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Biomedical subjects

P R Greipp

Publications and source records attributed to P R Greipp.

At least 91 records · Page 5Linked to original sources
PubMed1996

Detection of myeloma cells in the peripheral blood by flow cytometry.

Bone marrow plasma cells (PC) from patients with multiple myeloma (MM) express monoclonal cytoplasmic immunoglobulin (clg) light chain, strongly express CD38, and usually lack or dimly express CD45. The detection of malignant plasma cells in the peripheral blood (PB) by immunofluorescence microscopy (IM) distinguishes patients with active MM from those with stable disease. The aim of this study was to learn whether two-color (CD38 and CD45) flow cytometry (FC) on whole blood specimens (WBFC) and three-color FC (CD38, CD45, and anti-kappa or lambda clg) on mononuclear cells could identify circulating PC as well as the standard, more labor intensive IM technique. Split-samples of PB from 73 patients with plasma cell proliferative disorders were examined by both techniques. WBFC detected CD38+ CD45- cells in 94% (33/35) of patients with circulating monoclonal PC detected by IM and three-color FC detected monoclonal CD38+ CD45- cells in 77% (27/35) of these cases. The absolute number of monoclonal PC detected by IM was compared to the FC methods and the Spearman rank correlations were 0.77 with WBFC and 0.80 with three-color FC. This study indicates that WBFC, using antibodies to CD38 and CD45, offers a practical and reliable method to detect and quantify circulating malignant PC in patients with MM.

ADP-ribosyl Cyclase↗
PubMed1996

Presenting features and prognosis in 72 patients with multiple myeloma who were younger than 40 years.

The purpose of this study was to analyse the presenting clinical and laboratory features and the outcome of 72 patients with multiple myeloma (MM) who were younger than 40 years. The records of all Mayo Clinic patients with MM younger than 40 years who were seen between 1 January 1956 and 31 December 1992 were reviewed. Survival was measured from the date when treatment was required to the date of last follow-up or death. The frequency of MM in patients younger than 40 and 30 years in 3278 Mayo Clinic patients was 2.2% and 0.3%, respectively. The main presenting clinical features were bone pain (66%), fatigue (26%), extramedullary plasmacytomas (19%) and bacterial infection (11%). Renal function impairment (creatinine level > or = 177 micromol/l) and hypercalcaemia (serum calcium value > or = 2.75 mmol/l) occurred in 29% and 30% of patients, respectively. Among the 57 patients evaluable for response the objective response rate was 54%. 14/35 patients treated with a single alkylating agent achieved an objective response, whereas 17/22 patients given combination chemotherapy had an objective response (P=0.013). However, this higher response rate did not result in a significantly longer survival. The median survival for the 72 patients was 54 months. Patients with good prognostic features (normal renal function or low beta 2-microglobulin level) had a median survival of 8 years. The actuarial survival at 5 and 10 years after initiation of therapy was 43% and 13%, respectively. In summary, survival in very young patients with myeloma is longer than that observed in series of patients of all ages, especially in those with good prognostic factors.

Adult↗
PubMed1996

Biology and treatment of myeloma.

New strategies for the treatment of multiple myeloma, particularly high-dose therapy with peripheral blood stem cell transplantation, can achieve complete response in up to 50% of cases. The patient's condition eventually relapses because transplantation does not completely eliminate myeloma. Posttreatment interferon may prolong responses achieved by transplantation or chemotherapy, but it does not necessarily prolong survival. New approaches are being developed to further eliminate myeloma cells after an incomplete response achieved by transplantation or other chemotherapy. These approaches aim at myeloma cell surface antigens, T-cell immunity, and biological mechanisms of myeloma growth and dissemination. Biological targets include interleukin-6 (the central myeloma growth factor), interleukin-1 beta (an amplifier of stromal and bone cell production of interleukin-6), and serum soluble interleukin-6 receptor (an enhancer of myeloma cell response to interleukin-6). Efforts to eliminate circulating myeloma cells from peripheral blood stem cell harvests use positive selection or purging to provide a product that will engraft only normal stem cells, not myeloma cells. Multidrug resistance, a major factor in treatment failure, can be reversed by agents that inhibit the multidrug resistance protein on the myeloma cell surface. Finally, expanded knowledge of biologic mechanisms has led to the development of new prognostic factors. These aim to identify patients in clinical trials who can benefit from treatment regimens designed to overcome their impact on survival. Translating new biological advances into treatment programs is essential to improving therapy for patients with myeloma.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1996

Complete remission induction with combined VBMCP chemotherapy and interferon (rIFN alpha 2b) in patients with multiple myeloma.

The purpose of this study was to evaluate a new regimen for the treatment of multiple myeloma based on alternating 3-week cycles of chemotherapy and interferon (rIFN alpha 2). In this prospective phase II clinical trial the Eastern Cooperative Oncology Group evaluated a regimen consisting of 2 cycles of VBMCP (Vincristine 1.2 mg/M(2) IV d1, BCNU 20 mg/M(2) IV d1, Melphalan 8 mg/M(2) PO dl-4, Cyclophosphamide 400 mg/M2 IV d1, Prednisone 40 mg/M(2) PO d1-7) followed by alternating 3-week cycles of VBMCP and rIFN alpha2 5 Mu/M(2) SC 3x/week. Treatment was administered for 2 years. Fifty-eight patients with previously untreated multiple myeloma were entered. Objective response (OR) required 50% decrease in M-protein with correction of severe anemia and no progression of skeletal disease. Complete remission (CR) was defined by disappearance of M-protein and normalization of the bone marrow morphology. Life table analysis was utilized to express survival and response duration. Fifty-four patients were evaluable. Objective response was seen in 80% of patients including CR in 30% (16 patients). The median response duration is 35 months, 46 months for patients with CR. The median survival is 42 months for all patients. Five year survival is 42%. Although 78% of patients had neutrophil nadirs <1000 x 10(9)/L, the incidence of severe infection was only 9%. These data demonstrate that VBMCP + interferon is an effective new regimen combining chemotherapy with a biological response modifier for the treatment of multiple myeloma. The incidence of CR is high, and the response and survival durations appear to be 1 year longer than usually seen with standard chemotherapy. A current ECOG randomized trial compares VBMCP + interferon with VBMCP alone.

Aged↗
PubMed1996

Establishment and characterization of three myeloma cell lines that demonstrate variable cytokine responses and abilities to produce autocrine interleukin-6.

A consensus regarding myeloma cell growth factor responsiveness and ability to produce autocrine interleukin (IL)-6 has not yet been obtained. In this study, we have established three new human myeloma cell lines (DP-6, KAS-6/1 and KP-6) from patients with aggressive disease. Extensive characterization of these cell lines revealed considerable heterogeneity at several levels. Growth factor responsiveness was initially addressed. Although the potent myeloma cell growth factor, IL-6, induced the proliferation and allowed for the expansion of all three cell lines, a panel of other cytokines elicited heterogeneous responses in each cell line. IL-3, IL-10, IL-11, insulin-like growth factor-I and tumor necrosis factor-alpha also stimulated DNA synthesis in all three cell lines; however, the magnitude of the response was generally lower than that observed in cultures containing IL-6. Transforming growth factor-beta, by contrast, uniformly inhibited the growth of all three cell lines. IL-1alpha and IL-1beta induced the proliferation of the DP-6 cells, but had minimal effects on the KAS-6/1 and KP-6 cells. Interferon (IFN)-alpha stimulated DNA synthesis in the KAS-6/1 cells, but inhibited the proliferation of the DP-6 and KP-6 cells. By comparison, IFN-gamma induced the growth of the KAS-6/1 and DP-6 cells, but inhibited the KP-6 cells. The gp130-associated cytokines, IL-11, leukemia inhibitory factor and oncostatin M, stimulated the growth of the KAS-6/1 cells, but had minimal effects on the DP-6 and KP-6 cells. The cell lines were also analyzed for IL-6 expression. RT-PCR analysis demonstrated that all three cell lines expressed IL-6 mRNA. However, when culture supernatants were tested using a sensitive IL-6 ELISA or IL-6 bioassay only the DP-6 and KP-6 cells were shown to be secreting biologically active IL-6. In summary, although all three of these cell lines were established from myeloma patients, the heterogeneity observed between these cell lines was considerable and may reflect, as well as provide tools to study, the heterogeneity observed in clinical disease.

Aged↗
PubMed1995

Epoetin alfa for the treatment of the anemia of multiple myeloma. A prospective, randomized, placebo-controlled, double-blind trial.

BACKGROUND: To determine the efficacy of epoetin alfa for the treatment of the anemia of multiple myeloma, a prospective, randomized, placebo-controlled, double-blind clinical trial enrolled 25 patients with the anemia of multiple myeloma and a hematocrit less than 0.30. METHODS: Epoetin alfa, 150 U/kg, or a matching volume of placebo was administered subcutaneously three times per week for 6 weeks. If the criterion for a response was not met, the dose was doubled. After 12 weeks, nonresponders in the placebo arm were switched to an open-label study of epoetin alfa at a dose of 150 U/kg for 6 weeks. After 6 weeks, the dose was doubled if no response was obtained. A partial response was defined as an increase of 6 percentage points or greater in the hematocrit without transfusion. A complete response required a final hematocrit of 0.38 or greater without transfusion. Complete responders had reduction of epoetin alfa to the lowest dose capable of maintaining the complete response. RESULTS: Twenty patients were evaluable for response to therapy. During the double-blind phase, six patients who were receiving epoetin alfa had a complete response, one had a partial response, and three were non-responders. No responses occurred in the placebo arm. In the open-label phase, of the 10 patients who were originally receiving placebo, three had a complete response, one had a partial response, and six were nonresponders. Chemotherapy, pretreatment serum erythropoietin levels, disease duration, and reticulocyte count did not predict the response to epoetin alfa. The median final dose for the responding group was 120 U/kg three times per week to maintain a hematocrit greater than 0.38. There was no effect on the course of the myeloma, and no hypertension was seen. CONCLUSION: Treatment with epoetin alfa is effective and safe in patients with the anemia of multiple myeloma.

Anemia↗
PubMed1995

S-phase fraction by the labeling index as a predictive factor for progression and survival in low grade non-Hodgkin's lymphoma.

BACKGROUND: The purpose of this study was to learn if the bromodeoxyuridine labeling index (LI), a measure of the S-phase fraction, is an independent prognostic factor for overall survival (OS) for patients with newly diagnosed low grade non-Hodgkin's lymphoma (NHL). In addition, the ability of the LI to predict time to progression (TTP) in a group of patients observed without therapy after initial diagnosis was determined. METHODS: Patients eligible for this study had biopsy proven low grade NHL, adequate tissue to perform the LI, and were previously untreated. The bromodeoxyuridine LI was performed on fresh biopsy samples using a slide-based immunofluorescence procedure. RESULTS: One-hundred twelve patients were followed prospectively for OS, and 50 of these patients who initially were observed without therapy were eligible for an analysis of TTP. The LI (< or = 1% vs. > 1%) and presence of "B" symptoms were significant univariate prognostic factors for survival (P values of 0.004 and < 0.001, respectively). In a multivariate analysis, the LI and symptoms retained independent prognostic significance, whereas disease stage, histologic subtype, and age did not. In the group who were observed after diagnosis, the LI was not an independent predictor of TTP. CONCLUSIONS: The LI at initial diagnosis is an independent prognostic factor for OS of patients with low grade NHL, but it does not help choose patients for observation without therapy. Measurements of the LI should be considered as part of the on-study evaluation of patients entering cooperative group trials evaluating new therapies for this group of lymphomas.

Adult↗
PubMed1995

A variant glucocorticoid receptor messenger RNA is expressed in multiple myeloma patients.

In multiple myeloma cells resistant to glucocorticoids, we have previously identified a variant glucocorticoid receptor (GR) transcript (P. A. Moalli et al., Cancer Res., 53: 3877-3879, 1993). Here, we report a reverse transcription-PCR assay to assess whether this aberrant GR transcript is present in myeloma patients. We detected both the wild-type and variant GR transcripts in the patient isolate that was the source of our myeloma cell lines, in patients refractory to steroid treatment, and in healthy control subjects. Simultaneous amplification of wild-type and variant GR mRNAs indicates that the variant GR is more highly expressed in cells that are resistant to glucocorticoids. We hypothesize that the variant GR is a normal mRNA transcript that acts to modulate glucocorticoid responsiveness, and increased expression contributes to a resistant phenotype.

Base Sequence↗
PubMed1995

Refractory and relapsing multiple myeloma treated by blood stem cell transplantation.

Between June 1989 and June 1992, 12 patients with advanced multiple myeloma underwent peripheral blood stem cell autotransplantation after high-dose chemotherapy and radiotherapy. The conditioning regimen included melphalan (140 mg/m2), high-dose cyclophosphamide (120 mg/kg), methylprednisolone (2 g daily x 7), and total body irradiation (9-12 Gy). Transplant morbidity included severe mucositis (n = 7) and acute renal failure (n = 2) related to infusion of the stem cells. Engraftment was delayed (n = 4) in this heavily pretreated population, and two patients had complete graft failure. Despite the advanced nature and chemotherapy-refractory state of their disease, 11 of 11 evaluable patients achieved an objective response. Six patients survived to leave the hospital, and four remain alive--one died of acute leukemia induced by prior melphalan exposure. Three of the four are relapse-free at a median of 24.9 months (range, 18-28 months). Some patients with advanced refractory multiple myeloma can achieve objective responses from highdose chemoradiotherapy with peripheral blood stem cell rescue. Harvesting peripheral blood stem cells from high-risk patients early in their disease for later use may decrease the risk of graft failure. Peripheral blood stem cell transplantation after high-dose chemotherapy and total body irradiation can produce durable responses in patients with advanced refractory myeloma.

Acute Kidney Injury↗
PubMed1995

Clinicopathological correlates of CD56 expression in multiple myeloma: a unique entity?

Prior studies have suggested that loss of plasma cell CD56 expression in multiple myeloma defines a unique patient subset and that CD56 expression reliably discriminates between monoclonal gammopathy of undetermined significance (MGUS) and multiple myeloma (MM). We conducted a study of 68 untreated patients with MM from a single institution to define the clinicopathological correlates of CD56 expression. We find CD56 expression in 55% of MM. Lack of CD56 expression does not define a unique clinicopathological or prognostic entity in MM. Strong CD56 expression can also be found in MGUS and does not help to distinguish from MM.

Antigens, CD↗
PubMed1995

Detection of monoclonal plasma cells in the peripheral blood stem cell harvests of patients with multiple myeloma.

We evaluated the harvest product from 47 patients undergoing peripheral blood (BP) stem cell collections for monoclonal plasma cells (PC) using a sensitive immunofluorescence technique. 60% (28/47) had documented tumour cells in the apheresis product. The 32 patients in plateau had a mean of 1.62 x 10(6) PC/l v 74.64 x 10(6) in 15 relapsed patients (P < 0.01). 32% (6/19) of patients without any tumour cells in the initial sample had them detected on a subsequent apheresis sample. In four cases (all treated with GM-CSF) small numbers of tumour cells were detected initially but became undetectable on a subsequent sample.

Blood Component Removal↗
PubMed1995

Serial studies of peripheral blood myeloma cells in patients with multiple myeloma: when is the optimal time for stem cell harvest?

This study serially quantitated monoclonal plasma cells (PC) in the peripheral blood (PB) of 33 patients with multiple myeloma (MM) at diagnosis, after therapy, and at relapse using a sensitive immunofluorescence technique. The goal was to learn which disease phase is best for harvesting PB stem cells free of monoclonal PC. In 24 chemotherapy responders, 88% (21/24) had circulating PC at diagnosis; after therapy, 63% (15/24) had none, 33% (8/24) had < 3 x 10(6)/L, and only one had > or = 3 x 10(6)/L. In nine cases who failed to respond to initial chemotherapy, 89% (8/9) had high levels (> or = 3 x 10(6)/L) of circulating PC at diagnosis that remained high after therapy. In the relapse phase, 88% (21/24) had circulating PC and 63% (15/24) had high numbers. This study demonstrates that the PB is least likely to have circulating monoclonal PC during the period after successful chemotherapy. Patients who fail to respond to initial chemotherapy or are in relapse are likely to have tumor cells in the PB.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1995

Extramedullary hematopoiesis manifesting as a symptomatic pleural effusion.

The occurrence of extramedullary hematopoiesis in the pleura is rare and is usually asymptomatic. It is generally diagnosed on postmortem examination. Herein we describe a 61-year-old woman with agnogenic myeloid metaplasia who sought medical assessment because of progressive dyspnea. Thoracentesis yielded sanguineous fluid with 10% myeloblasts. A 99mTc bone marrow scan demonstrated increased tracer activity throughout both lungs, an outcome consistent with extramedullary hematopoiesis. Fine-needle aspiration and video-assisted thoracoscopy were considered but deferred because of the potential risk of profuse bleeding. Treatment with low-dose external beam irradiation to the left posterior pleura was successful. To date, no hemothorax has recurred.

Female↗
PubMed1995

Pathogenetic relation between monoclonal gammopathies of undetermined significance and multiple myeloma.

Plasma cell atypia and cell proliferation changes which occur during the progression from monoclonal gammopathy of undetermined significance (MGUS) to multiple myeloma (MM) are accompanied by critical changes in neoplastic plasma cells and marrow stromal cells. Key elements include paracrine secretion of interleukin 6 (IL-6) by marrow stromal cells resulting from interleukin 1 beta (IL-1 beta) secreted by myeloma cells. In addition, there are stable elevated levels of serum soluble IL-6 receptor (sIL-6R) in MM and MGUS. They are higher than levels seen in normals. Oncogenes such as c-myc and ras probably play a major role as do cell adhesion molecules and loss of apoptosis. Immune regulatory cells may also play a role. A key element yet to be clearly defined is delineating the role of circulating plasma cells and their precursors in spreading the disease.

Biomarkers↗
PubMed1995

A phase II study of high-dose methylprednisolone in refractory or relapsed multiple myeloma.

A single-arm, phase II perspective clinical trial was done in a tertiary care setting to determine the efficacy of high-dose methylprednisolone in the treatment of patients with refractory or relapsed multiple myeloma. Twenty patients who had failed at least one chemotherapeutic regimen received methylprednisolone (2 g) intravenously three times weekly for 8 weeks. After 8 weeks, responders were placed on a maintenance phase of 2 g intravenously weekly with an 8-week reinduction at the time of relapse. Five patients died within the first month of therapy. There were two complete responses, two objective responses and three minor responses. The median survival for all 20 patients was 2.2 months. Median survival for the seven responders was 19 months, with a relapse-free survival of 15 months. Five patients survived at least 16 months. High-dose methylprednisolone is an easily administered, relatively nontoxic, and effective therapy in a subset of patients with multiple myeloma.

Adult↗
PubMed1994

CD40 expression in malignant plasma cells. Role in stimulation of autocrine IL-6 secretion by a human myeloma cell line.

Myeloma is a neoplasia characterized by the accumulation of malignant plasma cells in the bone marrow. In these studies, we have demonstrated that CD40 is expressed in human myeloma cells and have used a recently established IL-6-dependent myeloma cell line, ANBL-6, to examine the potential function of CD40 expression in myeloma cells. In addition to its expression on the ANBL-6 cells, we show that CD40 is expressed on freshly isolated myeloma cells from seven of seven patients tested. To address the role of CD40 expression in myeloma cells, we have examined the responsiveness of the ANBL-6 cell line to a CD40-specific mAb, G28-5. This cell line has previously been shown to proliferate only in response to IL-6. Of interest in this study, G28-5 also induced proliferation of the ANBL-6 cells. This proliferation was substantially inhibited by an IL-6-neutralizing mAb. Analysis of ANBL-6 cell culture supernatants by ELISA demonstrated that G28-5-stimulated cells secreted significant levels of IL-6, whereas unstimulated cell culture supernatants contained undetectable levels of IL-6. Furthermore, CV-1/EBNA cells expressing the human CD40 ligand also induced the proliferation of the ANBL-6 cell line, an effect that was inhibited by the anti-IL-6 mAb. Lastly, RNA blot analysis demonstrated an increase in IL-6 message in G28-5-stimulated ANBL-6 cells over unstimulated cells. These results indicate that the primary mechanism of anti-CD40-stimulated proliferation of the ANBL-6 cells is the induction of autocrine IL-6 production. Moreover, these data suggest that the expression of CD40 in malignant plasma cells may play a role in tumor cell expansion, possibly by stimulating the induction of autocrine IL-6 secretion.

Antibodies, Monoclonal↗