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Biomedical subjects

W Hunstein

Publications and source records attributed to W Hunstein.

At least 55 records · Page 3Linked to original sources
PubMed1994

Sequential high-dose therapy with peripheral-blood progenitor-cell support in low-grade non-Hodgkin's lymphoma.

PURPOSE: To evaluate the feasibility of a sequential high-dose therapy with peripheral-blood progenitor-cell (PBPC) support in patients with follicular lymphoma. PATIENTS AND METHODS: Since July 1991, we have included 30 patients (17 men and 13 women) with a median age of 41 years (range, 26 to 55) in the study. At the time of study entry, 17 patients were in first and six in second or higher remission. Another six patients had relapse of disease and one had tumor progression. PBPC were collected during filgrastim-supported leukocyte recovery following high-dose cytarabine (ara-C)/mitoxantrone (HAM). RESULTS: A median of two leukaphereses (range, one to seven) resulted in a median of 5.7 x 10(6) CD34+ cells/kg (range, 2.9 to 23.7 x 10(6). A distinct population of B-lymphoid progenitors (CD34+/CD19+) was not detectable in the autografts, and the content of CD19+ B cells was remarkably low, comprising a median of 0.07% of the mononuclear cells. Using the polymerase chain reaction (PCR) assay for the major breakpoint regions (MBR) of the bcl-2/immunoglobulin H (IgH) translocation, 22 patients had autografts positive for the t(14;18) translocation, whereas seven patients had PCR-negative transplants. The autograft of one patient could not be assessed. Following myeloablative therapy, hematologic recovery was rapid without cytokine support. The median times to reach a platelet count > or = 20 x 10(9)/L and neutrophil count > or = 0.5 x 10(9)/L were 11 and 13 days, respectively. Nonhematologic toxicity was moderate. Twenty-nine patients were alive in remission after a median follow-up duration of 6 months (range, 1 to 18). Of 22 patients autografted with t(14;18)-positive harvests, 11 had PCR-detectable cells in bone marrow and/or peripheral blood as long as 16 months posttransplantation. In contrast, six patients became PCR-negative between 3 and 16 months after reinfusion. Follow-up examinations with PCR data for the remaining five patients are not yet available. CONCLUSION: Conversion to PCR negativity in patients autografted with PCR-positive harvests suggests that the myeloablative regimen is effective and that any reinfused t(14;18)-positive cells may not be sustained. Because conventional chemotherapy provides no cure, we believe that high-dose therapy including total-body irradiation (TBI) should be explored in these particularly radiosensitive lymphomas.

Adult↗
PubMed1994

Results of radiotherapy and combined modality treatment in early stage high grade non-Hodgkin's lymphoma.

PURPOSE: In combined modality treatment of early stage, high grade non-Hodgkin's lymphoma disease status after initial chemotherapy was analyzed to evaluate the impact of remission status on survival. Analysis of relapse patterns was performed to assess efficacy of radiation doses and volume. PATIENTS AND METHODS: Fifty-four patients with early stage high grade non-Hodgkin's lymphoma were treated with radiotherapy alone or with initial chemotherapy followed by involved field irradiation. Overall survival, relapse-free survival and relapse patterns were analyzed. RESULTS: In patients treated with radiotherapy alone (stage I n = 15, stage II n = 8) overall survival rate was 69%, relapse-free survival was 35% at 3 years. Patients achieving combined modality treatment (stage I n = 5, stage II n = 26) showed an actuarial 3 year overall survival of 78%, relapse-free survival was 62%. Complete remission status after chemotherapy was an important factor for durable disease control. Those patients, who achieved complete remission after chemotherapy showed an actuarial relapse-free survival of 75% at 3 years. Patients with partial remission or progressive disease after chemotherapy had a poor outcome (relapse-free survival 35%). Analysis of the first manifestation of lymphoma progression after radiotherapy in relation to the treatment portals demonstrated radiotherapy to be highly effective in achieving local control. Only 8% of recurrences occurred within the irradiated volume. 56% of failures were found in non-contiguous sites to the former radiation portals. CONCLUSION: This analysis suggests that effective chemotherapy in combination with involved field radiotherapy in CS I (with risk factors) and especially in CS II patients is necessary to control extension of non-Hodgkin's lymphoma.

Adolescent↗
PubMed1993

Interferon-alpha and interleukin-2 in the treatment of metastatic melanoma. Comparison of two phase II trials.

BACKGROUND: Interferon-alpha (IFN alpha) and interleukin-2 (IL-2) are active agents against malignant melanoma. There is, however, no consensus on the optimal dosing schedule of both drugs. This is a report of two sequential immunotherapy trials in patients with metastatic melanoma using two different IL-2 dosing schedules. METHODS: Schedule A consists of IFN alpha, 10 million U/m2/day subcutaneously for 5 days, followed by continuous intravenous infusion of IL-2, 1 mg/m2/24 hours for 5 days. Schedule B consists of the same dose of IFN alpha, but a modified regimen of IL-2. To improve the induction of high-affinity IL-2 receptors, the initial IL-2 dose was increased (1 mg/m2/6 hours, followed by 1 mg/m2/12 hours, and 1 mg/m2/24 hours). To reduce toxicity, the dose was reduced thereafter to 0.25 mg/m2/24 hours for the following 3 days. Both regimens were repeated after 4 weeks. RESULTS: 27 patients were treated with schedule A with a response rate of 18% (1 complete response [CR], 4 partial responses [PR]), 95% confidence interval, 6-36%. The response rate in 27 patients treated with schedule B was 41% (3 CR, 8 PR), 95% confidence interval, 22-61%. Severe, often dose-limiting toxicity was associated with IL-2 in schedule A, particularly hypotension and fluid retention. Toxicity was reduced significantly in schedule B. Maximal serum levels of soluble CD25 were 17,022 +/- 13,070 U/ml in schedule A, and 31,148 +/- 4227 U/ml in schedule B (P < or = 0.01). Serum levels of TNF alpha were significantly lower in schedule B than in schedule A, as were the side effects. CONCLUSIONS: Toxicity of IL-2 is reduced by modifying the schedule of administration, which also enhances the immunologic response and appears to increase the response rate.

Adult↗
PubMed1993

Differential expression and release of LFA-3 and ICAM-1 in human melanoma cell lines.

We examined 10 different melanoma cell lines for cellular expression and release of ICAM-1 (CD54) and LFA-3 (CD58) and the influence of cytokines, including IFN alpha, IFN gamma and TNF alpha. Cellular ICAM-1 expression and density varies considerably between the melanoma cell lines. While IFN alpha has no effect on cellular ICAM-1 (cICAM-1) expression, IFN gamma and to a lesser extent TNF alpha can effectively up-regulate cICAM-1. Soluble ICAM-1 (sICAM-1) is detected in the supernatants of all lines tested, release of sICAM-1 correlates with cellular expression. LFA-3 does not much differ in its expression level on melanoma lines, and cytokines have little or no effect on its expression. Soluble LFA-3 is released by only 6 out of 10 lines. Its release can effectively be inhibited by IFN gamma in all lines and by TNF alpha in one, while IFN alpha has no effect. These data show that expression and release of LFA-3 and ICAM-1 differ between melanoma cell lines. This may be of importance for the interaction of melanoma cells with immune effector cells in vivo.

Animals↗
PubMed1993

Evaluation of soluble tumor necrosis factor (TNF) receptors and TNF receptor antibodies in patients with systemic lupus erythematodes, progressive systemic sclerosis, and mixed connective tissue disease.

Two TNF binding proteins have been characterized as soluble fragments of TNF receptors. We measured the plasma concentrations of soluble type A (p75) and type B (p55) TNF receptors in patients with systemic lupus erythematodes (SLE), progressive systemic sclerosis (PSS), and mixed connective tissue disease (MCTD). In SLE and PSS patients plasma concentrations of both types of TNF receptors and in MCTD patients type A TNF receptors were significantly elevated compared to controls. Plasma concentrations of both soluble TNF receptors were highly correlated in SLE, PSS, and MCTD patients, indicating a possible coregulation of both TNF receptors. In contrast, soluble interleukin 2 receptor (sCD 25) plasma concentrations were not correlated and seem to be an independent parameter. The soluble forms of the TNF receptors neutralize TNF in cytotoxicity assays and are functionally active as TNF antagonists. In one patient with SLE, autoantibodies against type A TNF receptors were detected, TNF alpha, and TNF beta did not interfere with the autoantibody binding to the receptor.

Autoantibodies↗
PubMed1993

Hematopoietic growth factors for the mobilization of peripheral blood stem cells.

Hematopoietic growth factors can be used for the mobilization of peripheral blood stem cells that have the proliferative capacity to restore long-term hematopoiesis after myeloablative therapy. An association between specific cytokines and the composition of the blood-derived progenitor cells has not yet emerged. It appears that yield and composition of PBSC are influenced far more by the individual than by the use of specific growth factors. Our future studies will focus on how many and what kind of stem cells are needed for high-dose regimens with different myelotoxicity. In parallel, autografts will be assessed for contaminating tumor cells, if disease- or clone-specific markers are available. This approach may then provide the rationale for the increasing use of PBSC for autografting.

Blood Cells↗
PubMed1993

Expression of adhesion molecules and c-kit on CD34+ hematopoietic progenitor cells: comparison of cytokine-mobilized blood stem cells with normal bone marrow and peripheral blood.

We assessed the expression of the adhesion molecules leukocyte function antigen-1 (LFA-1, CD11a), intercellular adhesion molecule-1 (ICAM-1, CD54), homing-associated cell adhesion molecule (H-CAM, CD44), and c-kit (stem cell factor receptor) on the CD34+ progenitor population from the leukapheresis products of 23 patients (LP CD34+). For blood stem cell collection granulocyte colony-stimulating factor (G-CSF) or interleukin-3/granulocyte-macrophage colony-stimulating factor (IL-3/GM-CSF) was administered after cytotoxic chemotherapy. Furthermore, bone marrow- and blood-derived CD34+ progenitor cells from 6 normal volunteers (BM and PB CD34+) were analyzed. LFA-1 expression was higher on PB CD34+ (88.2 +/- 2.5%, mean +/- SEM) than on BM CD34+ (75.3 +/- 4.3%). Following cytokine administration, LFA-1 was expressed on only 59.7 +/- 3.7% of LP CD34+ at a low fluorescence intensity, suggesting that down-regulation of LFA-1 may facilitate the egress of cells from the bone marrow and prolong their circulation. In contrast, ICAM-1 was weakly positive on CD34+ cells from all sources. CD44 was expressed on the vast majority of CD34+ cells (> 95%) in all samples studied. The highest proportion of CD34+ cells costaining for c-kit was found in normal bone marrow (32.2 +/- 3.3%). In normal peripheral blood and after cytokine mobilization, fewer of the CD34+ cells weakly expressed c-kit (< 15%). The low percentage and level of c-kit expression may indicate that the majority of cytokine-mobilized CD34+ cells are lineage-committed progenitor cells, as reflected by the coexpression pattern for CD38, HLA-DR, and CD33.

Antigens, CD↗
PubMed1993

Hematogenous spread of malignant melanoma cells in different stages of disease.

Patients with malignant melanoma and distant metastases generally have an unfavorable prognosis, with a median survival of about 6 months. The mechanisms of hematogenous spread and implantation of melanoma cells are, however, poorly understood, because the standard diagnostic methods are not sensitive enough to detect oligocellular micrometastases. Recently a method using reverse transcription and polymerase chain reaction to determine tyrosinase mRNA in peripheral blood, which indicates the presence of circulating melanoma cells, has been developed. We utilized this assay to examine blood samples of 56 patients with malignant melanoma in different stages of disease. In one of 10 patients in stage I (localized disease) and in six of 17 patients with regional lymph nodes metastases (stage II) tyrosinase mRNA was detected. Tyrosinase transcripts were found in all 29 patients with distant metastases (stage III). Interestingly, tyrosinase mRNA was also detected in six patients with metastatic amelanotic malignant melanoma. In contrast, tyrosinase mRNA was not detectable in any of 39 healthy subjects or 17 patients with other malignancies. These findings may be helpful to define a patient group at high risk for systemic spread of disease.

Base Sequence↗
PubMed1993

Sustained remission of idiopathic hypereosinophilic syndrome following alpha-interferon therapy.

Two patients with idiopathic hypereosinophilic syndrome (HES) refractory to treatment with corticosteroids and hydroxyurea received alpha-interferon (alpha-IFN) for 3 and 1 years, respectively. Eosinophil counts dropped below 1.5 x 10(9)/l at weekly doses of 2-7 x 3 million units alpha-IFN. More than a year after discontinuation of alpha-IFN, 1 patient remains in a stable remission. Granulocyte-macrophage colony-stimulating factor (GM-CSF) plasma levels were found to be normal in this patient, although GM-CSF is known to stimulate eosinophil proliferation in vitro. Based on the favorable clinical results of alpha-IFN, further studies are necessary to define its role in the treatment of HES.

Adult↗
PubMed1993

Autografting with peripheral blood stem cells mobilized by sequential interleukin-3/granulocyte-macrophage colony-stimulating factor following high-dose chemotherapy in non-Hodgkin's lymphoma.

This report summarizes our results of sequential treatment with IL-3 and GM-CSF following high-dose chemotherapy with respect to the yield and composition of peripheral blood stem cells (PBSC). Eight patients with high-grade non-Hodgkin's lymphoma were included in the study. Starting 24 h after high-dose cytosine arabinoside (Ara C)/mitoxantrone, IL-3 was given for 6 days, followed by GM-CSF. The increase of circulating hematopoietic progenitor cells during leukocyte recovery varied substantially from patient to patient. Up to a 22-fold interindividual difference was observed for the peak levels of CD34+ cells. A special focus of our study was the antigenic profile of the CD34+ PBSC. On analysis of the antigenic profile of the CD34+ cells, the proportion of CD34+/HLA-DR- and CD34+/CD38- cells representing non-committed hematopoietic stem cells was consistently < 5%. The vast majority of CD34+ cells was found to coexpress CD33 (86.3 +/- 2.1%, mean +/- SEM), reflecting myeloid lineage commitment. CD71 antigen was present on 47.4 +/- 3.0% CD34+ cells with two populations (CD71dim/bright), while the percentage of early B lymphoid (CD34+/CD19+) progenitor cells was extremely low (0.38 +/- 0.13%). We therefore conclude that the cytokines currently available such as G-CSF, GM-CSF or IL-3 facilitate an ontogenetic phenomenon supporting the redistribution of hematopoietic progenitor cells after cytotoxic treatment. Six patients were autografted with the IL-3/GM-CSF-exposed blood stem cells following high-dose conditioning therapy. It is worth noting that no additional BM or hematopoietic growth factors were given post-transplantation.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1993

Increased serum levels of granulocyte colony-stimulating factor after autologous bone marrow or blood stem cell transplantation.

The objective of our study was to evaluate the biologic role of granulocyte colony-stimulating factor (G-CSF) for hematologic reconstitution following autologous bone marrow transplantation (ABSCT). Using a commercially available enzyme-linked immunosorbent assay, serum levels of G-CSF were measured in samples from 48 patients (30 male/18 female) who underwent ABMT or ABSCT. Their median age was 34.5 years (range 16 to 51). Autografting was performed (40 ABMT, 8 ABSCT) in 23 AML, 8 ALL and 17 malignant lymphoma patients. Patients transplanted with blood stem cells had a faster leukocyte and neutrophil recovery compared with the ABMT patients (p < 0.025 and p < 0.05, respectively). During marrow aplasia G-CSF serum levels were elevated in all patients, with a median peak value of 2199 pg/mL (range 453 to 8676 pg/mL). A strong reverse correlation (R = -0.76, p < 0.01) could be demonstrated between G-CSF serum level and white blood count (WBC). An additional increase of G-CSF serum levels on days of fever (> or = 38.5 degrees C) or documented infectious disease was observed. During the early phase of marrow aplasia, the endogenously produced amounts of G-CSF reached concentrations which are used for in vitro stimulation of colony-forming unit granulocyte (CFU-G). The relationship between G-CSF serum level and WBC supports the central role of this circulating hemopoietin following myeloablative treatment and autotransplantation. During periods of higher demand such as fever and infectious complications, endogenous G-CSF production is enhanced.

Adolescent↗
PubMed1993

Autologous blood progenitor cell transplantation in relapsed Hodgkin's disease--the role of haematopoietic growth factors.

Thirty-seven patients with Hodgkin's disease in sensitive relapse were autografted using blood-derived haematopoietic progenitor cells. At the time of transplantation 22 patients were in complete remission and 15 patients in partial remission. Twenty-six patients were male and 11 female, with a median age of 31 years (range 21-52). The pre-transplant conditioning therapy consisted of cyclophosphamide, BCNU and etoposide (CBV). Five patients died of transplant-related complications and 11 patients relapsed after a median time of four months following autografting. For the remaining 21 patients the probability of event-free survival (EFS) was 45% at 68 months. Blood progenitor cell collection can be integrated into salvage therapy by administering haematopoietic growth factors (HGFs) to enhance the chemotherapy-induced progenitor cell rebound during leucocyte recovery. In a subgroup of 14 patients, seven received recombinant human granulocyte-macrophage colony stimulating factor (rhGM-CSF) (250 micrograms/m2/day) by continuous intravenous infusion following dexamethasone, BCNU, etoposide and melphalan (Dexa-BEAM) as salvage therapy, while seven patients were treated without haematopoietic growth factor (HGF) post-chemotherapy. The yield of total nucleated cells (TNC) and granulocyte-macrophage colonies (CFU-GM) collected per leukapheresis was 2.2- and 2.4-fold higher respectively in the rhGM-CSF-treated patients. Following high-dose conditioning therapy, the seven patients autografted with rhGM-CSF-mobilised stem cells showed a faster leucocyte recovery compared with the control group. Neutrophil recovery (> 1.0 x 10(9)/L) and platelet recovery (> 20 x 10(9)/L) were also accelerated in the rhGM-CSF-treated group.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1993

Idarubicin/cytosine arabinoside and mitoxantrone/etoposide for the treatment of de novo acute myelogenous leukemia.

Since January 1989, 56 patients (31 females and 25 males) with de novo acute myelogenous leukemia have been included in the study. Their median age was 43 years (range, 15 to 60 years) with a distribution according to French-American-British morphologic subtypes as follows: six M1, 14 M2, four M3, 19 M4, nine M5, two M6, and two M7. The induction regimen (IDAC) consisted of idarubicin (12 mg/m2/d intravenously [IV] days 1 to 3) in combination with cytarabine (100 mg/m2/d continuous IV days 1 to 7). Patients achieving complete remission (CR) or partial remission received another cycle of IDAC followed by NOVE (mitoxantrone 10 mg/m2/d IV days 1 to 5 and etoposide 100 mg/m2/d IV days 1 to 5). Fifty-four patients are evaluable for response: after two cycles of IDAC, 42 patients had attained CR (78%), while 76% of these had already reached CR after the first cycle. Of the initial 11 nonresponders to IDAC, four obtained CR after NOVE. Thus, 46 of 54 patients (85%) achieved CR after sequential treatment with IDAC and NOVE. In the last 17 patients who entered CR or partial remission after the first cycle of IDAC, recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF; 3 micrograms/kg/d) was administered for 6 days starting 3 days prior to the second cycle of IDAC. For consolidation with NOVE, rhGM-CSF was given according to the same dosage schedule. After 72 hours of rhGM-CSF treatment, the white blood cell count showed a median 3.9-fold increase, without appearance of myeloblasts in the peripheral blood. During sequential chemotherapy, no significant complications (in particular, no major cardiac toxicity) were observed. Postremission, patients were either given bone marrow transplants, received late consolidation with high-dose cytarabine/mitoxantrone, or were followed up without any further treatment. Of the 46 patients evaluable for disease-free survival, 21 patients (45%) remain in CR with a 34% probability of disease-free survival at 37 months. The response-adapted treatment with IDAC/NOVE is effective and very well tolerated. To define the therapeutic impact of rhGM-CSF, a randomized trial will be required.

Acute Disease↗
PubMed1992

Regional administration of lymphokine-activated killer cells can be superior to intravenous application.

A patient with liver metastases of human lymphocyte antigen (HLA) class II-negative malignant melanoma was treated with several cycles of adoptive immunotherapy with interleukin-2 and lymphokine-activated killer (LAK) cells. The authors evaluated the efficacy of regional transfer of LAK cells versus systemic intravenous administration. Initially, the patient was treated according to a regional treatment protocol, consisting of perfusion of the spleen with interleukin-2 and transfer of LAK cells into the portal vein; a partial remission was observed. Because of technical problems, interleukin-2 and LAK cells were administered intravenously in a second treatment cycle. This systemic treatment course resulted only in a minor mixed response of the hepatic metastases. A third treatment course was administered with the use of intravenous interleukin-2 infusion and arterial perfusion of the liver with LAK cells. The patient had separate hepatic arteries to both lobes of the liver as an anatomic variation. Because most of the tumor mass was present in the right lobe of the liver, a third of the LAK cells were injected into the right hepatic artery and the remaining cells were administered intravenously. The lesions in the right lobe of the liver regressed, but disease progression occurred in the left lobe. A fourth treatment cycle, consisting of intravenous infusion of interleukin-2 and arterial perfusion of both lobes of the liver with LAK cells, resulted in a complete response of all hepatic lesions, which has lasted 18 months to date. Because, in this patient, tumor regression was observed only in anatomic areas of the liver, which were perfused with LAK cells, it is suggested that the regional administration of LAK cells was essential for successful treatment.

Adult↗
PubMed1992

Elevated TNF receptor plasma concentrations in patients with rheumatoid arthritis.

Two types of tumor necrosis factor receptors have been characterized, both capable of transmitting the signal and exerting the biological functions of TNF and lymphotoxin. We measured the plasma concentrations of two types of TNF binding proteins (sTNFR-A and sTNFR-B) in patients with rheumatoid arthritis (RA) and spondylarthropathies (SpA) using an enzyme-linked binding assay. In normal controls (n = 43), mean plasma concentrations were 1030 +/- 55 and 1461 +/- 59 pg/ml for sTNFR types A and B, respectively. In 67 patients with moderate RA, mean levels were 1422 +/- 82 pg/ml (type A) and 2088 +/- 109 pg/ml (type B); in 34 patients with severe RA, 2588 +/- 279 pg/ml and 4494 +/- 550 pg/ml, respectively, were measured (P less than 0.0001 compared to normal controls). Concentrations of both type A and type B sTNFR were highly correlated in severe RA (R2 = 0.7) but not in SpA or normal controls. T lymphocytes in synovial fluid of patients with RA expressed predominantly type A TNF receptors on their surface; in some patients a weaker expression of type B receptors was also detectable. Soluble TNF binding proteins in patients with RA were able to neutralize TNF in a cytotoxicity assay, demonstrating their ability to act as "TNF-inhibiting factors". We conclude that both types of TNF receptors are parameters of disease activity in RA and may also act as TNF antagonists.

Arthritis, Rheumatoid↗