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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 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.
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.
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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PURPOSE: To evaluate the role of MR imaging in the examination of multiple myeloma (MM) patients with bone-marrow transplants. MATERIAL AND METHODS: A total of 40 MR examinations were made of 20 patients: 33 examinations of the spine and pelvis in 20/20 patients; and 7 examinations of the femora in 5/20 patients. The 40 examinations were evaluated and the results compared with those found at radiography. Altogether 13/20 patients were re-examined: 10 after 1 year (1 patient twice); and 3 after 2 years. Five sequences were tested, 3 of them first without and then with i.v. contrast enhancement. RESULTS: In 24/33 examinations, active MM lesions were shown by MR. In 16/33 examinations, MR showed greater spread and detectability than radiography. In the 5/20 femoral patients, 3 had a peripheral red bone-marrow extension in the femora. In the 13 re-examinations, the lesions had spread in 4 patients, were unchanged in 7, and had decreased in 2. The lesions were easier to detect with the turbo inversion recovery (TIR) technique and with fat saturation than with the conventional spin-echo sequences. Contrast enhancement made the lesions more conspicuous in 8/17 examinations. CONCLUSION: MR has the potential to be a useful routine examination with T1-weighted and TIR sequences of selected areas, and without the use of contrast enhancement. However, further longitudinal studies are necessary in order to evaluate its possible predictive value.
BACKGROUND: Chemotherapy and radiation therapy result in increased free radical formation and depletion of tissue antioxidants. It is not known whether parenteral nutrition (PN) administered during bone marrow transplantation (BMT) supports systemic antioxidant status. OBJECTIVE: The aims of the study were to determine 1) whether high-dose chemotherapy decreases concentrations of major circulating antioxidants in patients undergoing BMT and 2) whether administration of standard PN maintains systemic antioxidant concentrations compared with PN containing micronutrients and minimal lipids alone. DESIGN: Twenty-four BMT patients were randomly assigned to receive either standard PN containing conventional amounts of dextrose, amino acids, micronutrients, and lipid (120 kJ/d) or a solution containing only micronutrients (identical to those in standard PN) and a small amount of lipid (12 kJ/d). Plasma antioxidant status was measured before conditioning therapy and serially at days 1, 3, 7, 10, and 14 after BMT. RESULTS: Plasma glutathione (GSH) and alpha- and gamma-tocopherol concentrations decreased and the GSH redox state became more oxidized after conditioning chemotherapy. Plasma cysteine concentrations were unchanged, whereas cystine concentrations increased. Plasma vitamin C and zinc concentrations and GSH peroxidase activity increased over time. Plasma alpha-tocopherol concentrations were lower in patients given standard PN. There were no differences in other plasma antioxidants between groups. CONCLUSIONS: A significant decline in GSH-glutathione disulfide, cysteine-cystine, and vitamin E status occurs after chemotherapy and BMT. Standard PN does not improve antioxidant status compared with administration of micronutrients alone. Further evaluation of PN formulations to support patients undergoing high-dose chemotherapy and BMT are needed.
PURPOSE: To improve autologous leukapheresis strategies in high-risk neuroblastoma (NB) patients with extensive bone marrow involvement at diagnosis. PATIENTS AND METHODS: Anti-G(D2) immunocytochemistry (sensitivity, 1 in 10(5) to 10(6) leukocytes) was used to evaluate blood and bone marrow disease at diagnosis and during the recovery phase of the first six chemotherapy cycles in 57 patients with stage 4 NB and bone marrow disease at diagnosis. A total of 42 leukapheresis samples from the same patients were evaluated with immunocytology, and in 24 of these patients, an anti-G(D2) immunomagnetic enrichment step was used to enhance tumor-cell detection. RESULTS: Tumor cytoreduction was much faster in blood compared with bone marrow (3.2 logs after the first cycle and 2.1 logs after the first two cycles, respectively). Bone marrow disease was often detectable throughout induction, with a trend to plateau after the fourth cycle. By direct anti-G(D2) immunocytology, a positive leukapheresis sample was obtained in 7% of patients after either the fifth or sixth cycle; when NB cell immunomagnetic enrichment was applied, 25% of patients had a positive leukapheresis sample (sensitivity, 1 in 10(7) to 10(8) leukocytes). CONCLUSION: Standard chemotherapy seems to deliver most of its in vivo purging effect within the first four cycles. In patients with overt marrow disease at diagnosis, postponing hematopoietic stem-cell collection beyond this point may not be justified. Tumor-cell clearance in blood seems to be quite rapid, and earlier collections via peripheral-blood leukapheresis might be feasible. Immunomagnetically enhanced NB cell detection can be highly sensitive and can indicate whether ex vivo purging should be considered.
A panel of commercially available monoclonal antibodies (MoAbs) including LN1, LN2, MB2, L26, Leu M1, UCHL1, MT1 and L60 was used to evaluate a diverse group of neoplastic processes in 256 Zenker's-fixed, decalcified, paraffin-embedded bone marrow biopsies using the ABC immunoperoxidase technique. LN2 and MB2 were useful in delineating the extent of B-cell lymphoproliferative processes and in identifying interstitial patterns of involvement. The combined application of LN2, MB2 and UCHL1 had utility in differentiating B-cell from T-cell lymphoproliferative processes; in no instance was reactivity with LN2 observed in T-cell processes. The combined application of these three MoAbs was also used in differentiating benign reactive lymphoid aggregates from focal malignant B-cell proliferations. LN2 exhibited positivity with the Reed-Sternberg cells (RSC) of Hodgkin's Disease (HD) and significantly aided in the identification of these cells. Staining of RSC with Leu M1 was inconsistent and was observed in only 50% of cases of HD. Use of the entire panel of MoAbs together with more recently available reagents such as Cathepsin G, MAC 387 and neutrophil elastase was essential in optimally evaluating a particular lesion; none of these MoAbs used singly reliably differentiated myeloid from lymphoid, hematopoietic from metastatic, or reactive from malignant processes.
The aim of this study was to establish how effective is the use of immunohistochemistry on formalin-fixed bone marrow in diagnosing low-grade B-cell neoplasms. We investigated a series of 41 consecutive patients with bone marrow involvement for whom no other diagnostic tissues were available. The sections were stained with the following antibodies: CD3, CD20, CD79a, CD5, CD10, CD23, anti-cyclin D1 and kappa and lambda light chains. Antigen retrieval was performed using either a microwave oven or a pressure cooker. Labelling was performed with an avidin-biotin-peroxidase labelling system. A final diagnosis was reached in 37 out of 41 cases (90%): B-chronic lymphocytic leukaemia (15 cases), follicular lymphoma (10 cases), mantle-cell lymphoma (eight cases) and lymphoplasmacytoid lymphoma/immunocytoma (four cases). In the remaining four cases, a generic diagnosis of low-grade B-cell neoplasm was made. The immunophenotyping of formalin-fixed marrow is a useful technique for diagnosing most of the low-grade B-cell neoplasms.