Complete response of severe symptomatic bone marrow metastases from heavily pretreated breast cancer with a 3-weekly trastuzumab schedule. A clinical case.
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Overexpression of HER-2/neu in breast cancer has been associated with more aggressive disease and poor overall survival. Trastuzumab, a recombinant humanized monoclonal antibody with high affinity for the HER-2 protein, inhibits the growth of breast cancer cells overexpressing HER-2. Trastuzumab showed, as second-line treatment, 15% of objective response in metastatic breast cancer. Bone marrow metastases are detectable in 23% of the patients with advanced breast cancer at first relapse and this rate increases in patients with metastatic disease. We report a case of a complete response of bone marrow metastases from breast cancer using a 3-weekly trastuzumab schedule, in a heavily pretreated patient with severe symptomatic pancytopenia. (+info)
Facilitating role of preprotachykinin-I gene in the integration of breast cancer cells within the stromal compartment of the bone marrow: a model of early cancer progression.
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Despite early detection of breast cancer, patients' survival may be compromised if the breast cancer cells (BCCs) enter the bone marrow (BM). It is highly probable that BCCs enter the BM long before clinical detection. An in vitro coculture model with BM stroma and BCCs (cell lines; primary cells from stage III BC, n = 7, and stage M0, n = 3) mimicked early entry of BCCs into the BM. In coculture, BCCs exhibit contact inhibition and do not require otherwise needed growth supplements. Stromal growth rate was increased 2-fold in coculture. The inclusion of BCCs in stromal support of long-term culture-initiating cell assay frequencies show no difference (38 +/- 3 versus 36 +/- 6). Nontumorigenic breast cells (patients and cell lines) did not survive in coculture, suggesting that the model could select for malignant population in surgical breast tissues. Cocultures were able to select cells with 73 +/- 7% cloning efficiencies and with the ability to form cocultures with BM stroma. Preprotachykinin-I (PPT-I), a gene that is conserved by evolution, facilitates BCC integration as part of the stromal compartment. This was deduced as follows: (a) nontumorigenic breast cells (n = 4) genetically engineered to express PPT-I and led to anchorage-independent growth, foci formation, and formation of cocultures; and (b) suppression of PPT-I in BCCs (n = 5) with pPMSKH1-PPT-I small interfering RNA reverted the cells to nontumorigenic phenotypes and was undetectable in the BM nude mice. The evidence supports that the PPT-I gene facilitates the integration of BCCs in the stromal compartment during a period before clinical detection, without disrupting hematopoietic activity. (+info)
A peripheral primitive neuroectodermal tumor with generalized bone metastases in a puppy.
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A peripheral primitive neuroectodermal tumor (pPNET), most consistent with a human Ewing's sarcoma, is described in a 5-month-old male Australian Shepherd puppy. The first tumor site detected was in the left frontal bone of the skull with apparent subsequent rapid metastases to multiple sites in the axial and appendicular skeleton and bone marrow, kidneys, and perihyphophyseal meninges. Radiographically, all bone lesions were lytic and there was also a humeral bone fracture. Histologically, the tumor was diagnosed as a small round blue cell tumor. At this stage, the differential diagnosis included a lymphoma, rhabdomyosarcoma, and a PNET of the peripheral nervous system. However, the cells had positive expression of triple neurofilament antigens as detected immunocytochemically. The cells were negative for a broad panel of canine-specific leucocyte cell marker antigens for desmin, smooth muscle actin, synaptophysin, and CD99. Ultrastructurally, the cells contained occasional dense core neurosecretory granules and intermediate filaments with intercellular desmosomal-like junctions and abundant glycogen clusters. Based on the age of the dog, the clinical history, the distribution of gross lesions, histologic characteristics of a small round blue cell tumor, and immunocytochemical and ultrastructural evidence of neuroectodermal differentiation, a diagnosis of a pPNET similar to a human Ewing's sarcoma was made. (+info)
Extramedullary multiple myeloma escapes the effect of thalidomide.
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BACKGROUND AND OBJECTIVES: Thalidomide is an antiangiogenic drug that produces a response rate ranging from 32 to 64% in patients with refractory/relapsed multiple myeloma (MM). However, the efficacy of thalidomide in patients with soft-tissue plasmacytomas is controversial. The aim of this study was to assess the response rate to thalidomide in patients with advanced MM and to correlate the response rate with the presence of extramedullary involvement. DESIGN AND METHODS: Thirty-eight patients with refractory/relapsed MM were treated with thalidomide. Eleven patients had extramedullary involvement when therapy was initiated. The response rate was evaluated according to the criteria of the European Group for Blood and Marrow Transplantation. RESULTS: Sixteen of the 38 patients (42%) responded to thalidomide. The response rate was significantly higher in patients without extramedullary involvement (59% vs 0%, p=0.0006). Although four of the 11 patients with extramedullary involvement had a serological response, a progression of the soft-tissue masses was observed in all of them. INTERPRETATION AND CONCLUSIONS: Thalidomide is effective in patients with advanced MM. However, extramedullary disease does not respond to thalidomide, as delivered in this series. The mechanisms to explain different response to therapy depending on tumor homing warrant further investigation. (+info)
Clonal stability of initial leukemia in a child with central nervous system relapse 7.4 years after bone marrow relapse of common acute lymphoblastic leukemic.
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Second central nervous system (CNS) relapses represent about 7.3% of subsequent recurrences of childhood acute lymphoblastic leukemia (ALL). In most children these subsequent CNS relapses occur during the first 18 months after diagnosis of the first relapse (mean 1.42 +/- 0.73 years). We present a patient who suffered a second ALL relapse in the CNS more than seven years after diagnosis of his first relapse. The leukemic clone was completely stable over more than ten years as shown by minimal residual disease techniques. Possible reasons for the recurrence of the leukemic clone after this very long period of dormancy (e.g. role of the disease site, immune system dysfunction) are discussed. (+info)
A relevant immunomagnetic assay to detect and characterize epithelial cell adhesion molecule-positive cells in bone marrow from patients with breast carcinoma: immunomagnetic purification of micrometastases.
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BACKGROUND: The efficient detection and characterization of micrometastatic cells in the bone marrow of patients with breast carcinoma are of prognostic and therapeutic importance. The technique used must overcome the challenges that result from the small number of target cells (1 per 1 million hematopoietic cells) and the heterogeneous expression of micrometastatic cell markers. In this study, the authors assessed and improved the current methods for purifying and characterizing rare disseminated carcinoma cells. METHODS: The authors developed a single-step assay that does not require density-gradient separation. This assay can be performed directly on crude human bone marrow aspirates and is based on the use of immunomagnetic beads coated with an antibody that recognizes an epithelial cell-surface epitope, the epithelial cell adhesion molecule (EpCAM). To determine the specificity of the assay, the authors evaluated bone marrow specimens from 46 control patients. RESULTS: The novel method was highly reproducible and was capable of detecting as few as 10 carcinoma cells among 50 million hematopoietic cells. The yield was nearly 100%, with only 0.01% nonspecific cell draining. The authors found that 68 +/- 51 cells were trapped per 50 million cells in control crude aspirates and that density-gradient separation increased this number by 2-fold to 29-fold. These trapped cells expressed EpCAM, represented 1.4 x 10(-4) % of the sample, and were characterized as of hematopoietic cell origin (CD45 positive) or progenitor cell origin (CD34 positive). CONCLUSIONS: The authors developed a highly efficient and reproducible, single-step immunomagnetic assay that may be performed directly on crude human bone marrow aspirates. The authors believe the current study is the first to demonstrate that some rare bone marrow cells (CD45-positive or CD34-positive cells) may express EpCAM and, to some extent, may contaminate the purified micrometastatic cell fraction. Thus, a universal marker for micrometastatic cells remains to be discovered. (+info)
Enrichment methods to detect bone marrow micrometastases in breast carcinoma patients: clinical relevance.
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INTRODUCTION: Improving technologies for the detection and purification of bone marrow (BM) micrometastatic cells in breast cancer patients should lead to earlier prognosis of the risk of relapse and should make it possible to design more appropriate therapies. The technique used has to overcome the challenges resulting from the small number of target cells (one per million hematopoietic cells) and the heterogeneous expression of micrometastatic cell markers. In the present study, we have assessed the clinical relevance of current methods aimed at detecting rare disseminated carcinoma cells. METHODS: BM aspirates from 32 carcinoma patients were screened for the presence of micrometastatic cells positive for epithelial cell adhesion molecule and positive for cytokeratins, using optimized immunodetection methods. A comparison with data obtained for 46 control BM aspirates and a correlation with the clinical status of patients were performed. RESULTS: We developed a sensitive and efficient immunomagnetic protocol for the enrichment of BM micrometastases. This method was used to divide 32 breast carcinoma patients into three categories according to their epithelial cell adhesion molecule status. These categories were highly correlated with the recently revised American Joint Committee on Cancer staging system for breast cancer, demonstrating the clinical relevance of this simple and reliable immunomagnetic technique. We also evaluated immunocytochemical detection of cytokeratin-positive cells and cytomorphological parameters. Immunocytochemistry-based methods for the detection of BM micrometastases did not provide any information about the clinical status of patients, but helped to refine the immunomagnetic data by confirming the presence of micrometastases in some cases. We also tested a new density gradient centrifugation system, able to enrich the tumor fraction of BM specimens by twofold to threefold as compared with standard Ficoll methods. CONCLUSION: These improved methods for the detection of micrometastatic cells in patient BM should help clinicians to predict the clinical status of breast cancer patients at the time of surgery or treatment. (+info)
HLA class I, NKG2D, and natural cytotoxicity receptors regulate multiple myeloma cell recognition by natural killer cells.
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The role of natural killer (NK) cells in multiple myeloma is not fully understood. Here, NK susceptibility of myeloma cells derived from distinct disease stages was evaluated in relation to major histocompatibility complex (MHC) class I, MHC class I chain-related protein A (MICA), MHC class I chain-related protein B (MICB), and UL16 binding protein (ULBP) expression. MHC class I molecules were hardly detectable on bone marrow cells of early-stage myeloma, while late-stage pleural effusion-derived cell lines showed a strong MHC class I expression. Conversely, a high MICA level was found on bone marrow myeloma cells, while it was low or not measurable on pleural effusion myeloma cells. The reciprocal surface expression of these molecules on bone marrow- and pleural effusion-derived cell was confirmed at mRNA levels. While bone marrow-derived myeloma cells were readily recognized by NK cells, pleural effusion-derived lines were resistant. NK protection of pleural effusion cells was MHC class I dependent. Receptor blocking experiments demonstrated that natural cytotoxicity receptor (NCR) and NK receptor member D of the lectin-like receptor family (NKG2D) were the key NK activating receptors for bone marrow-derived myeloma cell recognition. In ex vivo experiments patient's autologous fresh NK cells recognized bone marrow-derived myeloma cells. Our data support the hypothesis that NK cell cytotoxicity could sculpture myeloma and represents an important immune effector mechanism in controlling its intramedullary stages. (+info)