the tumor, including the coccygeal bone, was mandatory. During the registration period, 57 patients with mNSGCTs were entered: 37 protocol patients and 20 follow-up patients. The event-free survival for protocol patients at 57 months was 78% +/- 6% and that for follow-up patients was 40% +/- 10% (Kaplan-Meier): the crude survival for both groups was 83% +/- 6% and 54% +/- 12%, respectively. After a review by a panel of pathologists, the histological diagnoses in 7% of all registered cases of germ-cell tumors were changed. The results of the present studies show that the histological subclassification of mNSGCTs, tumor site and tumor stage no longer had prognostic value.
Adolescent↗
[131I]-metaiodobenzylguanidine in the treatment of metastatic neuroblastoma. Clinical, pharmacological and dosimetric aspects.
Ten children with stage III or IV neuroblastoma that had either relapsed or was refractory were treated with [131I]-metaiodobenzylguanidine (MIBG) from 1984 to 1986. The total dose ranged from 4,365 to 21,900 MBq and was given in one to five courses. Two patients achieved a complete remission (CR), two, a partial remission (PR), and three, an arrest of the disease. Pharmacological studies showed that 93% of detectable radioactivity was attributable to MIBG at the beginning of the infusion. However, by the end of the infusion this had decreased to 88%. The terminal half-life of MIBG was 37.0 h, whereas that of non-MIBG-bound iodine was 71.6 h. Therefore, the radioactivity-time product of non-MIBG-bound 131I was much higher than that of MIBG. Dosimetric studies showed a mean level of absorbed radiation for the total body of 160 microGy/MBq, a liver irradiation of 540 microGy/MBq and a mean tumour radiation of 10,500 microGy/MBq.
3-Iodobenzylguanidine↗
Resistance to methotrexate and multidrug resistance in childhood malignancies.
Resistance to drugs, either primary or acquired, is a main problem in cancer chemotherapy. The paper summarizes our results in regard to resistance to methotrexate and multiple drug resistance in human cell lines of pediatric malignancies and in children with resistant cancer. In cell lines as well as in children we could demonstrate amplification of the gene coding for dihydrofolate reductase as a cause for resistance to MTX. Procedures to overcome drug resistance such as treatment with high dose MTX and leucovorin rescue are discussed. The increased expression of the mdrl gene coding for the P-glycoprotein is related to multidrug resistance. This could be shown in cell lines and in children. The expression decreased when the drug, used for induction of resistance, was omitted for a few weeks from the cell culture medium. Readdition of the drug caused a rapid increase of expression. For the first time data in children are presented which demonstrate the amplification of the gene coding for dihydrofolate reductase or increased expression of the mdrl gene as cause of drug resistance. The clinical implications of these findings are discussed.
Adolescent↗
Lysis of neuroblastoma cells by the ADCC-reaction: granulocytes of patients with chronic granulomatous disease are more effective than those of healthy donors.
Granulocytes from healthy donors lyse human neuroblastoma cells in the ADCC-reaction using antibody MAb 14.18 directed to ganglioside GD2 present on the surface of most neuroblastoma cells. Addition of catalase, superoxide dismutase and azide do not impair this process. Granulocytes from patients with chronic granulomatous disease (CGD) kill neuroblastoma cells even better than those collected from healthy donors. These results indicate that reactive oxygen intermediates (ROI) are not involved in killing of neuroblastoma cells using MAb 14.18, and that granulocytes from patients with CGD may compensate for defects in generation of reactive oxygen intermediates by more effective oxygen-independent killing mechanisms. One patient with CGD was treated with interferon-gamma. During and after treatment, generation of ROI could not be detected and neuroblastoma cell killing was not significantly altered.
Antibody-Dependent Cell Cytotoxicity↗
The predictive value of initial cytostatic response in primary unresectable rhabdomyosarcoma in children.
The relation between the initial tumour regression produced by chemotherapy and the later event-free survival was studied in a prospective multicentre study on soft-tissue sarcomas in children. The event-free survival rate in patients with complete remission after seven weeks of chemotherapy was 95%; in patients with incomplete tumour reduction of greater than 2/3, 61%; and in patients with tumour reduction of less than 2/3 but greater than 1/3, 31%. Patients with partial remission at week 7, who achieved complete remission by week 16 after additional chemotherapy had an event-free survival rate of 64%. A multivariate analysis suggested that the response per unit of time was an important prognostic factor.
Antineoplastic Combined Chemotherapy Protocols↗
In vitro induction of lymphokine-activated killer (LAK) activity in patients with neuroblastoma.
Therapy of disseminated neuroblastoma remains an unsolved problem in pediatric oncology. Therefore, new therapeutic approaches have to be developed for this malignancy. In this paper, we investigated the possibility of the in vitro generation and expansion of lymphokine-activated killer (LAK) cells in patients with disseminated neuroblastoma. Although the patients had very low Natural Killer (NK) activity, it was possible to induce LAK activity in peripheral mononuclear lymphocytes (PMNC) by incubation with Interleukin-2 (IL-2). Moreover, the PMNCs could be expanded up to 50-fold in the presence of Interleukin-2 while maintaining or even increasing their LAK activity. The target cells were neuroblastoma cell lines and, in one case, autologous neuroblastoma cells. Additionally, it was possible to induce LAK cell activity against autologous neuroblastoma cells in bone marrow-derived mononuclear cells.
Bone Marrow↗
Cytotoxic effects of 6-hydroxydopamine, merocyanine-540 and related compounds on human neuroblastoma and hematopoietic stem cells.
6-Hydroxydopamine(6-OHDA) and Merocyanine-540(MC-540) have been used clinically for purging of neuroblastoma cells prior to autologous bone marrow transplantation. Both substances were found to be more toxic against neuroblastoma cells than against hematopoietic stem cells. The more pronounced cytotoxic effects of 6-OHDA against neuroblastoma cells were not caused by its selective uptake; the rapid autooxidation at physiological pH leads to the formation of H2O2 already in the incubation medium. Cytotoxic effects were not detected in short-time test systems (4 hour chromium-51 release assay) but only after longer incubation periods. In contrast, MC-540 proved to be toxic almost equally in short- and long-time test systems. 4-Hydroxynonenal(4-HNE) that may be formed in the plasma membrane subsequently to photoactivation of MC-540 was only slightly more toxic to neuroblastoma cells than to hematopoietic cells. Although the use of 6-OHDA and MC-540 in bone marrow purging has some limitations, the sensitivity of neuroblastoma cells against reactive oxygen compounds may be exploited more generally for therapy of this tumor.
Aldehydes↗
Bone marrow transplantation in childhood leukaemia--experience and strategies in the Federal Republic of Germany.
BMT has gained its place in the treatment of childhood leukaemia. Nevertheless, there are still many questions open. In acute lymphoblastic leukaemia children should normally be grafted in 2nd remission (CR). Some high risk cases, however, should probably be grafted in 1st CR. It is not clear whether children with late relapses benefit more from BMT than from renewed chemotherapy. Children with a relapse during maintenance therapy, however, have a better survival rate with BMT. In acute nonlymphoblastic leukaemia certain high risk patients should be grafted in 1st CR but it has still to be shown that BMT is superior to chemotherapy in such cases. It is not clear whether children with a relapse following intensive chemotherapy (such as the BFM-protocols) will benefit from BMT at all. In chronic myelocytic leukaemia, BMT in chronic phase should be performed. Thus, for the first time cure has become possible for this disease. Waiting for acceleration or even the occurrence of a blast crisis decreases the chance of survival after BMT dramatically. Since complications of BMT such as graft-versus-host reaction or severe infections are less frequent in children, relapses remain the main problem after BMT in childhood leukaemia.
Bone Marrow Transplantation↗
Bone marrow transplantation in children with neuroblastoma.
Neuroblastoma is the third most frequent malignant tumor in childhood. One-third of the patients over one year of age at the time of diagnosis suffer from the disseminated form (stage IV). Despite highly aggressive chemotherapy survival rates are poor. One hundred and eighty-seven patients with neuroblastoma stage IV have been treated according to the German protocol NB 85. The probability of disease free survival is only 15% after 70 months. Treatment strategy in our protocol includes autologous and allogeneic bone marrow transplantation (BMT) for patients with stage IV (and greater than 1 year old). Twenty-two patients were grafted (7 allogeneic and 15 autologous). The conditioning regimen consisted mainly of high-dose melphalan (180 mg/m2) and total body irradiation (TBI) (3.4 Gy). Survival rates are discussed in the context of the chemotherapy protocol. Our own experience with autologous BMT is poor, despite of different purging methods. For this reason we decided to focus on allogeneic BMT. We have grafted five patients within the last 3 years. Three of them are alive and well, on died from veno-occlusive disease 70 days after BMT, and the remaining patient, grafted from a syngeneic donor, died from relapsing tumor. The main problem in neuroblastoma stage IV is resistance to chemotherapy. Intensification of the conditioning regimen or double autografting leads to a rate of toxic deaths close to 20% (Zucker, EBMT 1987) which is not tolerable. New improvements in the conditioning regimen have to be found to increase the effect of BMT.
Bone Marrow Transplantation↗
Influence of allogeneic bone marrow transplantation on the endocrine system in children.
With increasing survival rates of children grafted for different malignancies concerns about the longterm side effects of this treatment are growing. Therefore, investigations on the function of endocrine systems were conducted in a total 28 patients grafted for various reasons: ALL (N = 18), AML (N = 1), SAA (N = 3), CML(N = 4), neuroblastoma (N = 2). The results can be summarized as follows: 1. The extent of hormonal derangements is primarily dependent on the extent of irradiation prior to BMT. Integrity of hormonal systems was found in cases without irradiation (SAA) or if TBI did not exceed 3 Gy. 2. Primary hypogonadism was present in 18 patients. 3. Primary hypothyroidism was present in 2 patients. 4. Growth impairment was observed in 8 patients. In four of these cases growth hormone deficiency was the cause. In four other cases with graft-versus-host-disease and hepatic involvement SmC/IGF I levels were severely diminished. The data suggest that in most cases BMT itself has relatively few negative effects on the endocrine regulatory system. However, more detailed investigations before and after BMT will be needed to further validate these observations.
Anemia, Aplastic↗
Interferon-gamma upregulates the susceptibility of human neuroblastoma cells to interleukin-2-activated natural killer cells.
The influence of interferon-gamma on the susceptibility of neuroblastoma cells in cell-mediated killing was investigated. Neuroblastoma cells were only weakly susceptible targets for peripheral mononuclear cells. However, enrichment of natural killer (NK) cells or activation of NK cells with interleukin-2 resulted in a considerable increase of neuroblastoma cell lysis. Pretreatment of neuroblastoma targets with interferon-gamma additionally increased the susceptibility to enriched NK cells as well as to interleukin-2-activated NK cells. The conjugate formation between enriched NK cells and the neuroblastoma targets was not affected by the pretreatment of the targets with interferon-gamma. Concomitantly, treatment of the neuroblastoma targets with interferon-gamma resulted in a strong induction of otherwise poorly expressed major histocompatibility complex (MHC) class I antigen expression. These results suggest that the increased expression of MHC class I antigens on target cells is not always correlated with decreased sensitivity for NK cells but can also be followed by an increased susceptibility for NK cells.
Antigens, Neoplasm↗
Influence of allogeneic bone marrow transplantation on the endocrine system in children.
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Adolescent↗
[Systemic salmonella infections in chemotherapy in 2 children with acute lymphoblastic leukemia].
A 15 year old patient with acute lymphoblastic leukemia, previously diagnosed as being a salmonella carrier, developed S. typhimurium sepsis after allogeneic bone marrow transplantation, in spite of pretreatment with chloramphenicol. Clinical improvement and termination of salmonella excretion were achieved by treatment with multiple antibiotics. Another patient with acute lymphoblastic leukemia, a 3 year old boy not previously identified as a salmonella carrier, also developed sepsis and osteomyelitis, together with pathological fractures during chemotherapy. Chloramphenicol, administered after isolation of S. typhimurium from blood cultures, led to resolution of the bony defects, complete recovery, and cessation of salmonella excretion. Selective cultures for salmonellae seem indicated in patients with malignant diseases, prior to chemotherapy.
Adolescent↗
Actual role and perspectives of BMT in children.
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Bone Marrow Transplantation↗
Cytotoxic effects of m-[131I]- and m-[125I]iodobenzylguanidine on the human neuroblastoma cell lines SK-N-SH and SK-N-LO.
As we have reported recently, the human neuroblastoma cell line SK-N-SH is able to take up and store m-iodobenzylguanidine (mIBG). This is in contrast to several other neuroblastoma cell lines, among which are SK-N-LO cells. Both cell lines were used in cell killing experiments with unlabeled and radioactive-labeled mIBG. Using 1-200 microCi m-[131I]IBG (1 h incubation time), only SK-N-SH cells could to a large extent be destroyed in a dose-dependent manner. This effect is completely caused by the radioactive labeling of the molecule, because unlabeled mIBG proved not to be toxic in the concentration range used in experiments with radiolabeled mIBG (30 nM-3 microM). The killing effect was strongly reduced when m-[131I]IBG with low specific activity (0.2-0.3 mCi/mg) was used instead of 20-30 mCi/mg. Similar effects in both cell lines were obtained using m-[131I]-and m-[125I]IBG. SK-N-SH cells that survived a first treatment with m-[131I]IBG were less sensitive to a second treatment. SK-N-LO cells were more sensitive against m-[131I]- and m-[125I]IBG than SK-N-SH cells if both cell lines are exposed to these radioactive compounds over a long period of time (24 h). The reason that only SK-N-SH cells could be destroyed in short-term incubation experiments is that mIBG is stored for approximately 7 days in these cells only. SK-N-LO cells could only be destroyed to a significant degree if m-[131I]IBG was permanently present in the test system. Bone marrow stem cells (CFU-c) also proved to be sensitive against m-[131I]IBG, although the effects were less pronounced than on SK-N-SH cells.
3-Iodobenzylguanidine↗