Elke Fritz

The Prognostic Significance of Proliferating Cell Nuclear Antigen, Epidermal Growth Factor Receptor, and mdr Gene Expression in Colorectal Cancer

Background. Proliferating cell nuclear antigen (PCNA), a proliferation marker, epidermal growth factor receptor (EGFR), a glycoprotein that plays a role in tumorigenesis by binding the mitogenic epidermal growth factor, and P‐glycoprotein, the mdr gene product, are considered to be of prognostic relevance in different tumor types. Parameters that allow prediction of the course of disease in colorectal cancer would aid the development of improved treatment strategies.

Erythropoietin Treatment of Anemia Associated with Multiple Myeloma

Anemia is a common complication of multiple myeloma. It resolves early in the disease if chemotherapy induces a complete remission, but persists if the disease progresses, causing disabling symptoms and often requiring blood transfusions. We treated 13 patients with myeloma-associated anemia by administering recombinant human erythropoietin three times a week for six months. Eleven patients (85 percent) had steady increases in hemoglobin levels and eventual correction of the anemia. Their symptoms of anemia subsided, and they reported a heightened sense of well-being. No patient had any adverse side effects, particularly episodes of hypertension. Monitoring of the serum M component showed a predominantly stable tumor load without apparent interaction between the underlying disease and the response to erythropoietin therapy. The number of erythroid burst-forming units in the bone marrow and peripheral blood and the level of erythropoiesis in bone marrow smears increased significantly during therapy. Pretreatment serum levels of erythropoietin were higher in the patients who did not respond and in those who required more than two months of treatment before they responded. Serum iron, ferritin, and transferrin concentrations reflected responses to treatment. We conclude that recombinant human erythropoietin is a promising therapeutic tool for treating myeloma-associated anemia.

Predictive Role of Interphase Cytogenetics for Survival of Patients With Multiple Myeloma

PURPOSE Recent metaphase cytogenetic studies suggested that specific chromosomal abnormalities are of prognostic significance in patients with multiple myeloma (MM). Because the true incidence of chromosomal abnormalities in MM is much higher than that detected by metaphase analysis, we used interphase fluorescence in situ hybridization (FISH) to determine the prognostic value of specific chromosomal aberrations. PATIENTS AND METHODS Bone marrow plasma cells from 89 previously untreated patients with MM were studied consecutively by FISH to detect the deletions of 13q14, 17p13, and 11q and the presence of t(11;14)(q13;q32). FISH results were analyzed in the context of clinical parameters (response to treatment and survival after conventional-dose chemotherapy), and a multivariate analysis of prognostic factors was performed. RESULTS By FISH, the deletion of 13q14 occurred in 40 patients (44.9%), deletion of 17p13 in 22 (24.7%), and 11q abnormalities in 14 (15.7%; seven with t(11;14)). Deletions of 13q14 and 17p13 were associated with poor response to induction treatment (46.9% v 77.3% in those without deletions, P =.006 and 40.0% v 73.2%, P =.008, respectively) and short median overall survival (OS) time (24.2 v 88.1 months, P =. 008 and 16.2 v 51.3 months, P =.008, respectively). Short median OS time was also observed for patients with 11q abnormalities (13.1 v 41.6 months, P =.02). According to the number of unfavorable cytogenetic features (deletion of 13q14, deletion of 17p13, and aberrations of 11q) that were present in each patient (0 v 1 v 2 or 3), patients with significantly different OS times could be discriminated from one another (102.4 v 29.6 v 13.9 months, P <.001, respectively). CONCLUSION For patients with MM who were treated with conventional-dose chemotherapy, interphase FISH for 13q14, 17p13, and 11q provides prognostically relevant information in addition to that provided by standard prognostic factors. This observation may be considered for risk-adapted stratifications of MM patients in future clinical trials.

Quality of life in chronic anemia of cancer during treatment with recombinant human erythropoietin

Background. Improvements in quality of life after treatment with recombinant human erythropoietin (rHuEPO) often have been reported in patients with endstage renal disease. In patients with chronic anemia of cancer, comparatively few systemic investigations have been performed.

LONG-TERM INTERFERON THERAPY FOR THROMBOCYTOSIS IN MYELOPROLIFERATIVE DISEASES

31 patients with thrombocytosis associated with myeloproliferative disorders were included in a prospective trial of long-term interferon therapy. 6 patients (19%) had side-effects which required withdrawal of interferon within one year. 22 patients (71%) achieved and maintained a complete response (platelet count less than 440 x 10(9)/l) for at least twelve months, with reduction or abolition of symptoms associated with thrombocytosis and a significant fall in bone-marrow megakaryocytes. At twelve months, 25 patients were randomly allocated to maintenance or withdrawal of interferon. Thrombocytosis recurred rapidly when treatment was stopped, but a second remission could be achieved by resumption of interferon therapy.

MAGNETIC RESONANCE IMAGING OF THE SPINE IN MULTIPLE MYELOMA

The lower thoracic and lumbar spine of patients with multiple myeloma was examined by magnetic resonance imaging (MRI), plain radiography, and bone scintigraphy. Three independent investigators evaluated the power of these diagnostic methods to detect bone lesions in 192 vertebrae from 18 patients and in 60 vertebrae from 7 controls. 41 foci with abnormal signal intensity were detected by MRI; X-ray films showed osteolytic lesions in 4 vertebral bodies; and bone scanning was positive in 2 cases. The superiority of MRI in detecting myeloma-associated focal bone lesions was statistically significant, and in one case the lesions were confirmed at necropsy. Deviations in shape and height of vertebral bodies were slightly more easily visible on radiographs. Early detection of imminent medullary compressions in 2 patients led to successful radiotherapy before symptoms appeared.

Interferon-alfa corrects thrombocytosis in patients with myeloproliferative disorders

SummaryDuring previous therapeutic trials with interferon, decreased levels of peripheral platelet counts have been observed. Taking advantage of this effect, we investigated the efficacy of recombinant interferon (rec-IFN) in the treatment of thrombocytosis in myeloproliferative diseases. A total of 15 patients with polycythemia vera, essential thrombocytosis, or chronic myeloid leukemia received rec-IFN-alfa at initial doses of 25–70×106 units/week; maintenance therapy following week 8 of treatment consisted of 20–35×106 units/week rec-IFN. Observation periods ranged from 24 to 48 weeks. Significant reductions in the number of platelets were noted in all cases; 12/15 patients achieved platelet counts below 440×109/1 and maintained those normal values for at least 4 weeks. The number of bone marrow megakaryocytes, which had been increased prior to treatment, diminished during rec-IFN therapy, while the previously shortened platelet half-life further decreased with rec-IFN treatment. During rec-IFN-induced remission, the plasma levels of platelet factors, the activity of natural killer cells, and platelet aggregation showed changes between slight improvement and normal values. Severe side effects were only observed with the highest rec-IFN doses; dosage adjustments were effective in improving or eliminating all treatment-related symptoms. Rec-IFN may prove to be a valuable therapeutic alternative to cytostatic treatment of thrombocytosis in myeloproliferative disorders.

Interferon alfa-2b with VMCP compared to VMCP alone for induction and interferon alfa-2b compared to controls for remission maintenance in multiple myeloma: interim results.

The present trial was designed to evaluate whether interferon (IFN) combined with standard induction chemotherapy and/or interferon remission maintenance treatment improve treatment results in patients with multiple myeloma. Up to now 89 patients have received IFN plus vincristine/melphalan/cyclophosphamide/prednisolone (VMCP) as induction therapy, and 86 conventional VMCP. The proportion of patients with progressive disease was significantly lower (P less than 0.005) under IFN + VMCP as compared to the VMCP treatment group. Survival times were significantly longer (P less than 0.02) after IFN + VMCP induction therapy than after VMCP alone. In the second phase of this investigation, 33 progression-free myeloma patients were assigned to receive IFN as maintenance therapy, and 41 patients served as untreated controls. Patients maintained with IFN showed a tendency towards increased progression-free survival. Haematological side effects were observed significantly more often in patients receiving IFN, with more severe haematological toxicity in patients on the combined IFN + VMCP regimen and an increased number of patients with mild haematological toxicity in the group maintained with IFN. Other side effects, such as fever and fatigue, remained within tolerable limits. In conclusion, the preliminary results of this current clinical trial indicate significant advantages of combined IFN + VMCP induction treatment in terms of reduced disease progression and prolonged survival and possible benefits of IFN maintenance therapy in patients with multiple myeloma.

A plasma clot culture system for growing and antiproliferative drug sensitivity testing of myeloma stem cells

An easy-to-perform clonogenic culture system for myeloma stem cells is presented which approaches the patients in vivo situation more closely and therefore seems particularly well-suited for antiproliferative drug sensitivity assays. Bone marrow cells are propagated in clotted autologous or allogenic plasma that is enriched with 2-mercaptoethanol, insulin, and synthetic nucleotides and co-factors for nuclear synthesis, no feeder layer or conditioned medium is necessary. Clusters and colonies consisting of between 8 and 60 cells readily formed within 6-8 days after cloning yielding a plating efficiency between 0.12 and 2.16%. A linear relationship between the number of cells plated and colony formation was found from 10(5) through 2 X 10(6) cells plated. The successful growth rate for 65 tests from 53 patients amounted to 90.8%. Morphological and histochemical examination of the clusters revealed lymphoid cells at various stages of maturation ranging from lymphocytic and lymphoblastoid to lymphoplasmacytic and plasma cells. Tumor origin of the clones was demonstrated by immunofluorescence studies in which Ig-positive cells stained only for the heavy and light chain isotypes identical to those of the patients serum paraprotein. Anti-idiotypic antisera confirmed the patients specific malignant phenotype of the colonies formed. The technique of the assay is described in detail.

Maximal androgen blockade in combination with methotrexate for treatment of metastatic prostate cancer.

Recently attention has been focused on the optimal timing of chemotherapy within the treatment regimen for patients with metastatic prostate cancer, i.e., hormonal manipulation, preferably maximal androgen blockage (MAB) consisting of chemical/surgical castration followed by treatment with antiandrogens. We have conducted a randomized prospective clinical trial, investigating the efficacy and toxicity of MAB (orchiectomy followed by flutamide therapy) alone as compared to MAB combined with methotrexate (MTX, 50 mg/m2/week) in 53 patients with newly diagnosed stage IV (M1) prostatic cancer (UICC TNM Classification 1987). The observed remission rates (complete+partial) of 42.3% in the MAB+MTX arm and 29.6% in the MAB arm did not differ significantly. The response rates (complete+partial+stable disease) of 73.1% and 66.7% for MAB+MTX and MAB, respectively, also showed no significant difference. Neither progression-free survival (median: 18.5 and 23.8 months for MAB+MTX and MAB, respectively) nor overall survival (median: 37.4 and 36.1) months in the MAB+MTX and MAB arm, respectively) could be improved by the addition of MTX to MAB. Only the extent of metastatic pain reported by the patients was consistently less under MAB+MTX than under MAB alone (P<0.1). Both treatment regimens were well-tolerated with slightly more undesirable effects in the MAB+MTX arm. Our results do not provide evidence for the achievement of marked gains by combining chemotherapy with endocrine therapy in newly diagnosed patients with stage IV (M1) prostate cancer.