Toxicity-reduced, myeloablative allograft followed by lenalidomide maintenance as salvage therapy for refractory/relapsed myeloma patients.

Relapse after dose-reduced allograft in advanced myeloma patients remains high. To reduce the risk of relapse, we investigated a myeloablative toxicity-reduced allograft (aSCT) consisting of i.v. BU and CY followed by lenalidomide maintenance therapy in 33 patients with multiple myeloma (MM) who relapsed following an autograft after a median of 12 months. The cumulative incidence of non-relapse mortality at 1 year was 6% (95% confidence interval (CI): 0-14). After a median interval of 168 days following aSCT, 24 patients started with a median dose of 5 mg (r, 5-15) lenalidomide without dexamethasone. During follow-up, 13 patients discontinued lenalidomide owing to progressive disease (n=6), GvHD (n=3), thrombocytopenia (n=2), or fatigue (n=2). Major toxicities of lenalidomide were GvHD II-III (28%), viral reactivation (16%), thrombocytopenia (III-IV°,16%), neutropenia (III/IV°, 8%), peripheral neuropathy (I/II°, 16%), or other infectious complication (8%). Cumulative incidence of relapse at 3 years was 42% (95% CI: 18-66). The 3-year estimated probability of PFS and OS was 52% (95% CI: 28-76) and 79% (95% CI: 63-95), respectively. Toxicity-reduced myeloablative allograft followed by lenalidomide maintenance is feasible and effective in relapsed patients with MM, but the induction of GvHD should be considered.

Dose-escalated CHOEP for the treatment of young patients with aggressive non-Hodgkin's lymphoma: II. Results of the randomized high-CHOEP trial of the German High-Grade Non-Hodgkin's Lymphoma Study Group (DSHNHL).

BACKGROUND: The addition of etoposide to combination chemotherapy with cyclophosphamide, doxorubicin, vincristine and prednisone [etoposide to combination chemotherapy with cyclophosphamide, vincristine and prednisone (CHOEP)] improved outcome of young patients with good-prognosis aggressive lymphoma. To improve results further, the maximal dose-escalated version of CHOEP-21 tolerable without stem-cell support (high CHOEP: cyclophosphamide 1400 mg/m2, doxorubicin 65 mg/m2, vincristine 2 mg, etoposide 175 mg/m2 x3, prednisone 100 mg x5) was compared with CHOEP-21. PATIENTS AND METHODS: Intention-to-treat analysis of 389 young (18-60 years) patients with good-prognosis (age-adjusted International Prognostic Index = 0, 1) aggressive lymphoma randomized to CHOEP-21 (n = 194) or high CHOEP (n = 195). RESULTS: There was no difference in 3-year event-free (64% versus 67%; P = 0.734) or overall survival (83% versus 87%; P = 0.849). Neither low-risk nor low-intermediate risk patients benefited from high CHOEP. High CHOEP was more toxic than CHOEP-21 (grades 3 and 4 leukocytopenia 100% versus 87.2%, P < 0.001; thrombocytopenia 80.8% versus 9.6%, P < 0.001; infections 35% versus 11%, P < 0.001; therapy-associated deaths 3.1% versus 0%, P = 0.03). CONCLUSION: Dose-escalated CHOEP-21 does not provide clinical benefit for young patients with good-prognosis aggressive lymphomas. Since differences between chemotherapy regimens are compressed by the addition of rituximab, the results of this trial have bearing on strategies aiming to improve outcome of good-prognosis aggressive lymphomas in the rituximab era.

An open, randomized, multicentre study comparing the use of low-dose ceftazidime or cefotaxime, both in combination with netilmicin, in febrile neutropenic patients. German Multicentre Study Group.

To reduce drug acquisition costs, the clinical and bacteriological efficacy of low-dose ceftazidime i.v. (1 g tid) was compared with cefotaxime i.v. (2 g tid). Both regimens were combined with netilmicin i.v. (2 mg/kg bodyweight tid), in an open, randomized, multicentre trial in febrile neutropenic patients. The addition of antibiotics for gram-positive coverage was part of the protocol; alteration in the antibiotics for gram-negative cover or premature discontinuation of the study antibiotics were judged as failure. One hundred and eighty six patients were randomized by nine German centres, the patients matched for age, underlying diseases and duration of neutropenia (median duration 14 days) in both treatment arms. Infections were documented microbiologically in 29% of the patients, clinically in 16% and suspected (fever of unknown origin) in 102/186 patients (55%). The 82 pathogens isolated were predominantly gram-positive bacteria. In an intent-to-treat analysis, the overall response rate without modification at the final evaluation was 58% in the ceftazidime group and 34% in the cefotaxime group (P < 0.01). The success rates with modification were 84% and 64%, respectively. The failure rate in a highly immunosuppressed subgroup of the patients (bone marrow transplant recipients) was higher for cefotaxime (53%) than for the ceftazidime arm (14%) (P < 0.001). Response rates were significantly higher in the ceftazidime group for patients with microbiologically documented and possible infections. No major bacterial superinfections occurred in the low-dose treatment arm. The tolerability was good for both regimens. Low-dose ceftazidime combined with netilmicin proved to be superior to recommended doses of cefotaxime/netilmicin in febrile neutropenic patients.

The use of dose-intensified chemotherapy in the treatment of metastatic nonseminomatous testicular germ cell tumors. German Testicular Cancer Study Group.

With the use of a cisplatin-based chemotherapy, metastatic testicular cancer has become a model for a highly curable malignant disease. Current data show that 70% to 80% of patients with this disease will achieve long-term survival following cisplatin/etoposide/bleomycin therapy. The role of high-dose chemotherapy with autologous stem cell support is being investigated in metastatic germ cell cancer in attempts to improve outcome for patients whose disease relapses after standard-dose chemotherapy and for those who present initially with advanced metastatic disease. Prognostic categories for patients receiving high-dose salvage chemotherapy have recently been developed: cisplatin-refractory disease, beta-human chorionic gonadotropin values greater than 1,000 U/L, and primary mediastinal germ cell tumors are factors characterizing patients who will derive less benefit from high-dose chemotherapy than those with chemosensitive disease at relapse. While standard-dose salvage chemotherapy achieves only a 20% long-term survival rate, high-dose salvage chemotherapy may yield a cure rate of approximately 40%. A randomized study comparing high-dose therapy with conventional-dose therapy (IT94 coordinated by the European Group for Blood and Marrow Transplantation) in patients with relapsed disease is ongoing to substantiate this observation. The use of dose-intensive therapy as first-line treatment is currently being studied by several institutions. High-dose therapy may be better tolerated when used first line compared with its use in the salvage situation, and may also achieve a rapid initial cell kill before cytostatic drug resistance develops. The German Testicular Cancer Study Group has developed a sequential high-dose combination regimen of cisplatin/etoposide/ifosfamide given with granulocyte colony-stimulating factor and peripheral blood stem cell support for four cycles every 3 weeks. This ongoing study, started in 1990, had accrued 218 patients with advanced testicular germ cell tumors as of June 1997. Of 141 evaluable patients receiving dose levels 1 through 5, 82 (58%) have achieved complete remission with no evidence of disease and 32 (23%) have achieved partial remission with marker normalization. The early death rate was 8%. Overall and event-free survival rates at 2 years are 78% and 73%, respectively, with a projected 5-year overall survival rate of 74%. Despite favorable preliminary results, this approach cannot be considered standard treatment. Currently, high-dose chemotherapy with peripheral blood stem cell transplantation should be administered to patients with testicular cancer only within controlled clinical trials to allow long-term cure rates and treatment-related late side effects to be evaluated.

Differential expression and biological activity of the heparin-binding growth-associated molecule (HB-GAM) in lung cancer cell lines.

The growth of human lung cancer cells is regulated positively and negatively by a variety of growth factors through autocrine as well as paracrine mechanisms. In the present report, we studied the differential role and expression of a neuropolypeptide growth factor in 26 lung cancer cell lines. Expression of the heparin-binding growth-associated molecule (HB-GAM) in 12 small cell lung cancer (SCLC) cell lines was compared to that in 14 non-small cell lung cancer (NSCLC) cell lines. HB-GAM mRNA was expressed in 9 of 12 SCLC and 3 of 14 NSCLC cell lines as determined by RT-PCR analyses. Normal human bronchial epithelial cells were used as negative controls. All cell lines which expressed HB-GAM mRNA produced HB-GAM protein as well. Western blot analysis showed that the tumor cells secreted HB-GAM into the media. HB-GAM, purified from lung cancer cell lines, exerted biological activity on fibroblasts, endothelial cells and SW13 cells as determined by thymidine incorporation and soft agar cloning assays. In addition, the biological activity of HB-GAM was blocked by a specific antibody in a dose-dependent way. Our findings suggest that HB-GAM may serve as a marker for SCLC cell lines and that it may function as a paracrine growth factor in human lung cancer. HB-GAM may be a further member of the network of growth factors involved in proliferation, angiogenesis and metastasis of lung tumors.

Cutaneous monoblastic leukemia as a first sign of relapse six years after autologous bone marrow transplantation for acute leukemia.

A patient with acute monoblastic leukemia (AML, M5A) was treated successfully in December 1987. In 1993 after 6 years in complete remission, she presented with an intracutaneous nodular mass on her right upper arm which was resected in toto and shown to be undifferentiated monoblastic leukemia. Two further chloroma lesions were excised in July 1994 and March 1995 respectively. Bone marrow cytology and histology always showed a continuing complete remission with no evidence of leukemia relapse. In July 1995 she presented with a disseminated skin infiltrate and a relapse with 80% monoblasts in the bone marrow. After one course of chemotherapy (Idarubicin/Ara-C), a second complete remission was achieved and her leukemic skin infiltrate disappeared completely. This case illustrates that chloromas of the skin can occur as late as 6 years after treatment for AML and also emphasizes that the occurrence of a chloroma does not necessarily mean immediate leukemia relapse. It also stresses that a second complete remission can be achieved with standard AML-induction therapy despite widespread leukemic skin infiltrates in such patients.

Severe lymphocytopenia and interstitial pneumonia in patients treated with paclitaxel and simultaneous radiotherapy for non-small-cell lung cancer.

PURPOSE: In a phase II trial with paclitaxel and simultaneous radiotherapy in non-small-cell lung cancer (NSCLC) patients, an unexpected high incidence of interstitial pneumonias was observed. The type of immunodeficiency associated with this treatment approach is characterized. PATIENTS AND METHODS: Fifteen patients with inoperable stage IIIA/B NSCLC were treated with paclitaxel as a 3-hour infusion on day 1 in weeks 1 to 3 and 6 to 8 at dose levels between 50 mg/m2 and 86 mg/m2 and with simultaneous radiotherapy in daily doses of 2 Gy, 5 days per week, in weeks 1 to 3 and 6 to 8 up to a total dose of 56 Gy. Hematologic parameters and lymphocyte subsets were monitored. RESULTS: Fourteen patients are assessable for response. The overall response rate was 78%, with four major responses, six partial remissions, and four minor responses. The major toxic effect observed was a moderate to severe protracted lymphocytopenia (380 +/- 310/microL) in all patients. Seven patients developed moderate to severe interstitial pneumonia; one had an additional herpes zoster infection, while an eighth patient had a cytomegalovirus infection. During treatment, all lymphocyte subsets were reduced, as follows (n = 9, mean +/- SD): CD4+ T cells (100 +/- 90/microL), CD8+ T cells (130 +/- 160/microL), natural killer (NK) cells (70 +/- 80/microL), and B cells (20 +/- 10/microL). Thus, the most pronounced toxicity was seen in CD4+ T and B cells. There was no recovery of lymphocyte subsets during a 3-month follow-up period. CONCLUSION: Paclitaxel with simultaneous radiation induces lymphocytopenia and promotes opportunistic infections. Long-term antibiotic and antimycotic prophylaxis is recommended. Whether the lymphocytopenia is an additive effect of paclitaxel and radiation or whether it can be induced by low-dose weekly paclitaxel alone remains to be determined.

Successful treatment of osteoporosis in systemic mastocytosis with interferon alpha-2b.

Osteoporosis is frequently seen in systemic mastocytosis. Although diphosphonate therapy has been shown to be transiently effective, therapy options for this form of osteopenia are very limited. We have treated three patients with systemic mastocytosis and osteopenia successfully with interferon alpha-2b. Two patients had urticaria pigmentosa and two severe back pain due to vertebral compression fractures. All patients received a daily interferon dose of 3 x 5 mio units/week s.c. for a period of 6 months. Therapy was well tolerated, and back pain resolved in both patients. A marked decrease of mast cell numbers in the bone marrow and a significant increase of bone mineralization and bone density was observed in all patients. Our data suggest that alpha interferon may be a new treatment option for osteopenia in systemic mastocytosis.

Limited sampling models for reliable estimation of etoposide area under the curve.

Limited sampling models are able to estimate the area under the concentration-time curve (AUC) from plasma concentrations measured at only a few time points. The purpose of this study was to establish a model estimating etoposide AUC independently of specific chemotherapy protocols, underlying malignancies, concomitant diseases and age. Pharmacokinetic parameters were measured in 30 patients treated with polychemotherapy including etoposide (80-150 mg/m2). Etoposide analysis was performed by thin layer chromatography and consecutive quantitative sample detection by 252Cf-plasma desorption mass spectrometry. Data from the first 15 patients formed the training set. Based on the training data, five different models were generated, with the multiple regression coefficient r ranging from 0.91 to 0.96. The following model was selected as "most accurate": AUC = 343 (min)C4h(micrograms/ml) + 650(min)C8h(micrograms/ml) + 1252 (min micrograms/mol), where C4h is the plasma concentration of etoposide at 4 h after the end of infusion and C8h at 8 h. This model was validated on the test set, comprising the data of the remaining 15 patients. The mean predictive error (MPE) was -0.2% and the root mean square predictive error (RMSE) was 4.7%. When used for a large number of patients, this practicable and simple model is an instrument for use in prospective studies, to measure a correlation between drug dosage and efficacy or toxicity of the drug.

The role of decreased retinoblastoma protein expression in acute myelomonocytic and monoblastic leukemias.

The results of different investigators show that lack of p105 expression is relatively common in human myeloid leukemias, especially in monocytic leukemias. This suggests that loss of p105 expression could contribute to the altered growth control of these cells. So far no clear data exist which show that low p105 levels in AML blasts predict a poor therapy outcome. Therefore it is not very likely that p105 expression will become a strong prognostic factor for the different treatment strategies in AML.

Primary osteosarcoma of the kidney. Case report and review of literature.

Primary osteosarcoma of the kidney is an extremely rare phenomenon with less than 20 previously reported cases in the English literature since 1936. Diagnosis usually is made in advanced stages of disease with weight loss, palpable tumor, flank pain and gross hematuria being the characteristic features of clinical presentation. Radiographically bizarre renal calcifications may be suggestive of this uncommon neoplasm. The atypic location is explained by metaplastic changes of originally primitive embryonic mesenchymal tissue. Though the primary treatment for sarcomas is surgical resection, because of their usual late and high stage presentation multimodal adjuvant therapy may be desirable. We describe the clinical course of a 48-year-old male patient with a primary renal osteosarcoma discovered by ultrasound. A marked reduction of vital tumor cells and an impressive increase of neoplastic bone formation following polychemotherapy is demonstrated histopathologically. The principal clinical findings, differential diagnosis, etiology, pathogenesis and treatment modalities of this uncommon malignancy are discussed.

Myeloperoxidase deficiency: an epidemiological study and flow-cytometric detection of other granular enzymes in myeloperoxidase-deficient subjects.

MPO deficiency, as first studied in the 1960s, has been recorded with increasing frequency, following the introduction of the automated cytochemical count into clinical routine. However, with regard to the diseases correlated to MPO deficiency, no exact data on the frequency of co-existence have been recorded. Moreover, the question remains whether or not a further deficiency of other granular enzymes co-exists, especially with regard to acquired MPO deficiency. In order to answer these questions, an epidemiological study of more than 70,000 unselected patients was performed; the resulting prevalence of MPO deficiency was 0.15%. Within this patient group the intercellular content of elastase-like protease (ELP) and lactoferrin was measured semiquantitatively in a flow cytometer by means of indirect immunofluorescence staining. The frequency of coinciding diseases did not differ from the frequency of diseases in the hospital patients in general. The flow-cytometric studies revealed a normal content of ELP and lactoferrin in one group and a reduced content in another, suggesting the inherited form in the former and acquired MPO deficiencies in the latter group and thus indicating that differing mechanisms characterize the two forms of MPO deficiency. Nevertheless, we do not suggest distinguishing between acquired and inherited deficiencies solely with this technique. Instead, molecular-biologic and/or genetic methods should be referred to.

Successful treatment of neutropenia in T-LGL leukemia (T gamma-lymphocytosis) with granulocyte colony-stimulating factor.

Severe neutropenia is a common feature in patients with T-large granular lymphocytic (LGL) leukemia. Neutropenia often causes severe infections and septicemia, thus representing a major cause of morbidity and mortality in this disease. We have treated two outpatients with T-LGL leukemia who had severe neutropenia (neutrophils < 0.2 x 10(9)/l) successfully with G-CSF (5 micrograms/kg daily, s.c.). After 10 days of treatment the neutrophil count was within the normal range and a severe oral infection healed rapidly. We conclude that G-CSF therapy is able to normalize the neutrophil count in T-LGL leukemia within a few days and that it can be used to treat severe infections in these patients even on an outpatient basis.

Prognosis of high dose chemotherapy/autologous bone marrow transplantation candidates not receiving this treatment after failure of primary therapy of Hodgkin's disease.

In a multicenter study on the therapy of Hodgkin's disease, in 88 out of 297 patients with primary advanced stages IIIB/IV, a failure to the treatment with the alternating chemotherapy COPP/ABVD +/- radiation was recorded. The cause of failure was as follows: tumor progression under current therapy (PD) 23/88, partial response at the end of therapy (PR) 28/88, early nodal relapses 13/88, late nodal relapses 16/88, extranodal relapses 7/88, undetermined localization 1/88.36 months after manifestation of the failure to treatment, 45% of all patients were still alive. In cases of primary PD the prognosis was the worst of all. Only 1/23 of these patients received a long-term continuous complete remission (cCR) with the salvage therapy. 11 patients with only a nodal relapse received a cCR with irradiation alone. These cases could be regarded as low risk relapses. For the high risk relapse group (n = 57) an indication for high dose chemotherapy with subsequent autologous bone marrow transplantation (HDC/ABMT) would have been imperative, following the present-day definition. The probability of survival of these patients who, however, only received a conventional salvage therapy was up to 38% (95% confidence interval 22-54%). Comparing these data with the literature our results seem not to be substantially worse than those for patients who underwent HDC/ABMT. Only in a randomized comparison can the decision be made on whether HDC/ABMT would be superior to high dose conventional chemotherapy supported by hematopoietic growth factors. It is suggested that such a therapy study be performed as soon as possible.

Relationship of calcitonin mRNA expression to the differentiation state of HL 60 cells.

Raised plasma levels of immunoreactive human calcitonin (ihCT) can be found in patients with myeloid leukemia and seem to indicate a poor prognosis. High levels were found in acute undifferentiated and acute myeloblastic leukemia. To test whether CT expression could be a marker of myeloid differentiation, we used the promyelocytic leukemia cell line HL 60 which also expresses ihCT as a model system for myeloid differentiation. Exponentially growing HL 60 cells as well as differentiation induced HL 60 cells expressed a single 1.0 Kb CT transcript. The induction of HL 60 cell differentiation along the granulocytic lineage by DMSO or HMBA had no effect on the level of CT transcripts. Induction of monocytic/macrophagic differentiation by TPA resulted in a transient, about 10-fold elevated expression of CT steady state mRNA after 24 h. In contrast to TPA, induction of HL 60 cell differentiation along the monocytic pathway by Vit D3 had no detectable effect on the level of the CT in RNA expression at corresponding time points. These findings suggest that the transient induction of CT steady state mRNA expression by TPA is rather a direct effect of the phorbol ester than commitment along the monocytic line of differentiation.

Randomised comparison of CHOEP versus alternating hCHOP/IVEP for high-grade non-Hodgkin's lymphomas: treatment results and prognostic factor analysis in a multi-centre trial.

BACKGROUND: With CHOP, the standard protocol of recent decades, about 30% of long-term survival has been reported. A number of studies using more aggressive multidrug regimens or alternating chemotherapies have recently suggested higher CR rates and increased survival. In 1989 we reported similar results with a combined-modality treatment administering 6 cycles of CHOP supplemented with etoposide and an involved field irradiation for patients in PR or CR. PATIENTS AND METHODS: To confirm the efficacy of this approach, we initiated a prospective randomised trial comparing 4 cycles of CHOP-VP16 (CHOEP) with 4 cycles of two alternating regimens, 'hCHOP and IVEP'. One hundred seventy-five patients with high-grade non-Hodgkin's lymphomas stages II-IV were stratified for age, stage and LDH and randomised to receive either four cycles of cyclophosphamide, doxorubicin, vincristine, etoposide, prednisolone (CHOEP) in arm A or four cycles of chemotherapy with a dose-intensified CHOP (hCHOP) alternating with ifosfamide, etoposide, vindesine, prednisolone (IVEP) in arm B. After four cycles of chemotherapy an involved field irradiation with a total dose of 35 Gy was given to all patients demonstrated to be in complete or partial remission. RESULTS: Of the 185 randomised patients, 175 were eligible and 171 evaluable for response and survival. One hundred forty-six of the 171 patients (85%) achieved complete remission (CR) with 87% and 84% CRs in arms A and B, respectively. With a median follow-up of 36 months the estimated overall survival at 2 years is 66% and 73% for arms A and B, respectively. The percentage of all patients in first CR is estimated to be 59% and 55% at 2 years for arms A and B, respectively. None of the differences in CR rate, survival, or relapse-free survival are statistically significant. Multivariate analysis of subgroups incorporating the factors of sex, age, performance status, stage, B symptoms, bulky disease, LDH and histology revealed that only stage and LDH were factors which independently affected outcome. The estimated 2-year survival rate of patients with stages II, III and IV is predicted to be 84%, 62% and 52%, respectively. Patients with LDH > 250 U/l have an estimated survival of 52% at 2 years versus 84% for patients with LDH < or = 250 U/l. According to the newly proposed international score system, the 2-year survival was 81% for low-risk-, 64% for low intermediate risk-, 50% for high intermediate risk-, and 43% for high-risk patients. The toxicity in both arms was tolerable. Three patients died of treatment-related causes (2 in arm A, 1 in arm B). The main toxicity was haematological with 75% of patients suffering from grades 3 or 4 neutropenia at some point during treatment. CONCLUSIONS: We observed no superior benefit for alternating regimens, and conclude that both are effective treatment protocols for aggressive histologic-type malignant lymphomas. The results obtained with four cycles of poly-chemotherapy followed by an involved field irradiation are comparable to programs using more aggressive and/or prolonged chemotherapy.

Altered expression of the retinoblastoma gene product in human high grade non-Hodgkin's lymphomas.

The retinoblastoma gene (RB) is a growth suppressor gene on the human chromosome 13q14. It encodes a 105 kDa phosphoprotein (p105), with DNA-binding capacity. P105 is thought to be involved in cell cycle control. Inactivation of RB is responsible for the development of retinoblastomas and occurs frequently in osteosarcomas and small cell lung cancer. In this study we looked at the RB-structure and expression in cell lines and primary lymphoma samples from patients with high grade non-Hodgkin's lymphoma (NHL). Forty five primary high grade NHL, the B-lymphoblastoid cell line IM-9 and the NHL cell line WSU-NHL were studied for RB structure by Southern blotting and for RB-expression by Northern blotting, Western blotting and immunocytochemistry. In all experiments freshly cryopreserved material was used. Southern and Northern experiments were performed with the 0.9 kb and 3.8 kb RB-cDNA probe. For the detection of p105 two different anti-p105-monoclonal antibodies were used in immunocytochemistry and Western blotting experiments. No RB mRNA and no p105 could be found in IM-9 cells. Twenty six high grade NHL samples (58%) showed no p105 expression. In the subgroup of centroblastic lymphomas 16 out of 21 and in Burkitt's lymphomas five out of eight showed no p105-expression. P105 expression is absent in 58% of high grade NHL, particularly in centroblastic and Burkitt's lymphomas, suggesting that inactivation of RB may play a crucial role in the pathogenesis of high grade NHL.

Biochemical characterization of a novel autocrine transferrin-like growth factor in acute myeloblastic leukemia.

Serum-free conditioned media (CM) of acute myelogenous leukemia cell lines induce growth stimulation of other leukemic cell lines. A transferrin (Tf)-like iron binding kD 50 protein was found to be the main growth factor of these CM's. Purification and further characterization of this protein was performed by chromatographic methods, SDS-PAGE, peptide mapping and amino acid analysis. In addition m-RNA of leukemic cell lines was analysed by Northern blot analysis with oligonucleotide probes specific for human serum Tf and melanotransferrin (p97) respectively. No hybridization signals for these probes have been detected. Biochemical results show significant differences between human serum Tf and kD 50 growth factor with respect to retention time on reversed phase FPLC, pattern of digestion peptides in SDS-PAGE and amino acid composition, which suggests, that this protein is an additional tumor associated member of the transferrin superfamily.