Showing papers in "Leukemia & Lymphoma in 1998"
TL;DR: Although primary hepatic lymphoma is an aggressive disease, it is resectable, and responsive to chemotherapy and radiotherapy, and should be considered in the differential diagnosis for patients presenting with mass lesions in the liver or hepatic disease.
Abstract: Primary non-Hodgkin's lymphoma of the liver is an extremely rare lymphoma subset that often presents with diagnostic difficulties to both clinicians and pathologists. Using MEDLINE search, 90 cases of primary hepatic lymphomas reported in the literature were reviewed. The epidemiology and etiology, clinical presentation, pathologic features, management, and outcome of these patients have been summarized and described. Results of this review show that middle-aged males are most often affected. Abdominal pain or discomfort, weight loss and fever are the most frequent presenting symptoms. Most cases have a solitary or multiple mass lesions in the liver, and are frequently misdiagnosed as having a primary liver tumor or metastatic cancer. Diffuse large cell lymphoma is the most commonly encountered histologic subtype. Surgery, chemotherapy and radiotherapy have been used alone or in combination as treatment but the outcome is generally poor. Although primary hepatic lymphoma is an aggressive disease, it is resectable, and responsive to chemotherapy and radiotherapy. Because of the profound therapeutic implications, it should be considered in the differential diagnosis for patients presenting with mass lesions in the liver or hepatic disease.
199 citations
TL;DR: It is suggested that CD117 in combination with other antigens may be of great help for the identification of leukemia-associated phenotypes that could be used to monitor MRD in both acute myeloid leukemias and multiple myeloma patients achieving morphological complete remission.
Abstract: The c-kit proto-oncogen (CD 117) has been shown to be present in several cell types including normal and neoplastic hemopoietic cells. Among normal BM cells, CD117 expression has been found in about half of the CD34+ precursors including progenitors committed to the erythroid, granulo-monocytic, and megakaryocytic cell lineages. In addition, strong CD117 expression is detected in bone marrow mast cells as well as in a small subset of NK cells displaying strong reactivity for CD56, and in a relatively important proportion of CD3 /CD4 /CD8 prothymocytes. These results suggest that CD117 expression can be detected in both myeloid and lymphoid lineages although for the lymphoid lineage it would be restricted to a small NK-cell subset and early T-cell precursors. In acute leukemias CD117 expression was initially associated with AML. Nevertheless, at present it is well established that CD 117 expression may also be found in a relatively important proportion of T-ALL while it is usually absent in B-lineage ALL. Moreover, recent studies have shown that in about one-third of multiple myeloma cases and patients with monoclonal gammopathy of undetermined significance plasma cells display reactivity for CD1117. The prognostic influence of CD117 expression has not yet been clearly established. The analysis of this marker may also be of value for the investigation of minimal residual disease (MRD). It has been suggested that CD117 in combination with other antigens may be of great help for the identification of leukemia-associated phenotypes that could be used to monitor MRD in both acute myeloid leukemias and multiple myeloma patients achieving morphological complete remission.
132 citations
TL;DR: PSGL-1 is unique in that it is the only selectin glycoprotein ligand that has been directly demonstrated to mediate cell-cell adhesion in vitro and in vivo.
Abstract: Directed emigration of leukocytes into inflammatory sites and lymphatic tissues is orchestrated by the regulated expression of adhesion and signaling molecules on cells within the vasculature. The selectin family of adhesion molecules that are expressed on activated endothelial cells (E-selectin and P-selectin), activated platelets (P-selectin), and peripheral blood leukocytes (L-selectin), mediate tethering and rolling of leukocytes to the vessel wall in the microcirculation. Selectins promote these interactions by binding to glycoconjugate ligands expressed on apposing cells. Selectin-mediated rolling is a prerequisite for firm adhesion and subsequent transendothelial migration of leukocytes into tissues. This review will focus on the structure and function of P-selectin glycoprotein ligand-1 (PSGL-1, CD162). PSGL-1 is a disulfide-bonded homodimeric mucin-like glycoprotein on leukocytes that interacts with P-, L-, and E-selectin. PSGL-1 mediates leukocyte-endothelial and leukocyte-platelet adhesion by binding to P-selectin expressed on activated endothelium and platelets and PSGL-1 mediates leukocyte-leukocyte adhesion by binding to L-selectin expressed on apposing leukocytes. PSGL-1 is unique in that it is the only selectin glycoprotein ligand that has been directly demonstrated to mediate cell-cell adhesion in vitro and in vivo.
118 citations
TL;DR: CRP may be considered as a valuable and easy prognostic biomarker of NHL and on univariate analysis there is a significant relationship between CRP and IL-6 levels, and CRP levels and B symptoms.
Abstract: Interleukin-6 plays a central role in normal B-cell maturation and in proliferation of some B-cell malignancies including multiple myeloma and some non Hodgkin's lymphomas (NHL). Furthermore, this cytokine also plays a major role in acute phase response by mediating synthesis of acute phase proteins such as C-reactive protein (CRP). In order to evaluate the exact role of CRP serum level as a simple prognostic factor, we analyzed CRP and IL-6 serum levels in 39 patients with NHL. Eleven patients had low grade NHL, 15 intermediate grade NHL, and 13 high grade NHL. Thirty percent of the patients presented detectable IL-6 serum levels (mean+/-SD: 33.6+/-95.2 U/ml, range: 0 to 500). Increased serum CRP levels were found in 42% of the patients with a mean of 29.2+/-41.97 mg/l] (range: 0 to 129). Thirty seven patients were studied for both markers. Three groups of patients were determined. One with low IL-6 and CRP serum levels (N=21), a second with high level of both markers (N=10), and the third with high serum CRP levels alone (N = 5). Only one patient had high level of serum IL-6 with no detectable CRP. The correlation of serum IL-6 and CRP levels with patient survival was investigated. Median survival in the group with low IL-6 level was not reached. 67% of patients of this group were still alive at 32 months from diagnosis. The group of patients with detectable IL-6 had a median of survival of 12 months (p<0.025). The survival of patients with a CRP<10 mg/l was not reached. 75% of patients survive at 32 months from diagnosis, whereas the group with higher CRP level reached a median survival at 8.5 months (p<0.009). As expected, on univariate analysis, there is a significant relationship between CRP and IL-6 levels (p<0.00017), and CRP levels and B symptoms (p<0.001). Furthermore there is a significant relationship between CRP and LDH levels (p<0.042).These results indicated that CRP may be considered as a valuable and easy prognostic biomarker of NHL.
118 citations
TL;DR: The Bcl-2/Bax was significantly greater in the cell fractions resistant to chlorambucil-induced apoptosis, supporting the suggestion that Bax is the pivotal protein in determining the fate of cells following apoptotic signals.
Abstract: We investigated the relationship between drug resistance and Bcl-2/Bax in B-cell chronic lymphocytic leukaemia (B-CLL). Apoptosis was induced in vitro with chlorambucil and cell death was monitored by dual-labelled FACS analysis using Annexin V and propidium iodide. Bcl-2 and Bax protein expression was quantified using FACS and a correlation between drug-induced apoptosis and Bcl-2/Bax was established. Cells were then sorted into viable and nonviable populations according to their forward and side-scatter characteristics and re-analysed for Bcl-2/Bax. The most resistant cells had elevated Bcl-2 levels and low Bax expression. Furthermore, those cells which were undergoing apoptosis showed only a marginal reduction in Bcl-2 expression, but significantly elevated Bax expression following exposure to chlorambucil. The Bcl-2/Bax was significantly greater in the cell fractions resistant to chlorambucil-induced apoptosis. This observation further supports the suggestion that Bax is the pivotal protein in determi...
107 citations
TL;DR: In young patients with MM, particularly in those with good prognostic features and also in those younger than 30 years, the survival is longer than that in series of patients of all ages with MM.
Abstract: Multiple myeloma (MM) in patients younger than 40 or 30 years accounts for only 2% and 0.3% of all myelomas, respectively. The presenting clinical and laboratory features are similar to those observed in patients of all ages who have myeloma, except a higher proportion of young patients have only light-chain myeloma. Some very young patients, particularly those younger than 30 years, have multiple skeletal lesions with extramedullary spread and a small M-component with few bone marrow plasma cells. In young patients with MM, particularly in those with good prognostic features (that is, normal renal function or low beta2-microglobulin level) and also in those younger than 30 years, the survival is longer than that in series of patients of all ages with MM. Young patients with MM might benefit from early high-dose therapy followed by autologous or allogeneic stem cell rescue. The current status of autologous and allogeneic transplantation in MM is reviewed.
96 citations
TL;DR: Findings combined with recent reports linking Stat3alpha with proliferation and transformation suggest that the beta isoform of Stat3 may be more critical for G-CSF-mediated differentiation.
Abstract: Granulocyte colony-stimulating factor (G-CSF) is the cytokine critical for directing neutrophilic granulocyte differentiation. Early G-CSF signaling events in myeloid cells involves activation of STATs, proteins that serve the dual function of signal transduction and activation of transcription, especially the activation of Stat3. A dominant-negative mutant construct of Stat3 inhibited G-CSF-mediated neutrophilic differentiation indicating that Stat3 is a essential component for driving the G-CSF-mediated differentiation program in myeloid cells. Three isoforms of Stat3 have been identified, aL (p92), β (p83) and γ (p72) each derived from a single gene. Stat3aL is the predominant isoform expressed in most cells. Stat3γ is derived from Stat3aL by alternative RNA splicing. Stat3β is derived from Stat3aL by limited proteolysis. Mapping of Stat3aL and Stat3β activation in M1 murine myeloid leukemia cells revealed that their optimal activation required G-CSFR constructs containing both Y704 and Y744. These ami...
78 citations
TL;DR: In patients with myelodysplastic syndrome and chronic myelomonocytic leukemia, complete responses associated with topotecan therapy often involve the disappearance of abnormal, poor-prognosis karyotypes, which is particularly encouraging.
Abstract: The activity of topotecan was evaluated in patients with myelodysplastic syndrome (MDS) and chronic myelomonocytic leukemia (CMML). Sixty patients with a diagnosis of MDS (n=30) or CMML (n=30) were treated. Their median age was 66 years, with 50 patients (83%) being over 60 years of age at time of study entry. Chromosomal abnormalities were present in 50% of patients and thrombocytopenia of less than 50 × 109/L in 50%. Topotecan was administered as 2 mg/m2 by continuous infusion over 24 hours daily for five days (10 mg/m2 per course) every 4 to 6 weeks for two courses, then at maximum tolerated dose level (1-2 mg/m2by continuous infusion over 24 hours daily for five days) once every 4-8 weeks for a maximum of 12 courses. Evaluation of outcome and of differences among subgroups was performed according to standard methods; the criteria for response were those used for acute leukemia. Nineteen patients (31%) achieved a complete response (CR). A CR was achieved in 11 of 30 patients with MDS (37%) and in eight...
73 citations
TL;DR: Patients with expanded T cell clones have a downregulated T cell CD28 expression and lack B7-1 expression on their malignant plasma cells, consistent with the concept that engagement of the T cell receptor by tumour antigen on B 7-1 deficient malignant Plasma cells would result in T cell anergy rather than productive immunity.
Abstract: Presentation of tumour antigen by malignant cells not expressing costimulatory molecules is considered to be a major cause of the failure of the host's immune response against tumours. This study has determined the expression of the B7 family of costimulatory molecules on malignant plasma cells and the expression of the counter receptor molecules, CD28 and CD152 (CTLA-4), on T cells of patients with multiple myeloma. CD28 expression was present on most CD4 cells but was lower on CD8 cells especially from those patients who also showed evidence of expanded T cell clones (median 40%. z=2.4; p<0.02). CD152 expression was increased in 50% (9/18) of patients with myeloma. CD80 (B7-1) expression was present on the plasma cells of only 1 of 27 samples but CD86 (B7-2) expression within the normal range was present on the plasma cells of 14 of 27 samples. Primitive plasma cells (CD38++ CD45++) had a higher expression of CD86 (median 78%) than mature plasma cells (CD38++ CD45-) (median 19%, z=3.7; p<0.01). Thus patients with expanded T cell clones have a downregulated T cell CD28 expression and lack B7-1 expression on their malignant plasma cells. These results are consistent with the concept that engagement of the T cell receptor by tumour antigen on B7-1 deficient malignant plasma cells would result in T cell anergy rather than productive immunity.
69 citations
TL;DR: Understanding the critical functional role of STAT mediated signalling events as well as their regulation by interfering pathways provides new insights into the mechanisms involved in malignant cell proliferation.
Abstract: STAT proteins become activated upon tyrosine and serine phosphorylation, are subsequently translocated from the cytosol to the nucleus where they exert DNA-binding activity. Several STAT binding consensus motifs have been identified in the promoters of distinct genes. These consensus elements mediate STAT recruitment and influence the kind of STAT proteins that are bound at a specific promoter site. Recent structure function analyses have revealed conserved amino terminal sequences to be crucial for phosphatase dependent deactivation of the STAT proteins. Todate an increasing amount of data is available concerning the on- and off-regulation of STAT activity. Considerable convergence as well as crosstalk has been shown between the JAK-STAT pathway and the MAPK, RAS, PI3K, PKC., and PKA involving pathways. Moreover, the nature of the genes that are regulated by STAT proteins as well as the cell functions that result from STAT activation are of great current interest. Understanding the critical functional ro...
68 citations
TL;DR: IL-12 enhancement of IFN-gamma, NK, and LAK activity in activated cord blood MNC up to comparable levels in adult PBMC suggests that exogenous IL-12 stimulation can compensate for the immaturity in cord blood cellular immunity.
Abstract: Interleukin 12 (IL-12) is a pleiotropic cytokine and mediates several biological activities on human T and natural killer (NK) cells, including induction of IFN-gamma production, enhancement of cell-mediated cytotoxicity and comitogenic effects on resting T-cells. The major cellular sources producing IL-12 are antigen-stimulated monocytes, macrophages, and B-cells isolated from peripheral blood mononuclear cells (PBMC). Our laboratory has investigated the regulation of IL-12 gene expression in both cord blood and adult PBMC, and the effects of IL-12 on induction of IFN-gamma production, NK, and lymphokine-activated killer (LAK) cytotoxicity. IL-12 mRNA expression and protein production in LPS-stimulated cord blood MNC were 3-4 fold decreased when compared with adult PBMC. There were no differences between cord blood and adult PBMC in both basal levels of transcription or the degree of transcriptional activation of the IL-12 gene. Additionally, the half-life of IL-12 p40 mRNA was 3-fold lower in activated cord blood compared to adult PBMC. Exogenous IL-12 induced a significant increase of IFN-gamma from both cord and adult PBMC. Cord MNC has significantly reduced levels of NK activity, and IL-12 significantly enhanced cord blood NK cytotoxicity up to similar levels in adult PBMC. IL-12 also significantly enhanced cord blood NK and LAK activities against a broad range of neuroblastoma, leukemia, and lymphoma cell lines. Lower doses of IL-12 and IL-15 concomitantly generated either synergistic or additive effects on cord blood NK and LAK cytotoxicities. In light of the important biological functions of IL-12, reduced expression and production of IL-12 from activated cord blood may contribute to the immaturity of cord blood cellular immunity and contribute, in part, to decreased severe graft vs. host disease following unrelated cord blood stem cell transplantation. IL-12 enhancement of IFN-gamma, NK, and LAK activity in activated cord blood MNC up to comparable levels in adult PBMC suggests that exogenous IL-12 stimulation can compensate for the immaturity in cord blood cellular immunity. These characteristics of IL-12 biological activity strongly suggest its potential usefulness in future cancer immunotherapy.
TL;DR: Syndecan-1 is a useful marker to detect malignant plasma cells in the blood or marrow; however, it is not helpful in distinguishing MGUS from active myeloma, and there is heterogeneity of expression within and between patients.
Abstract: Syndecan-1 is a low-affinity receptor for basic fibroblast growth factor (bFGF). In this study, we used flow cytometry to examine expression of syndecan-1 on monoclonal cells from the blood (n = 37) and marrow (n = 81) of patients with plasma cell (PC) proliferative disorders (PCPD) and blood cells from patients (n = 39) with B cell chronic lymphocytic leukemia (B-CLL). The marrow CD38+CD45- and CD38+CD45+ PC were syndecan-1 positive in all patients with PCPD and there was no difference between patients with monoclonal gammopathy of undetermined significance (MGUS) vs multiple myeloma or cases with vs without bone lesions. In 38% of cases, syndecan-1 expression on the PC was heterogeneous with > or =25% of PC syndecan-1 negative. We found similar syndecan-1 expression on blood and marrow PC in the 36 cases with paired samples. CLL cells were syndecan-1 negative in 97% (38/39) of the cases. Syndecan-1 is a useful marker to detect malignant plasma cells in the blood or marrow; however, it is not helpful in distinguishing MGUS from active myeloma. In addition, syndecan-1 is present on the less mature (CD45+) PC, and there is heterogeneity of expression within and between patients. The relevance of the bFGF bound to myeloma cells via syndecan-1 remains to be elucidated.
TL;DR: The demonstration of HCV productive infection in bone marrow-recruited and circulating pluripotent hematopoietic CD34+ stem cells indicates that HCV replication occurs in the early differentiation stages of hematosynthesis, likely to represent the initial site of infection and a continuous source of virus production.
Abstract: Hepatitis C virus (HCV) is a single-stranded RNA agent which expresses its genetic informations in the form of a single, large polyprotein encoded by an open reading frame (ORF) that extends through most of its genomic RNA. Proteolytic cleavage of the ORF product is essential for the virogenesis and the production of viral progeny. HCV is responsible for chronic liver disease, cirrhosis and possibly hepatocellular carcinoma. Viral persistence is considered the greatest problem in the management of HCV infection. It may result from several mechanisms, two of which are established. In the first, the high rate of genetic variations during viral replication results in the production of mutants capable of escaping the immune attack. In the second, the virus infects cells of the immune system itself, which represent a privileged site that cannot be reached by virus-specific T cell response. Involvement of lymphoid cells in the early stages of HCV infection may provide insight into the pathobiologic patterns of ...
TL;DR: The data show a correlation between the expression of es transporters and the in vitro sensitivity to nucleoside drugs of blasts from acute leukemia patients, and show that the flow cytometry assay of es expression provides a facile means of predicting resistance of leukemia cells to the cytotoxicity of araC and other nucleosides.
Abstract: Nucleoside analogs are important components of treatment regimens for acute leukemia in adults. Plasma membrane permeation of the nucleoside analog molecules, the initial event in the cellular conversion of nucleosides to active agents, is mediated by nucleoside-specific membrane transporters. The widely-expressed es nucleoside transporter accepts as substrates diverse nucleoside analogs, including cytarabine (araC), 2-chlorodeoxyadenosine, and fludarabine. The cellular content of es transporter sites has been measured in blasts from patients with acute lymphoblastic leukemia and acute myelogenous leukemia, by a sensitive, quantitative flow cytometry assay that employs the tightly-bound es ligand, SAENTA fluorescein. Values for es transporter expression varied ten-fold among samples from patients with acute myelogenous leukemia. In this article, we review current findings that document, in confocal fluorescence microscopy images and in flow cytometry assays of SAENTA fluorescein-stained cells, the patient-to-patient variance of es transporter expression in leukemic blasts from patients. Our data show a correlation between the expression of es transporters and the in vitro sensitivity to nucleoside drugs of blasts from acute leukemia patients. These findings show that the flow cytometry assay of es expression provides a facile means of predicting resistance of leukemia cells to the cytotoxicity of araC and other nucleosides.
TL;DR: These studies suggest that expression of ALK protein, a novel orphan receptor tyrosine kinase, is normally confined to the nervous system, which creates a novel fusion protein, NPM-ALK, which has transforming properties in vitro and can cause large-cell lymphoma in vivo when transfected into murine bone marrow.
Abstract: A recurrent, reciprocal balanced translocation, t(2;5) (p23;q35), has been recognize CD30+ anaplastic large-cell lymphomas (ALCL), a newly recognized subtype comprising approximately 5% of all non-Hodgkin's lymphoma (NHL). This translocation creates a novel fusion protein, NPM-ALK, which has transforming properties in vitro and can cause large-cell lymphoma in vivo when transfected into murine bone marrow. Multiple techniques including reverse transcriptase-polymerase chain reaction (RT-PCR) amplification of NPM-ALK fusion transcripts, genomic DNA-PCR, RNA in situ hybridization, and fluorescence in situ hybridization (FISH) of metaphase chromosomes and interphase nuclei, and immunohistochemical detection of the 80 kilodalton protein (p80) derived from the NPM-ALK fusion have enabled surveys of normal and lymphoma tissues for evidence of the translocation. These studies suggest that expression of ALK protein, a novel orphan receptor tyrosine kinase, is normally confined to the nervous system. In lymphoma, ...
TL;DR: 15 mg/m2 is the maximal tolerated dose (MTD) of RFT5-SMPT-dgA in patients with refractory Hodgkin's lymphoma, and in an extension of the phase I trial, five additional patients have been treated at the MTD.
Abstract: Immunotoxins (ITs) consisting of a cell-binding component and a potent toxin were developed as a new class of biological anti-tumor agents to improve adjuvant therapy. Hodgkin's lymphoma (HL) has been demonstrated to be an excellent target for ITs because high concentrations of lymphocyte activation markers such as CD25 and CD30 are expressed on Hodgkin and Reed-Sternberg (H-RS). Several ITs against these antigens have shown potent antitumor effects against H-RS cells in vitro and in different HL animal models. On the basis of its superiority in preclinical models, the anti-CD25 IT RFT5-SMPT-dgA was subsequently evaluated in a phase I study in patients with refractory Hodgkin's lymphoma. The IT was constructed by linking the monoclonal antibody (Moab) RFT5 via a sterically hindered disulfide linker (SMPT) to deglycosylated ricin A-chain (dgA). All 15 patients enrolled in this trial were heavily pretreated with a mean of five different prior therapies. The IT was administered intravenously over four hours on days 1-3-5-7 for total doses per cycle of 5, 10, 15, or 20 mg/m2. Side effects were reversible and related to the vascular leak syndrome (VLS), i.e. decrease in serum albumin, edema, weight gain, hypotension, tachycardia, myalgia, and weakness. In all three patients receiving 20 mg/m2 NCI toxicity grade III was observed. Thus, 15 mg/m2 is the maximal tolerated dose (MTD) of RFT5-SMPT-dgA. 50% of the patients developed human anti-ricin A-chain antibodies (HARA) and/or human anti-mouse antibodies (HAMA). Clinical results included two partial remissions (PR), one minor response (MR), three stable disease (SD) and nine progressive disease (PD). In an extension of the phase I trial, five additional patients have been treated at the MTD.
TL;DR: The results confirm both the good prognosis of primary CBCL and the efficacy of polychemotherapy and there are no indications for the use of COP/CHOP regimens as first-line chemotherapy in CTCL patients.
Abstract: The efficacy of systemic poly chemotherapy in the treatment of primary cutaneous B-cell lymphomas (CBCL) or T-cell lymphomas (CTCL) is still controversial. A series of 81 patients (46 primary CBCL and 35 CTCL) were treated with COP or CHOP regimens. In primary CBCL, the overall objective response rate (RR) was 98%, with an 89% CR rate and a 33% relapse-rate. Five-year disease-free survival was 70%, 5-year survival 97%. Patients with leg or widespread lesions showed a higher relapse-rate (55% vs 26%) than those with trunk or head lesions. The overall objective RR was 40% in CTCL patients, with a 23% CR rate; median response duration was 5.7 months, median survival 19 months. The results confirm both the good prognosis of primary CBCL and the efficacy of polichemotherapy. CHOP regimen is to be preferred to COP in as much as it reduces relapse rates. Conversely, there are no indications for the use of COP/CHOP regimens as first-line chemotherapy in CTCL patients.
TL;DR: Evidence of significant clustering of replacement amino acids, in CDRs, particularly in V(L), indicates that the B-cell of origin is likely to have been selected by antigen, and that the somatic mutation mechanism may still be operative following neoplastic transformation.
Abstract: Analysis of usage of V(H) and V(L) genes, and the degree and pattern of somatic mutation, has been used to investigate the cell of origin and clonal history in cases of Burkitt's lymphoma (BL). Tumor cell lines and biopsy material from patients with endemic, sporadic and AIDS-associated BL have been compared. V(H) genes were most commonly derived from the V(H)3 (52%) and V(H)4 (39%) families. This shows a similar gene usage of the V(H)3 family to that seen in the normal peripheral blood repertoire (55%), but a biased usage of the V(H)4 family (22% in normal). There was no restriction in V(L) gene usage. This overall distribution was similar in all subsets of BL. In all categories, there was significant somatic mutation in both V(H) and V(L) sequences. There was no evidence for accumulation of mutations in cell lines cultured in vitro indicating that all mutations in BL-derived cell lines have accumulated in vivo. The mean percentage level of mutation +/- standard deviation was greater in endemic BL (V(H) = 7.7 +/- 4.0, V(L) = 5.3 +/- 2.2) and AIDS-associated BL (V(H) = 7.5 +/- 3.6, V(L) = 3.9 +/- 1.9) than in sporadic BL (V(H) = 4.0 +/- 2.5, V(L) = 2.2 +/- 1.2). The pattern of somatic hypermutation was similar in V(H) and V(L) sequences of the different types of BL although the light chain genes were less mutated. Mutational patterns in the V(H) genes did not reveal a conventional role for antigen in selection of tumor cell sequences in 23/25 V(H) genes analysed. In contrast, patterns in V(L) sequences were consistent with a role for antigen in 8/13 sBL +/- eBL cases and 8/17 cases overall. The presence of EBV did not seem to influence the quantity or pattern of somatic mutations. Evidence for intraclonal variation was seen in uncloned cell lines from cases of eBL and AIDS-associated BL and confirmed in biopsy material in some, but not all cases of eBL, sBL and AIDS-associated BL examined. These common features indicate that the B-cells involved in all types of BL are derived from cells that have traversed the germinal centre, and that the somatic mutation mechanism may still be operative following neoplastic transformation. Overall, in 10/30 cases, there was evidence of significant clustering of replacement amino acids, in CDRs, particularly in V(L), indicating that the B-cell of origin is likely to have been selected by antigen.
TL;DR: It is suggested that there are no clinically appreciable differences between tr-CML and de novo CML cases, and the need for a large epidemiological study to specifically assess the risk of developing second primary CML after chemotherapy and/or radiotherapy is stressed.
Abstract: Second primary cancers represent an important complication of modern chemotherapy and radiotherapy. Therapy-related (tr) leukemias are among the most common second malignancies in both pediatric and adult populations. Whereas a reasonable amount of data is available regarding the epidemiology, molecular pathogenesis, clinical behavior and response to therapy of second primary acute leukemias, very little is known about therapy-related chronic myeloid leukemia (tr-CML). A better characterization of this entity could increase our understanding about the mechanisms of carcinogenesis, specially the induction of specific genetic abnormalities, e.g., BCR-ABL fusion, following chemotherapy and/or radiotherapy exposure, could facilitate the investigation of the kinetics of the development of CML, and also provide a model to study molecular events that might precede its development. Review of 32 tr-CML cases suggests that there are no clinically appreciable differences between tr-CML and de novo CML cases. Analysis of large epidemiological studies that investigated the risk of second primary leukemias has not shown any clear evidence of a higher risk of CML among individuals who underwent treatment for a primary cancer over the general population. The cancer-predisposing syndromes, the detection of BCR-ABL transcripts in healthy individuals, and the induction in vitro of BCR-ABL fusions by ionizing radiation, are all discussed in the context of tr-CML. Finally, the need for a large epidemiological study to specifically assess the risk of developing second primary CML after chemotherapy and/or radiotherapy is stressed.
TL;DR: These studies provide clinical evidence that a dose-response effect is present for cytarabine in AML, and it is likely that remission duration may be a useful clinical tool to study the influence of new induction therapies on residual resistant leukemia.
Abstract: Induction therapy of acute myeloid leukemia (AML) with standard dose chemotherapy will result in approximately 55-75% of patients achieving a complete remission (CR). Intensification of induction treatment with etoposide and high dose cytarabine does not alter the CR rate but appears to significantly improve the subsequent outcome. Updated results of the comparison of high dose cytarabine with daunorubicin and etoposide in induction (HIDAC-3-7) versus a standard dose combination (7-3-7) demonstrated a highly significant increase in relapse free survival, (RFS) on the high dose arm (p = 0.007) with RFS of 48% at 5 years with HIDAC-3-7 and 25% on 7-3-7. The high dose arm had a more modest survival advantage at 5 years of 33% compared with 25% on standard treatment, possibly because of a higher initial death rate with HIDAC-3-7. The improvement seen in patients with CR after high dose induction appear to parallel results obtained with post-remission therapies intensified with high dose cytarabine. These studies provide clinical evidence that a dose-response effect is present for cytarabine in AML. Intensified treatment is more toxic, gives more profound myelosuppression post-remission and has been shown to benefit younger patients only. Issues of patient selection and the optimal placement of intensification in the treatment sequence require further study. In the future, it is likely that remission duration may be a useful clinical tool to study the influence of new induction therapies on residual resistant leukemia.
DSM1
TL;DR: Historical landmarks in the establishment of unique leukemia-lymphoma-derived cell lines from the various cell lineages are summarized; their special importance in hematopoietic research is emphasized.
Abstract: Continuous human leukemia-lymphoma cell lines have become indispensable tools in hematological research since the establishment of the first human lymphoma cell line Raji in 1963. We summarize here historical landmarks in the establishment of unique leukemia-lymphoma-derived cell lines from the various cell lineages; their special importance in hematopoietic research is emphasized. The first cell lines were derived from African Burkitt lymphomas and were found to integrate the Epstein-Barr virus in their genome leading to the discovery and isolation of this virus. However, it was later recognized that not every cell line derived from a patient with leukemia-lymphoma represents a malignant cell line as residual normal B-lymphocytes can also be immortalized by EBV infection. During the following 20-30 years many other types of hematopoietic cell lines, commonly derived from hematopoietic neoplasms, were established. These panels of cell lines now span almost the whole spectrum of hematopoietic cell lineages (except for dendritric cells) and the various distinct stages of differentiation along the respective cell axes. From early on, cell lines became important tools for basic and clinical hematological research, initially mainly in the field of immunology, but later expanding to other areas also. It became apparent that leukemia-lymphoma cell lines are of monoclonal origin, are arrested at a discrete maturational stage during differentiation in each lineage, and show sustained and growth factor-independent or -dependent unlimited proliferation. Categorization of cell lines might best be based on the physiological stages of hematopoietic differentiation in the various cell lineages. For an adequate classification, detailed characterizations of both the cell lines and the primary cells from which the cell lines originated are absolutely mandatory. In summary, the availability of large numbers of continuous leukemia-lymphoma cell lines has greatly facilitated clinical and immunobiological studies of normal and malignant hematopoiesis. Human leukemia-lymphoma cell lines will continue to provide exquisite model systems for many biomedical disciplines.
TL;DR: The results indicate that the expression of dCK gene varies in patients and suggests decreased expression of the dCk gene as one of the mechanisms responsible for clinical resistance to ara-C.
Abstract: Competitive RT-PCR was used to determine the quantitative variation in the expression of deoxycytidine kinase (dCK) gene in childhood leukemic cells. The degree of dCK gene expression varied over a 50-fold range. In two cases in which both primary and relapsed leukemic cells were analysed, decreased expression of dCK gene was found in relapsed leukemic cells. The sequence variation analysis using bisbenzimide/polyethylene glycol electrophoresis demonstrated no sequence alteration of dCK cDNA in all cases. These results indicate that the expression of dCK gene varies in patients and suggests decreased expression of the dCK gene as one of the mechanisms responsible for clinical resistance to ara-C.
TL;DR: A minority (25%) of patients with indolent non-Hodgkin's lymphomas have elevated serum levels of IL-6 at diagnosis, and in these individuals, high IL- 6 levels are associated with adverse disease features, and predictive of a shorter failure-free survival.
Abstract: Interleukin-6 (IL-6) is a potent immunomodulatory cytokine that may have pathogenetic and prognostic significance in a number of disorders. The objective of this study was to examine the correlation between serum IL-6 levels and phenotypic characteristics, as well as failure-free survival of patients with low-grade non-Hodgkin's lymphomas (NHL). Using a sensitive enzyme-linked immunoabsorbent assay (ELISA), we measured IL-6 in frozen sera from 55 healthy controls and in the pre-treatment frozen sera from 100 low-grade lymphoma patients who were enrolled on protocols at MD Anderson Cancer Center. Serum IL-6 levels were correlated with clinical and laboratory features at diagnosis and with failure-free survival. The serum IL-6 levels were > or =2 pg/mL in 9% (median, or =3.0 mg/L) (p = 0.00013), and unfavorable International Index (p = 0.03). Patients with elevated serum IL-6 levels had an inferior failure-free survival (log rank p = 0.008) compared with those with normal serum IL-6 levels (three-year-failure-free-survival = 55% versus 81%, respectively). In conclusion a minority (25%) of patients with indolent non-Hodgkin's lymphomas have elevated serum levels of IL-6 at diagnosis. In these individuals, high IL-6 levels are associated with adverse disease features, and predictive of a shorter failure-free survival.
TL;DR: DLI is a direct demonstration of the graft-versus-leukemia effect (GVL), and it may be advisable in such situations to redirect the conditioning regimens for BMT towards engraftment and less immediate cytotoxicity.
Abstract: The results of donor lymphocyte infusion (DLI) for treatment of relapse after bone marrow transplantation (BMT) are reviewed Durable complete remission can be achieved at the molecular level for a majority (more than 70%) of patients with CML, when treated at early relapse Results are less favourable for acute leukemias, although useful responses have been reported Data are scarce though promising for myelodysplastic syndromes and multiple myeloma Major treatment-associated toxicities are GVHD and bone marrow aplasia The latter complication can be predicted by evaluating the level of residual donor-derived hematopoiesis Modification of infused cells (CD8 negative selection or transduction with a suicide gene), addition of peripheral blood stem cells, and early implementation of escalating doses may counteract the complications and increase the response rate Response rate is variably influenced by the presence of chronic GVHD after initial BMT, T-cell depleted BMT, underlying disease and stage at relapse, and the level of mixed chimerism DLI is a direct demonstration of the graft-versus-leukemia effect (GVL) Because GVL after BMT is sometimes the predominant cause of cure, it may be advisable in such situations to redirect the conditioning regimens for BMT towards engraftment and less immediate cytotoxicity
TL;DR: A striking tendency of blastoid MCL subtypes to harbour chromosome numbers in the tetraploid range is a feature clearly separating these neoplasms from other types of B-cell NHL and possibly being related to its unphysiological expression of cyclin D1.
Abstract: Mantle cell (centrocytic) non-Hodgkin's lymphoma (MCL) is a malignant tumour with unique biological features. The pathogenesis of MCL seems to be strongly associated with aberrant function of the cell cycle. 110 cases of MCL have been analysed for their cytomorphological features, mitotic and proliferation indices, bcl-1 rearrangements, p53 expression patterns and DNA content by both interphase cytogenetic as well as DNA flow cytometric analyses. According to cytomorphology, three subtypes were recognized: a common, a lymphoblastoid and a pleomorphic variant of MCL. Blastic MCL subtypes were characterized by distinctly elevated mitotic and proliferation indices, frequent bcl-1 rearrangements at the MTC locus, and overexpression of p53. The most interesting finding, however, was a striking tendency of blastoid MCL subtypes to harbour chromosome numbers in the tetraploid range, a feature clearly separating these neoplasms from other types of B-cell NHL and possibly being related to its unphysiological expre...
TL;DR: The results show that this high dose rIL-2 regimen induces significant biological effects and provides some anti-leukemic activity in patients with advanced leukemia, and considering the severe toxicity observed and the limited remission rate achieved here, ril-2 does not appear to be a valuable therapeutic option for such patients.
Abstract: In this report we present the results of a multicenter phase II study of high-dose recombinant Interleukin-2 (rIL-2) in patients with refractory or relapsed acute leukemia. Forty-nine patients with acute myeloid leukemia (AML: 30 patients) or acute lymphoblastic leukemia (ALL: 19 patients) were included. Median age was 30 years (range: 4-71). Four patients were treated for primary refractory disease and 45 for relapsed disease (16 patients > 2nd relapse). Twenty-four patients (49%) had previously received bone marrow transplantation (allogeneic: 5, autologous: 19). Patients were scheduled to receive three 5-day cycles of rIL-2 given every other week. rIL-2 was administered as bolus I.V. infusion of 8 x 10(6) UI/m2 every 8 hours during cycle I and every 12 hours during cycles 2 and 3. Patients received a mean of 76% of rIL-2 planned dose. Main toxicity was hematologic (grade IV thrombopenia: 84%). Hemodynamic and metabolic toxicities lead to treatment discontinuation in 10 patients (20%). Strong immune activation was achieved including a significant increase in activated T-cells and Lymphokine-Activating-Killer cell (LAK) activity. Twenty-seven out of 30 AML patients could be evaluated for response: 2(7%) achieved complete remission (CR) which lasted 3 and 4 months. No response was observed in the 18 assessable ALL patients, most of whom (77 %) presented absolute drug resistance. These results show that this high dose rIL-2 regimen induces significant biological effects and provides some anti-leukemic activity in patients with advanced leukemia. Considering the severe toxicity observed and the limited remission rate achieved here, rIL-2 does not appear to be a valuable therapeutic option for such patients. However, the undoubted anti-leukemic activity of this cytokine invites further investigation especially in the minimal residual disease situation.
TL;DR: The importance of RFC1 expression in transport-mediated antifolate drug resistance is demonstrated and studies of both MTX uptake in cancer cells and of folate transport in physiologic systems indicate that there are other proteins with uptake characteristics similar to RFC.
Abstract: Methotrexate (MTX), the antifolate drug widely used as both an anticancer chemotherapeutic drug and as an immunosuppressive agent, mimics natural folates to inhibit critical cellular biosynthetic pathways. One of the most important determinants of cellular sensitivity to MTX is the degree to which this drug is internalized by cancer cells, and one of the major pathways of folate uptake results from the activity of the reduced folate carrier (RFC). Decreased RFC activity has been associated with several models of transport-mediated MTX resistance. Recently, the rodent and human genes which encode this protein have been isolated (RFC1), and defects in the expression of RFC1 genes have been identified in transport-deficient, MTX-resistant cell lines. Therefore, these studies have demonstrated the importance of RFC1 expression in transport-mediated antifolate drug resistance. In addition, however, studies of both MTX uptake in cancer cells and of folate transport in physiologic systems indicate that there are other proteins with uptake characteristics similar to RFC, and which maybe encoded by genes other than RFC1.
TL;DR: IL-6 favoured and maintained adhesion of MM cells to stromal cells spontaneously since its reintroduction in the favoured co-culture system, suggesting a functional overlap between cytokines and adhesion molecules for the paracrine IL-6 production.
Abstract: Bone marrow (BM) environment is thought to support the growth of myeloma cells and thus to play an important role in the pathogenesis of multiple myeloma (MM) Because interleukin-6 (IL-6) is an essential growth factor in MM, we have examined the effects of two myeloma cell lines (U266 and ARH-77) on the IL-6 production by BM stromal cells in a co-culture system These cell lines strongly stimulate the IL-6 production and IL-6 triggering was partially dependent on physical contact between lines and stroma The percentages of cell adhesion to stromal layers were 39% and 25% respectively for ARH77 and U266 cell lines Inhibition studies with blocking monoclonal antibodies showed the importance of CD49d/CD106 and CD11a/CD54 interactions in the stimulation of IL-6 production by stromal cells However, cell-to-cell contact was not an absolute requirement for IL-6 production Cytokines, of which TNF-alpha and IL-1beta produced by MM or accessory cells, were also able to stimulate IL-6 production by fibroblasts and show additive effects In adhesion assays, TNF-alpha and IL-1beta were able to increase the adhesion of MM cells to stromal cells CD54 was upregulated by IL-1beta, TNF-alpha or a contact with MM cells while CD106 expression was not, suggesting only a functional change of this molecule However, the role of monoclonal antibodies, directed against these factors, confirmed the role of TNF-alpha in the IL-6 production by stromal cells, while any IL-1beta intervention was not shown in our co-culture system IL-6 favoured and maintained adhesion of MM cells to stromal cells spontaneously since its reintroduction in the favoured co-culture system restored their decreased adhesion observed on a glutaraldehyde fixed stromal layer Overall our data suggest a functional overlap between cytokines and adhesion molecules for the paracrine IL-6 production
TL;DR: Immunohistochemical studies indicate neoplastic hemopoietic cells can contain PTHrP, and thus have the capacity to act in a paracrine manner to enhance local bone resorption and contribute to the development of hypercalcemia.
Abstract: Hypercalcemia is an important complication in multiple myeloma as well as T-cell leukemia/lymphoma, and is moderately common in high and intermediate grade non-Hodgkin's lymphoma. The underlying mechanism has been unclear because the neoplastic cells are usually present in the bone marrow, where they are in a position to produce short range effects on bone resorption which are difficult to identify. This contrasts with the situation in hypercalcemia associated with non-metastatic carcinoma, where it has been clearly demonstrated that the most common cause is release from the tumor of a humoral mediator, Parathyroid Hormone-related Protein (PTHrP). Roles have been advocated in multiple myeloma for release of a number of other cytokines with osteolytic capacity on the basis of their enhancement of osteolytic activity in cultured fetal rat bone, although a causal relationship in patients has not been established. PTHrP has more recently been implicated in the genesis of hypercalcemia in patients with hematological malignancies by the demonstration in a proportion of cases of increased circulating levels of PTHrP, comparable to those in hypercalcemia due to cancer. Immunohistochemical studies indicate neoplastic hemopoietic cells can contain PTHrP, and thus have the capacity to act in a paracrine manner to enhance local bone resorption and contribute to the development of hypercalcemia.
TL;DR: In this paper, the expression of EBER (EBV small RNA's), and EBV latent antigens LMP-1 and EBNA-2 in 43 cases of AIDS-related NHL and related this to histology and immune status.
Abstract: In patients with the acquired immunodeficiency syndrome, the incidence of non-Hodgkin's lymphoma is increased. Two major subgroups of AIDS-related NHL (ARL) have been defined: Burkitt-type NHL (BL) and polymorphic centroblastic/immunoblast-rich large cell lymphomas (CB/IB LCL). These subgroups differ in their association with the Epstein-Barr virus (EBV) and thus possibly in their pathogenesis. We studied the expression of EBER (EBV small RNA's), and EBV latent antigens LMP-1 and EBNA-2 in 43 cases of ARL and related this to histology and immune status (CD4-cell count). In addition, in 19 cases the expression of adhesion molecules (LFA-1 (CD 18), ICAM-1 (CD54), aL4β1 integrin (CD49d/CD29), L-selectin (CD62L) and CD44) was studied. We found major differences between the two subgroups. Patients with BL had significantly higher CD4-cell counts; only 40% of their lymphomas were EBV-positive, and when EBV-positive, were of the type I latency phenotype. Expression of adhesion molecules important for immune reco...