The efficiency of a new cell separation technique in bone marrow purging without damaging the purged tumor cells.
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Antibodies, Monoclonal↗
Biomedical subjects
J Treuner
Publications and source records attributed to J Treuner.
Soft tissue sarcomas in infants younger than 1 year of age: a report of the German Soft Tissue Sarcoma Study Group (CWS-81).
Of 357 patients with soft tissue sarcomas (STSs) who were registered between 1981 and 1986 in the CWS-81 study, 21 (5.8%) were younger than 1 year of age. Six cases were probably of congenital origin since they were diagnosed in the 1st month of life. There was no difference in clinical grouping (staging and primary site) between infants and older patients. The major histological subsets comprised 12 patients with embryonal rhabdomyosarcoma (57% vs. 44% in older patients) and five patients with fibrosarcoma (23% vs. 2% in older patients). Of 21 patients, 17 received chemotherapy. The response rate (tumor reduction more than 1/3) to exclusive cytostatics therapy within 7-9 weeks, of ten evaluable patients, was 100% (vs. 86% in older patients). Eight of the responders achieved complete remission after 16 weeks of therapy and are in continuous complete remission (CCR). Most patients received 20-50% of the recommended chemotherapy dose for older children, which was calculated using body surface area. No fatal or life-threatening complications were observed. The event-free survival rate for children younger than 1 year of age with rhabdomyosarcoma was 70% vs. 47% in older children (no significant difference). Now, 2-5 years after therapy all five fibrosarcoma patients are alive and free of disease. Our data indicate that children under 1 year of age with rhabdomyosarcoma have a slightly better prognosis than older children, when therapy modalities are adapted to age.
Age Factors↗
Surgical aspects in the treatment of soft tissue sarcomas: a preliminary note.
This preliminary analysis of surgical data is based on the evaluation of 323 patients operated on for soft-tissue sarcoma of varying histology. Data were collected for the Cooperative Soft-Tissue Sarcoma Study of the Gesellschaft für Pädiatrische Onkologie (Society of Paediatric Oncology). The following preliminary results are presented: 1. The number of mutilating operations, formerly undertaken with great frequency, can be reduced by chemotherapy, except where very aggressive tumours necessitate radical tumours excision. 2. According to the protocol in use, second look operations were performed in 117 patients, usually following the second course of chemotherapy. It is concluded that second look operations should be performed between the 16th and 19th post-operative week. Patients with scars in the former tumour bed must be assessed particularly critically, since residual tumour nodes may be masked by the scars.
Child↗
New aspects in the treatment of childhood rhabdomyosarcoma: results of the German Cooperative Soft-Tissue Sarcoma Study (CWS-81).
The results of the German Co-operative Soft-Tissue Sarcoma Study (CWS-81) of the treatment of rhabdomyosarcoma are presented. Prior to the introduction of chemotherapy only 10%-20% of the children were successfully treated. Combined multi-agent cytostatic treatment improved the results dramatically. In patients with primary stage III rhabdomyosarcoma, local tumour control by surgery or radiotherapy should be undertaken earlier than week 16, if complete remission has not been achieved by 7-9 weeks. Patients with complete remission or partial tumour regression should be treated with the same combination of chemotherapy, while only partial responders need radiotherapy in addition. Patients with tumours which are primarily resectable without mutilation have a 90% chance of cure; this also applies to patients with primarily unresectable tumours who achieve complete remission after 7-9 weeks of chemotherapy. Total disease-free survival rate for stage III rhabdomyosarcoma patients was 53%. The role of surgery includes primary removal of the tumour or assessment of remission by means of histological spot checks.
Child↗
High-dose ifosfamide with mesna uroprotection in Ewing's sarcoma.
The German Society of Pediatric Oncology (GPO) has studied the efficacy of high-dose ifosfamide with mesna uroprotection in patients with Ewing's sarcoma. A phase II trial of ifosfamide (IFO) (2 g/m2 per day, days 1-5) in eight patients with recurrent evaluable disease resulted in three partial and two complete responses lasting from 3 to 12 months (median, 6 months). In a second phase II trial in 15 patients, the combination of IFO and cisplatin (20 mg/m2 per day, days 1-5) resulted in 7 partial and 2 complete responses lasting from 3 to 32 months (median, 6 months). Consequently, in 1985 IFO was incorporated into first-line chemotherapy for newly diagnosed patients (replacing cyclophosphamide) and given in combination with vincristine, actinomycin D, and adriamycin (VAIA) in patients considered to be at high risk for relapse. IFO was given at a dose of 3 g/m per day on days 1 and 2 as a 48-h continuous infusion, in combination with actinomycin D (0.5 mg/m2 per day on days 1-3) or Adriamycin (30 mg/m2 per day on days 1 and 2). The study was piloted from March to December 1985 and has been open since January 1986; 37 patients were entered during the pilot phase and 65 have been entered in the ongoing main trial since January 1986. At present, Kaplan-Meier disease-free survival projects that disease-free survival in patients with large primary tumors has improved compared with that reported for the previous CESS 81 trial. The toxicity of the VAIA regimen was comparable with that of the conventional vincristine, actinomycin D, cyclophosphamide, and adriamycin (VACA) regime used in the previous CESS 81 trial.
Actuarial Analysis↗
Comparison of the rates of response to ifosfamide and cyclophosphamide in primary unresectable rhabdomyosarcomas.
In the 1981 cooperative soft-tissue sarcoma (CWS-81) study, a clear correlation between the degree of response to initial chemotherapy comprising vincristine, actinomycin D, cyclophosphamide, and Adriamycin (VACA) and the survival of patients with rhabdomyosarcoma was found. In the subsequent CWS-86 study, cyclophosphamide was replaced by ifosfamide (VAIA) in the expectation that the combination VAIA might be more effective than VACA. In both studies, the initial cytostatic response for primary unresectable tumors was evaluated after the first cycle of chemotherapy at weeks 7-9. The reduction in tumor volume was measured by computerized axial tomographic (CAT) scan or sonography, and the patients were categorized as complete responders, patients with a tumor regression of greater than 2/3 albeit incomplete, patients with a tumor regression of less than 2/3 but greater than 1/3, and nonresponders, who underwent either a tumor regression of less than 1/3 or tumor progression. We compared the response rate obtained with VACA chemotherapy and that resulting from VAIA chemotherapy. The preliminary data from this comparison show a tendency for a higher rate of good responders (complete and less than 2/3 tumor regression) to be induced by VAIA therapy (71%) than that obtained using the VACA combination (55%). From the response-prognosis relationship, we confidently expect that the final outcome for patients in the present study will be better than that in the previous study.
Antineoplastic Combined Chemotherapy Protocols↗
[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↗
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↗
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↗
Ifosfamide in pediatric malignancies.
In pediatric malignancies, particularly sarcomas, alkylating agents play an important role in the curative, combination chemotherapy approach. Since high doses of ifosfamide, the structural isomer of cyclophosphamide, were made tolerable with mesna uroprotection, high-dose ifosfamide (5 to 10 g/m2) has replaced conventional-dose cyclophosphamide (900 to 1,500 mg/m2) in some combination chemotherapy regimens. In Ewing's sarcoma and soft tissue sarcoma, the response rate and proportion of patients surviving disease free have been increased (at least for poor-prognosis patients) by 15% to 20% with an ifosfamide-containing regimen, as used in ongoing trials of the German Society of Pediatric Oncology. In germ cell tumors, the combination of ifosfamide and etoposide has proved to be an effective salvage regimen in patients resistant to vinblastine, bleomycin, and cisplatin. In stage IV disseminated neuroblastoma, however, the introduction of ifosfamide-containing regimens has not altered the poor prognosis. Results reflecting the value of ifosfamide in osteosarcoma, Wilms' tumor and Hodgkin's and non-Hodgkin's lymphomas are pending. It is not yet known whether high doses of akylating agents will increase the risk of late sequelae in cured patients.
Antineoplastic Combined Chemotherapy Protocols↗
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↗
Malignant peripheral neuroectodermal tumors. A retrospective analysis of 42 patients.
The clinical presentation of the disease and the results of treatment in 42 patients with malignant peripheral neuroectodermal tumors (MPNT) entered into the Cooperative Ewing's, soft tissue, and neuroblastoma trials of the German Society of Pediatric Oncology were retrospectively analyzed. Within the Ewing's sarcoma trial, patients with chest wall lesions were particularly analysed for MPNT features. The period of observation ranged from 15 to 86 months; the median relapse-free time was 24 months. There were 28 male and 14 female patients, the median age of patients was 15 years (range, 9 months-23 years). Thirty-two patients had localized disease (M0), and ten patients presented with primary metastases (M1). The predominant location of the tumors was the thoracopulmonary region, followed by the extremities, the abdominal/pelvic, and head and neck region. Thirty-one of 42 tumors involved the adjacent bone. The disease-free survival according to Kaplan-Meier life-table analysis was 56% +/- 11% for Stage M0 patients at 3 years. Nine of ten patients with M1 disease showed progression of their disease. Most patients had combined modality treatment with surgery, chemotherapy and radiation therapy. Best results were obtained with extensive surgery. Radiation doses ranged from 20 to 60 Gy and could not be correlated with the outcome of the disease. Most recurrences occurred at the site of the primary tumor. In patients with primary chemotherapy after biopsy-proven diagnosis, the responsiveness of this disease to chemotherapy could be demonstrated. Combination chemotherapy containing anthracyclines and high doses of alkylating agents appeared superior.
Actuarial Analysis↗
Multidisciplinary treatment of primary Ewing's sarcoma of bone. A 6-year experience of a European Cooperative Trial.
The German Society of Pediatric Oncology in 1981 initiated the Cooperative Ewing's Sarcoma Study (CESS 81) using a four-drug combination of chemotherapy prior to definitive local control with surgery and/or radiation. From January 1, 1981 until February 28, 1985, 93 patients were registered at the trial office from 54 participating institutions in West Germany, Austria, Switzerland, and the Netherlands. On February 1, 1987, 54 of 93 patients were disease-free. Using the Kaplan-Meier life table analysis, the estimated disease-free survival (DFS) rate was 60% at 36 months and 55% at 69 months. The median period of observation was 29 months, ranging from 22 months to 69 months. Twenty-one of 93 patients (23%) had local failure, 18 of 93 patients (19%) developed systemic metastases. The local failure rate was particularly high in patients treated with radiation and was reduced when radiation planning was centralized within the study based upon the extent of disease at diagnosis. Cox regression analysis of prognostic factors showed that tumor volume was a significant factor influencing prognosis. The estimated 3-year DFS rate was 80% for patients with small tumors (volume less than 100 ml) compared to 31% for patients with large tumors (volume greater than or equal to 100 ml). In patients who had surgery for local control, the histologic response to chemotherapy was analyzed on the surgical specimen and had a strong influence on survival: 79% DFS at 3 years for patients with less than 10% viable tumor (good responders) compared to 31% DFS for patients with more than 10% viable tumor (poor responders). Tumor load and responsiveness to chemotherapy are the two major factors influencing prognosis in patients with primary Ewing's sarcoma of bone.
Adolescent↗
[Metastatic neuroblastoma with secondary hypersecretion of vasoactive intestinal peptide].
A 18-month-old boy with stage 4 neuroblastoma needed intensive care because of prerenal acute renal failure related to an intractable watery diarrhoea syndrome occurring 10 months after the diagnosis of the primary tumor. This diarrhoea was in relation with a late hyperproduction of vasoactive intestinal peptide by the relapsing neuroblastoma itself and stopped with intravenous somatostatin administration.
Diarrhea, Infantile↗
[Accomplishments of tumor surgery in soft tissue sarcoma in childhood].
Malignant soft tissue tumors, a group of neoplasms with various biological characteristics, have been of oncologic interest only for the last 20 years. More than half of all soft tissue sarcomas are Rhabdomyosarcomas (RMS). Extensive comparative therapy studies have yielded both improved results and a lot of biological data on RMS and other malignant soft tissue tumors. The results of CWS 81/86 are analysed and a therapy protocol is proposed.
Child↗