Biomedical subjects
Publications and source records attributed to D Urbanitz.
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An immunoglobulin M (IgM)-positive cell line, Ms 28, apparently spontaneously transformed by Epstein-Barr virus (EBV) was established from peripheral blood cells of a patient with immature myeloblastic leukemia. It has been characterized according to phenotype, cytochemistry, and membrane antigen pattern. The cell line expresses lymphoid markers like CD 19, CD 22, and CD 30 and synthesizes and secretes IgM. Monocyte markers CD 11c, CD 14, and CD 15 are absent. Neither interleukin-1 (IL-1), nor tumor necrosis factor (TNF-alpha) are produced. But Ms 28 cells show strong phagocytic activity and engulf Latex particles and sheep RBCs (SRBCs) that need not to be opsonized. The phagocytic activity can be inhibited by chloroquine. Both phagocytosis and EBV nuclear-antigen (EBNA) expression can be observed in one and the same cell. Ms 28 cells might be useful to study immunologic activities like antigen processing and presentation.
Results of chemotherapy in head and neck cancers are reported with a regimen of cisplatinum, bleomycin and methotrexate. In 63 previously untreated patients, the overall response rate was 73%, including 13/63 CR and 33/63 PR. The response rate in 20 previously treated tumors was 20%. The chemotherapy protocol was well tolerated without severe complications. Initial chemotherapy as a third modality in addition to radiotherapy and/or surgery is discussed.
In order to better assess the prognosis of adult patients with urticaria pigmentosa, 35 patients with generalized maculopapular skin lesions and biopsy-proved cutaneous mast cell increase had light and electron microscopic examinations of their bone marrow; 46% had an increased mast cell content that was focal in all but four patients. Additional frequent findings in this group were an increased cellularity, nuclear-cytoplasmic dissociation of maturation, eosinophilia, and macrophages that contained ingested nuclei. Similar changes were found in far fewer patients without increased marrow mast cells. Only one patient with massive cutaneous mastocytosis had mast cells with relatively large nuclei and immature granules in the extensively involved marrow. Repeated biopsies in this and in six other patients over 3 years showed no worsening of the marrow findings, and the clinical course of all patients was stable over up to 10 years of follow-up. The variable findings in the patients suggest that mastocytosis with cutaneous involvement is a heterogeneous disease where diverse stimuli may cause an increase of mast cells. The clinical course is, however, relatively stable.
Major chemotherapeutic alternatives for AML have been implemented and compared in three multicenter studies, including a total of 877 adult patients of all ages. The results strongly suggest that myelosuppressive postinduction treatment is a prerequisite for the achievement of long-term remissions. In addition, it was possible to establish an important antileukemic effect of monthly maintenance chemotherapy. Initial results from an intensive two-course preremission therapy concept revealed good practicability and acceptable toxicity, as well as promising response and remission durations by this new approach.
Between July 1, 1981, and July 1, 1985, 167 patients with acute myelogeneous leukemia (AML) were treated with one or, if necessary, two courses of a modified TAD regimen (TAD9) for induction. 96 patients (58%) achieved a complete remission (CR); 62 achieved CR after one and 34 patients after two courses of TAD9. 29 patients (17%) were considered early deaths, and 42 patients (25%) nonresponders. For CR maintenance 64 patients were eligible according to protocol criteria; 33 patients were randomized to chemotherapy, only, (CT) by monthly courses of cytosine arabinoside (ARA-C) alternatingly combined with daunorubicin or thioguanine or cyclophosphamide, while 31 patients were randomized to receive immunotherapy in addition to chemotherapy (CIT) by intradermal injections of 10(10) neuraminidase-treated viable allogeneic blasts per immunization interspersed between the CT courses. Maintenance therapy was given for up to 3 years. The median survival in CT patients is 23 months, while in CIT patients the median has not been reached after 54 months; corresponding median relapse-free survival is 15 months for the CT patients as opposed to 40 months for the CIT group. The differences are not significant. Comparing CT with CIT, the survival data show a persistent trend in favor of CIT; under the conditions of the study, however, a substantial benefit of immunotherapy may be restricted to a certain subset of patients with low risk for early relapse.
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The 1982 randomized, multicenter trial on adult-AML in West Germany revealed a superiority of remission duration (p = 0.004) and survival (p = 0.06) for patients receiving monthly myelosuppressive maintenance chemotherapy after TAD9-induction and consolidation as compared to patients without maintenance. In the 1985 pilot study double induction as a new approach followed by consolidation and monthly maintenance in patients up to 60 years of age was found well practicable, with 77% complete remissions and 12% early deaths in 81 patients. In addition preliminary remission duration and survival at 1 1/2 years appear favorable.
Lysostaphin, a staphylococcus-derived staphylocidal substance, has widely been used in assays of granulocyte phagocytic and bactericidal capability. It rapidly kills extracellular bacteria. Thus, a separate determination of intracellular surviving bacteria can be performed. One prerequisite for this approach is the safe inactivation of lysostaphin (usually brought about by trypsin) before the intracellular bacteria are externalized for plating. This inactivation has been found by others to be incomplete. Data are presented demonstrating a safe inactivation of lysostaphin by trypsin, if the pH value is maintained within the alkaline range. A low variation of results is obtained by plotting the total number of bacteria killed per incubate vs the logarithm of initial bacterial inoculum or of the intracellular surviving bacteria, leading to linear regression lines. The variation of the results increases greatly for initial bacteria/granulocyte proportions of greater than 5/1. The results obtained for two different St. aureus strains are significantly different. Dexamethasone pretreatment (12 mg p.o. within 8 h) had no detectable influence, when fresh blood was assayed, while blood storage at room temperature for 12 h (without dexamethasone pretreatment) led to a significant functional impairment, mainly of bactericidal capability when analyzed in a pairwise fashion. A major limitation of this kind of assays is that killed bacteria cannot be determined directly.
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By a review of relevant clinical studies on adult AML no substantial progress can be seen in the eighties so far. After the development of successful chemotherapy regimens during the seventies, further improvement can only be expected in small steps. Clinical studies, therefore, should concentrate on the analysis of the different components and new elements of treatment in order to utilize and combine them more effectively. For this purpose, a standardization of treatment and, for many aspects, a randomized comparison is inevitable. Thus, the role of monthly maintenance as well as of a special type of immunotherapy could be elucidated for the first time by our multicenter trial.
This is a report on induction chemotherapy of 20 oropharyngeal and 20 hypopharyngeal squamous cell carcinomas with cis-platinum, bleomycin, and methotrexate. The response rate, defined as a tumour regression of at least 50%, was 70% for the hypopharynx and 80% for the oropharynx. The lymph nodes responded in 50% of the cases. The toxicity was low. Induction chemotherapy is considered to be significant, but it must be stressed that surgery and/or radiation therapy must follow to sustain the initial success.
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102 patients with AML (leukemia after preleukemia, 2nd neoplasia included) were treated for remission induction by a modified TAD regimen in Munster; 55 patients (54%) achieved a complete remission (CR). For CR maintenance 40 patients were eligible for randomization according to the study protocol: cyclic chemotherapy (CT) alone vs. chemoimmunotherapy (CIT: plus allogeneic Neuraminidase-treated blasts in high dosage). 5 CR patients, induced identically in Essen, were randomized additionally. Evaluating all patients randomized there is only a marginally beneficial effect of CIT (21 patients) compared to CT (24 patients) concerning median survival (1020+ vs. 612 days) and relapse-free survival (494 vs. 380 days) until now. For patients receiving more than 2 cycles of maintenance therapy, however, CIT prolongs relapse-free survival significantly (930+ vs. 409 days; p = 0,02); that is also true for remission duration. This suggests that only repeated application of blasts may induce an immune response leading to a biologically relevant antileukemic effect.
In a phase I/II study the tolerable doses and antileukemic efficacy of the combination AMSA and etoposide (VP 16-213) was assessed in 20 patients with refractory acute myeloid leukemia. The following 5 day treatment course was found tolerable and effective: AMSA 210 mg/m2/die on days 2, 3 and 4, and etoposide on days 1 and 5 as a 1 h infusion of 100 mg/m2 followed by a 23-h continuous infusion of 230 mg/m2. In 5 of 20 patients partial remissions were achieved; 4 of these patients were primarily resistant against two TAD induction cycles. Bone marrow aplasia without a residual blast population was achieved in 7 of the 8 patients with primary TAD resistance. AMSA/etoposide thus seems to express an antileukemic efficacy without cross-resistance against TAD.
In two multicenter trials, a total of 576 patients with acute myeloid leukemia (AML) were treated and found to be evaluable. Two hundred forty-two patients were in a 1978 pilot study and 334 patients were in a 1982 randomized study. Ages were between 15 and 78 years (median, 48). The uniform remission induction therapy in both studies consisted of one to two courses of a 9-day combination of 6-thioguanine (TG) with cytosine arabinoside (ARA-C) and daunorubicin (DNR) [TAD9]. The timing and sequencing of TAD9 was designed according to cell kinetic effects of ARA-C. A complete remission (CR) was achieved in 65% (70% and 61%, respectively) of patients within a median of 33 days, and in 68% of responders after only one course. The CR rate in patients 60 to 78 years of age was 51% (66% and 39%, respectively). In the 1978 pilot study, different protocols of post-remission treatment were applied at the different centers: monthly 5-day maintenance, TAD9 consolidation, both consolidation and maintenance, or no further therapy. The group receiving treatment during CR showed 24% probability of remissions at 4 years v 0% probability of remissions in the untreated group. Between the different post-remission protocols, no significant differences were observed. Remission duration was not influenced by age, WBC, or morphologic cell type, but was longer in patients achieving CR within 30 days (P = .017). In the subsequent 1982 study, 145 patients in CR were randomized for TAD9 consolidation with or without monthly maintenance. The updated life-table analysis revealed a predicted rate of continuous remission at 2 1/2 years of 30% for the maintenance and 17% for the nonmaintenance arm (P = .003). These results of response and remission duration in adult patients of all ages support the validity of intensified induction therapy and of consequent myelosuppressive treatment in remission.