[Diagnostic value of morphologic blood determination in metastatic bone marrow neoplasms].
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Ifosfamide, in combination with other cytostatics, was given to 15 patients with advanced neoplasia derived from bone marrow cells. A response to therapy was obtained in 8 patients. It is suggested that ifosfamide, in combination with other drugs, deserves larger trials in the treatment of advanced bone marrow neoplasia.
BACKGROUND: This is the first report of the long-term results of CD34(+) cell transplantation in children with neuroblastoma. We investigated the hematologic and immune recovery, posttransplant morbidity, and clinical outcome of these children. PROCEDURE: Twenty-three children with advanced neuroblastoma had PBPCs (20 patients) or BM (3 patients) collected, followed by CD34(+) cell selection on Ceprate column. The purge of residual neuroblastoma cells was evaluated using an RT-PCR for tyrosine hydroxylase (TH) mRNA assay. Reinfusion of CD34(+) cells followed busulfan + melphalan myeloablative chemotherapy. RESULTS: A median of 2.9 x 10(6) CD34(+) cells/kg was reinjected. Median days to achieve ANC > 0.5 x 10(9)/liter and platelets > 50 x 10(9)/liter were 13 (range 9-33) and 59 (range 22-259), respectively. Circulating T cells were primarily CD4(-)/CD8(+) with fewer than 0.2 10(9)CD4(+) cells/liter throughout the first 6 months. CD19(+) cells and CD56(+) cells were not detectable up to day +35 posttransplant. At 1 year posttransplant, 16 evaluable patients had stable hematopoiesis with 2.3 x 10(9) ANC/liter (range 0.8-4.1), 1.4 x 10(9) lymphocytes/liter (range 0.5- 2.0) and 251 x 10(9) PLT/liter (range 35-490). After the completion of hematopoietic reconstitution, six events of severe septicemia/septic shock were noted. Six children had severe VZV infections, and 2 had EBV-associated lymphoproliferation. Thirteen patients are alive with a median follow-up of 40 months (range 2-54). Ten patients have died; 8 relapsed or developed progressive disease, 1 died from nondocumented pneumopathy at day 56, and 1 developed AML-M4 at 3 years posttransplant. CONCLUSIONS: In children, CD34(+) cell transplantation can be accomplished with a reduction of neuroblastoma cell inoculum in the selected graft as assessed by RT-PCR analysis. CD34(+) cell grafts provide successful neutrophil reconstitution. However, delayed platelet recovery, persistent decrease in CD4(+) lymphocyte levels and a high incidence of serious and life-threatening late infections were observed in these children. There remains a critical need to evaluate any real clinical benefit of CD34(+) cell autografts in neuroblastoma patients.
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This article reviews developments in both pulse sequence design and gradient technology that facilitate rapid imaging of the whole body. It discusses its application in patients with bone marrow neoplasms, including metastases, lymphoma, and myeloma and emphasizes the value of whole-body magnetic resonance imaging in patients with known vertebral lesions to detect other bone lesions that are easier to biopsy. It outlines possible applications in well-defined clinical situations, including pregnancy and unknown primary tumor.
This article discusses the clinical significance of bone marrow metastases and the current methods being used to detect tumor cells in marrow. The strategies being investigated for eradicating cancer cells from marrow in patients receiving hematopoietic cell autografts also are reviewed.
We assessed mammaglobin (MMG) gene expression in bone marrow (BM) aspirates from patients with advanced breast cancer who had received a reduced-intensity conditioning and stem cell allografting, in order to detect a graft-versus-tumor effect on micrometastatic disease. Nine patients received a reduced-intensity conditioning with fludarabine, cyclophosphamide, and thiotepa, followed by peripheral blood allografting from HLA-identical sibling donors. Nested RT-PCR analysis with sequence-specific primers for MMG was carried out on a monthly basis on BM samples. Three patients had MMG-positive BM, four patients had MMG-negative BM before allografting, and two were undetermined. In two patients, a clinical response after allografting (partial remission) occurred concurrently with the clearance of MMG expression, at a median of 6 months after allografting, following immune manipulation. In two patients, a prolonged stable disease and negative MMG expression occurred after day +360 from allografting. In two patients, progression of the disease was associated with MMG RT-PCR changing from negative to positive. In one case, a disease response occurring after donor lymphocyte infusion and grade II acute GVHD was heralded by negativization of MMG expression. Although preliminary, these data suggest that a graft-versus-breast cancer effect is detectable on micrometastatic BM disease.
PURPOSE: To evaluate the effect of extensive screening of women with high-risk, node-positive breast cancer on the detection of occult metastatic disease and patient eligibility for a randomized trial of the addition of high-dose chemotherapy and autologous bone marrow support (ABMT) to standard adjuvant therapy. PATIENTS AND METHODS: Women with resected T1-3N1,2 primary breast cancer and > or = 10 positive axillary lymph nodes referred for possible trial participation were evaluated for this report. All had normal chest x-ray, bone scan, and liver ultrasound performed by the referring physician. Those who provided informed consent for the randomized trial were further evaluated according to protocol with computed tomographic (CT) scans of the head, chest, abdomen, and pelvis and bilateral bone marrow biopsies; those with metastatic disease detected by any of these tests were excluded from study registration. RESULTS: Forty-four women were evaluated between February 1993 and April 1995. Fourteen did not undergo further protocol staging because of refusal to participate or the presence of metastatic disease on clinical assessment or review of outside radiologic studies. The remaining 30 underwent additional investigations, and seven (23%; 95% confidence interval [CI], 12% to 41%) had metastases detected by CT scanning (four patients) or bone marrow biopsy (three patients) not detected by routine screening. CONCLUSION: Although the number of patients evaluated is small, these data suggest that some of the improvement in outcome of women with > or = 10 positive axillary lymph nodes who receive ABMT as part of adjuvant chemotherapy in phase II trials may be from the exclusion of patients with occult metastatic disease. The importance of these exclusions can only be determined by ongoing, randomized controlled trials.
PURPOSE: The present study evaluates the clinical significance of detection of cytokeratin 19 (K19) in the bone marrow of patients with breast cancer undergoing high-dose chemotherapy (HDCT) and autologous bone marrow transplantation (ABMT). PATIENTS AND METHODS: We studied retrospectively cryopreserved bone marrow aspirates from 83 patients with high-risk stage II, III, and IV breast cancer obtained before bone marrow harvest but after induction chemotherapy. All samples were histologically negative for metastases. Polymerase chain reaction (PCR) for K19 was performed according to methods described previously and results were correlated with the probability of relapse following HDCT and ABMT. RESULTS: The incidence of occult metastases as defined by PCR for K19 message was 52% for 19 stage II, 57% for 14 stage III, and 82% for 50 stage IV patients (two-tailed P = .0075, chi 2 test). The probability of relapse at 3 years after ABMT was 32% and 94% for K19-positive stage II/III and stage IV patients, respectively, versus 10% and 14% for K19-negative stage II/III and stage IV patients, respectively. The difference was significant for stage IV patients (two-tailed P = .0002). CONCLUSION: It has been shown that PCR is a highly sensitive method to detect K19 message in the bone marrow. The incidence of K19 positivity in bone marrow increases significantly with advancing stage. In patients with breast cancer, especially metastatic breast cancer, undergoing HDCT and ABMT, the presence of K19 is associated with a poor prognosis.
PURPOSE: To determine whether occult tumor contamination of autologous bone marrow or peripheral-blood progenitor cells (PBPC) influences clinical outcome after high-dose chemotherapy in patients with stage IV breast cancer. PATIENTS AND METHODS: We used an immunocytochemical assay capable of detecting one tumor cell in 5 x 10(5) hematopoietic cells to analyze bone marrow and/or PBPC collections obtained from 57 consecutive women with chemotherapy-sensitive metastatic breast cancer who received high-dose chemotherapy. The influence of occult tumor on time to progression, overall survival, and first site of recurrence (old or new) was studied. RESULTS: Twenty-three of 57 (40%) patients received bone marrow (n=6) or peripheral-blood progenitor collections (n=17) that contained microscopic cancer. Median time to progression and overall survival were 9 and 22 months in patients who did not receive infused tumor cells, compared with 10 and 24 months, respectively, in those who received occult tumor (P=not significant [NS]). Worse survival, but not time to progression, was observed in six patients who received > or = 2/100,000 tumor cells. Regardless of whether occult tumor was infused, the majority of relapses occurred in prior, rather than new sites of disease. Three patients who received stem-cell products contaminated by microscopic breast cancer remain free from progression at 21+, 47+, and 52+ months. CONCLUSION: Microscopic tumor was frequently detected by immunocytochemistry in hematopoietic stem-cell products, but did not predict for inferior treatment outcome in this cohort of patients with metastatic breast cancer. Quantitative information regarding infused tumor burden may have prognostic significance.
PURPOSE: Data of a multicenter study in non-Hodgkin's lymphoma (NHL) by the Dutch Hovon Group were reanalyzed to assess the risk of relapse in the central nervous system (CNS) related to the international risk index for NHL. In addition we assessed the risk for CNS disease in relation to the presence of bone marrow localisation at presentation. DESIGN: We focused our analysis on those patients reaching a complete remission (CR). Two hundred eighty-six patients (histological subtypes D-H Working Formulation) and with stages II-IV were analyzed. One hundred ninety-three (67%) patients reached a CR. RESULTS: Relapse occurred in 78 patients of whom 10 patients with concomitant or isolated CNS disease. According to the international risk index the following observations were made: low risk (n = 38) nine out of 34 CR relapsed, none had CNS involvement; low-intermediate risk (n = 115) 27 out of 83 CR relapsed, three had CNS involvement; high-intermediate risk (n = 110) 37 out of 68 CR relapsed, six had CNS involvement; high risk (n = 22) four out of seven CR relapsed, one had CNS involvement. Two out of 10 developed isolated CNS disease and eight out of 10 patients developed CNS disease with systemic relapse. CONCLUSION: Our data show that the number of CNS relapses after CR is relatively low (10 out of 193 = 5%), with an increasing incidence in the high-risk groups according to the international risk index. The occurrence of CNS relapse seems to be related to the risk of systemic relapse after CR. No subgroup could be discriminated in which prophylactic treatment would be of substantial benefit.
A highly sensitive and specific methodology to detect neuroblastoma cells in the bone marrow and peripheral blood of children with neuroblastoma is of critical importance for proper staging and treatment of these patients. In addition, patients with bone marrow infiltration at diagnosis need to undergo regular investigation to measure the effectiveness of chemotherapy (so called "in vivo" purging). Finally, the evaluation of autologous stem cells taken from bone marrow or peripheral blood is necessary to rule out or minimise the possibility of reinfusing tumor cells to the patient following myeloablative therapy. The authors provide a "state of the art" data on this complicated issue and give their preliminary results of their own experience, mainly concerning the immunocytological methods.
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The distinction between mantle cell lymphoma (MCL) and other low-grade B-cell neoplasms is important because MCL has a more aggressive clinical course. In bone marrow biopsy specimens, this distinction can be especially difficult. We examined 70 bone marrow biopsy specimens involved by various B-cell lymphoid neoplasms to assess the utility of cyclin D1 immunostaining in distinguishing MCL from other B-cell lymphoproliferative disorders. We used a cocktail of two monoclonal anti-cyclin D1 antibodies and a heat- and sonication-induced epitope retrieval procedure. The neoplasms assessed included MCL (32 cases), small lymphocytic lymphoma/chronic lymphocytic leukemia (18 cases), follicular lymphoma (11 cases), hairy cell leukemia (5 cases), splenic marginal zone lymphoma (2 cases), and small lymphocytic lymphoma with plasmacytoid differentiation (2 cases). The diagnosis of MCL in bone marrow was confirmed by review of the original diagnostic biopsy specimens along with additional data, such as immunophenotypic or molecular studies. Most MCL (23/32; 72%) cases expressed cyclin D1 protein. In contrast, one case of small lymphocytic lymphoma/chronic lymphocytic leukemia (1/18; 6%) and one case of hairy cell leukemia (1/5; 20%) expressed cyclin D1 protein. These findings demonstrate that immunostaining for cyclin D1 protein expression is useful in distinguishing MCL from other B-cell lymphoid neoplasms in the bone marrow.
We present the case of a 3-year-old child with neuroblastoma metastatic to the bone marrow. [123I]MIBG total body scintigraphy revealed a diffuse pattern of intense fixation throughout the skeleton. This was analogous to the "super scan" described with 99mTc-MDP bone scintigraphy when extensive metastatic or metabolic bone disease is present. Essentially, a high bone-to-soft tissue ratio was found without uptake in the liver, kidney and bladder, owing to a "steal" mechanism caused by the avid bone metastases.
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