Elevated levels of serum CD44 and E-cadherin predict an unfavourable outcome in myelodysplastic syndromes.
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Adult↗
Biomedical subjects
R Stauder
Publications and source records attributed to R Stauder.
Gemtuzumab ozogamicin (Mylotarg) as single-agent treatment for frail patients 61 years of age and older with acute myeloid leukemia: final results of AML-15B, a phase 2 study of the European Organisation for Research and Treatment of Cancer and Gruppo Italiano Malattie Ematologiche dell'Adulto Leukemia Groups.
The therapeutic activity and toxicity profile of gemtuzumab ozogamicin were assessed in 40 patients >60 years of age with acute myeloid leukemia (AML) who were not considered eligible for conventional chemotherapy because of advanced age or poor performance status. The drug was administered at the dose of 9 mg/m2 as a single 2-h i.v. infusion on days 1 and 15. Patients who achieved a complete remission (CR/CRp) were to receive a consolidation with two additional injections of the immunotoxin at the same dose. The overall CR/CRp rate was 17% (95% CI, 8-32%). The CR/CRp rate in patients 61-75 years old was 33% (6/18), and 5% (1/22) in patients older than 75 years. Induction death occurred in seven patients (17%), all aged above 75 years. Overall survival was significantly longer in patients aged 61-75 years than in older individuals (P=0.05), and in CD33+ cases than in CD33- cases (P=0.05). We conclude that the dose/schedule of gemtuzumab ozogamicin used in this trial is too toxic in the age group over 75 years. For these patients, additional studies with reduced doses of the immunotoxin are warranted.
Acute Disease↗
Refinement of the international prognostic scoring system (IPSS) by including LDH as an additional prognostic variable to improve risk assessment in patients with primary myelodysplastic syndromes (MDS).
The international prognostic scoring system (IPSS) is considered the gold standard for risk assessment in primary myelodysplastic syndromes (MDS). This score includes several prognostic factors except serum lactate dehydrogenase (LDH). We evaluated the prognostic power of LDH as an additional variable in IPSS-based risk assessment. For this purpose, a total of 892 patients with primary MDS registered by the Austrian-German cooperative MDS study group was analyzed retrospectively. Multivariate analysis confirmed the value of established parameters such as medullary blasts, karyotype and peripheral cell counts and showed that elevated LDH was associated with decreased overall survival (P<0.00005) and increased risk of AML development (P<0.00005), independent of the system used to classify MDS (FAB or WHO). Moreover, elevated LDH was found to be a significant predictor of poor survival within each IPSS risk group and within each FAB group except RAEB-T. To exploit these results for refined prognostication, each IPSS risk group was split into two separate categories (A=normal LDH vs B=elevated LDH). Using this LDH-assisted approach, it was possible to identify MDS patients with unfavorable prognosis within the low and intermediate IPSS risk groups. We propose that the IPSS+LDH score should improve clinical decision-making and facilitate proper risk stratification in clinical trials.
Adolescent↗
CD44 variant isoforms are involved in plasma cell adhesion to bone marrow stromal cells.
Expression of CD44v9-containing isoforms (CD44v9) on myeloma plasma cells correlates with unfavorable prognosis, suggesting that CD44 variant molecules are involved in the disease process. In this study, the presence of CD44v on B cell lines from different stages of development was analyzed by flow cytometry and a role in adhesion to stromal cells from different tissues was evaluated in in vitro binding assays. CD44v3, v6 and v9 isoforms were exclusively expressed on plasma cell lines and CD44v9 expression correlated with IL-6-dependent plasma cell growth. Binding studies using CD44 isoform- specific reagents showed that CD44v6 and CD44v9 were involved in binding to bone marrow stromal cells, but not to in vitro synthesized ECM or hyaluronic acid. CD44v9-mediated plasma cell binding resulted in a significant induction of IL-6 secretion by bone marrow stromal cells. Large differences in quantitative plasma cell binding to stromal cells from different tissues were observed. These, however, could not be related to a differential use of CD44v in these binding processes. The role of CD44v9 in adhesion induced IL-6 secretion and its preferential expression on IL-6-dependent plasma cell lines may explain the previously observed correlation between CD44v9 expression and adverse prognosis in multiple myeloma.
Adult↗
Blood levels of angiogenin and vascular endothelial growth factor are elevated in myelodysplastic syndromes and in acute myeloid leukemia.
Angiogenesis is of prognostic importance not only in solid tumors but also in malignant blood diseases. We measured levels of vascular endothelial growth factor (VEGF), angiogenin (ANG), and basic fibroblast growth factor (bFGF) in peripheral blood samples from 65 patients with myelodysplastic syndrome (MDS), from 25 patients with de novo acute myeloid leukemia (AML), and from 50 healthy donors. In matched samples, VEGF levels in serum were substantially higher than VEGF levels in plasma (380.7 +/- 56 pg/ml vs. 45.3 +/- 4.5 pg/ml, mean +/- SEM, p < 0.001), whereas serum and plasma levels of ANG were comparable and significantly correlated (r = 0.8; p < 0.01). Compared to normal controls (1.3 +/- 0.09 pg), serum levels of VEGF corrected for the peripheral blood platelet count (VEGF/10(6) platelets, VEGF(PLT)) were elevated in patients with refractory anemia (RA; 3.1 +/- 0.8 pg, p < 0.01), and reached maximal values in patients with advanced stage MDS (RAEB, RAEB-t) (3.5 +/- 0.6 pg, p < 0.001), de novo AML (3.6 +/- 1.1 pg, p < 0.05), and chronic myelomonocytic leukemia (CMML; 3.7 +/- 0.9 pg; p < 0.001). Levels of soluble ANG were elevated in RA (351 +/- 25.7 ng/ml, p < 0.001), in RAEB/RAEB-t (402 +/- 17.9 ng/ml; p < 0.001), in CMML (413.8 +/- 29.5 ng/ml; p < 0.001), and in patients with AML (305.1 +/- 17.1 ng/ml; p < 0.01, controls 255.4 +/- 8.1 ng/ml). Serum bFGF was neither elevated in MDS nor in AML patients. These results suggest that VEGF(PLT) is a marker of disease progression in MDS. Moreover, we show for the first time that elevated blood levels of ANG can be found in patients with myeloid malignancies, suggesting a role of ANG in the pathogenesis of these diseases.
Acute Disease↗
Spontaneous remission in a secondary acute myelogenous leukaemia following invasive pulmonary aspergillosis.
Spontaneous remission of adult acute myelogenous leukaemia (AML) represents a rare event. We report a 60-year-old female patient suffering from secondary AML M1 and severe invasive pulmonary hyalohyphomycosis highly suggestive of aspergillosis. Two months after the diagnosis of leukaemia, she achieved a spontaneous remission lasting 3 months, although neither cytostatic drugs nor corticoids were administered because of a septic condition. At the time of remission, a chronic hepatitis C virus infection and a polyclonal hypergammaglobulinaemia were present, and the patient received granulocyte colony-stimulating factor once. This report represents the first documentation of a spontaneous remission in AML following invasive pulmonary hyalohyphomycosis. Possible mechanisms of this phenomenon are discussed.
Aspergillosis↗
CD44 isoforms are differentially regulated in plasma cell dyscrasias and CD44v9 represents a new independent prognostic parameter in multiple myeloma.
To evaluate the role of CD44 variant isoforms (CD44v) in plasma cell dyscrasias, CD44v expression was analysed in bone marrow (BM) biopsies of multiple myeloma (MM) and monoclonal gammopathy of undetermined significance (MGUS) patients, in biopsies of soft tissue infiltration by MM and in extramedullary plasmacytoma samples. Expression of CD44 isoforms containing the 3v, 4v, 6v or 10v domain was observed in 15, 7, 13 and 5% of 87 samples from 49 consecutive MM cases, but could not be detected in ten normal persons or 11 MGUS patients. In contrast, CD44v9 revealed a broader pattern of expression and was observed in plasma cells in three out of ten normal persons and in three out of 11 MGUS cases. In MM, CD44v9 was detected in 32 out of 87 samples (37%) of BM infiltrates and was associated with an advanced Durie and Salmon stage (P<0.03), a progressive disease (P<0.01) and an IgA subtype (P<0.01). Furthermore, CD44v9 expression was observed in three out of five cases of MM soft tissue infiltrates, was often upregulated during disease progression, was significantly correlated with a shorter overall survival (P<0.03) and emerged as an independent prognostic factor in multivariate analysis (stage: relative risk 1.36, P<0.02; CD44v9 expression: relative risk 1.45, P<0.04). These results substantiate the clinical relevance of CD44v domains in plasma cell disorders and establish CD44v9 as a new independent prognostic parameter in MM.
Adult↗
Optimal timing for the collection and in vitro expansion of cytotoxic CD56(+) lymphocytes from patients undergoing autologous peripheral blood stem cell transplantation.
To identify the optimal time for the collection of CD56(+) cytotoxic lymphocytes for adoptive immunotherapy in patients undergoing high-dose chemotherapy (HDCT) and peripheral blood stem cell (PBSC) transplantation, 18 breast cancer patients receiving either three cycles of epirubicin/paclitaxel (CT x 3) followed by HDCT and PBSC transplantation (n = 12) or CTx6 (n = 6) were studied. Blood samples were obtained before each CT/HDCT cycle, from PBSC collections, and repeatedly after autografting for up to 12 months. The number of CD56(+)3(-) and CD56(+)3(+) lymphocytes, their in vitro expandability with interleukin-2, and their cytotoxicity against MCF-7 and Daudi cells were analyzed. Six healthy females served as controls. CD56(+) cell counts in both treatment groups were subnormal but stable during the observation period. The cytotoxicity of the expanded CD56(+) cells was normal and unaffected by the treatment. The in vitro CD56(+) cell expandability (controls, 100 +/- 31-fold, mean +/- SEM) was normal before CT1 and CT2, but reduced in PBSC harvests performed after CT2 and application of G-CSF (21 +/- 6-fold; p < 0.01). After PBSC harvesting, the CD56(+) cell expandability increased to 185 +/- 74-fold and 170 +/- 69-fold (before CT3 and HDCT). This increase was not observed in those patients who did not undergo PBSC mobilization. Two weeks after autografting, the CD56(+) cell expandability was minimal (6 +/- 1-fold), and recovered to 34 +/- 6-fold. Thus, CT, HDCT and autografting do not alter the frequency and inducible cytotoxicity of CD56(+) cells in breast cancer patients. However, the proliferative capacity of CD56(+) cells obtained from PBSC harvests and after autografting is impaired. Therefore, instead of the PBSC graft, maximally expandable CD56(+) cells obtained at least 1 week after PBSC collection should be considered for adoptive immunotherapy after PBSC autografting.
Adult↗
Expression of LFA-1 identifies different prognostic subgroups in patients with advanced follicle center lymphoma (FCL).
In a retrospective immunohistochemical study based on 27 patients with stage IV follicle center lymphoma (FCL) the expression of CD44standard (CD44s), LFA-1 (CD11a, CD18), VLA-4 (CD49d, CD29) and ICAM-1 (CD54) was analysed on lymphoma cells in bone marrow infiltrates. The results were correlated to clinical data and overall survival. Our data demonstrate that the expression of LFA-1 on lymphoma cells is predictive for the prognosis of patients with advanced FCL. In detail, patients exhibiting weak to moderate expression (+/++) of CD11 and CD18 showed a significantly shorter median survival (51 months and 33 months, respectively) than did those presenting with strong expression ( ) of the LFA-1 adhesion molecule (P = 0.04 and P = 0.0051, respectively). Furthermore, multivariate analysis identified CD18 as a new independent prognostic factor in patients with advanced FCL. Our findings emphasize the relevance of adhesion molecules for the pathology of FCL and give further support for their impact on clinical course and overall survival.
Adult↗
A strong expression of CD44-6v correlates with shorter survival of patients with acute myeloid leukemia.
CD44 is a ubiquitous cell-surface glycoprotein that displays many variant isoforms (CD44v) generated by alternative splicing of exons 2v to 10v. The expression of variant isoforms is highly restricted and correlated with specific processes, such as leukocyte activation and malignant transformation. We have herein studied CD44v expression in acute myeloid leukemia (AML) and, for comparison, in normal myelopoiesis. Protein expression of total CD44 and of CD44-3v, -6v, and -9v isoforms has been measured using specific monoclonal antibodies and flow cytometry. The composition of variant exon transcripts has been analyzed by semi-quantitative reverse transcriptase-polymerase chain reaction followed by Southern hybridization with exon-specific probes. Our data show that (1) CD44-6v isoforms are expressed on 12.0% +/- 2.5% of normal CD34(+) cells; this expression is sharply upregulated through monopoiesis and, inversely, downregulated during granulopoiesis. Also, CD44-3v and CD44-9v isoforms are detected on 10% and 14% of normal monocytes, respectively. (2) Sixty-nine from a total of 95 AML patients display a variable proportion (range, 5% to 80%) of CD44-6v+ leukemic cells. (3) A shorter overall survival characterizes the group of AML patients displaying more than 20% of CD44-6v+ leukemic cells (8 months v 18 months, P < .02). These data suggest, for the first time, that the protein expression of CD44-6v containing isoforms may serve as a new prognostic factor in AML.
Acute Disease↗
Functional involvement of CD44, a family of cell adhesion molecules, in immune responses, tumour progression and haematopoiesis.
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Alternative Splicing↗
CD44 isoforms distinguish between bone marrow plasma cells from normal individuals and patients with multiple myeloma at different stages of disease.
CD44 variant isoforms (CD44v) have been shown to be important factors in adverse prognosis in hematological malignancies. To investigate whether CD44 expression is associated with malignant transformation in multiple myeloma, RNA and protein expression of CD44 standard (CD44s) and CD44v4, v6, v9, v10 containing isoforms was compared on bone marrow plasma cells from normal individuals and myeloma patients at different stages of disease. CD44s protein expression is strongly decreased on myeloma plasma cells and non-malignant B cells in affected bone marrow of myeloma patients, while no differences in CD44s expression were found between blood B cells from normal individuals and myeloma patients. CD44v isoforms were expressed on plasma cells in the majority of normal and myeloma samples analyzed. CD44v9 and v10 containing isoforms were differentially expressed on bone marrow plasma cells from normal individuals (predominantly CD44v9+v10+) and myeloma patients with stable (predominantly CD44v9-v10+) or progressive (predominantly CD44v9+v10- disease. Normal and myeloma plasma cells contained CD44 mRNA transcripts consisting of multiple CD44v exons. In addition, CD44v9 positive myeloma cells carried large CD44 transcripts. These results imply that detection of CD44v isoforms may be a valuable diagnostic tool for monitoring myeloma disease progression and response to treatment.
Bone Marrow Cells↗
Different CD44 splicing patterns define prognostic subgroups in multiple myeloma.
CD44 variant isoforms (CD44v) are generated by alternative splicing of the nuclear RNA resulting in the expression of additional protein domains in the extracellular region of the CD44 standard molecule (CD44s). In multiple myeloma (MM), CD44 mediates binding of tumor cells to stroma and regulates interleukin-6 production. To evaluate the role of CD44v isoforms in MM, CD44v expression was analyzed by immunohistochemical staining of 64 bone marrow biopsies from 38 MM patients. Expression of variant isoforms containing the 9v domain was observed in 36% of cases and was associated with an advanced stage (P < .02; n = 61), a progressive disease (P < .001; n = 61), and a shorter overall survival (P < .02; n = 36). In contrast, 3v, 4v, 6v, or 10v isoforms were detected only in a small percentage of the patients. To analyze the exon composition in RNA-transcripts, reverse transcriptase polymerase chain reaction analyses followed by Southern hybridization with exon-specific probes were performed in fluorescence-activated cell sorted myeloma plasma cells. Tumors expressing the 9v domain showed complex, 9v-containing transcripts in combinations with the 3v, 7v, 8v, and 10v exons. Identical transcripts were detected in several myeloma cell lines and in a Ki-1 B-immunoblastic lymphoma. Similar to high-grade non-Hodgkin's lymphoma and gastric and renal cell carcinoma, overexpression of 9v-containing isoforms in MM is related to an unfavorable clinical presentation and represents a new prognostic parameter.
Adult↗
An aggressive subtype of B-CLL is characterized by strong CD44 expression and lack of CD11c.
In a retrospective study based on 107 B-CLL patients, the expression of the adhesion molecules CD44, CD11a, CD11b, CD11c, CD18, CD25 and CD54 was analysed in bone marrow cryostat sections by immunohistochemistry. CD44 expression clearly identified two subgroups of B-CLL patients with different clinical course. In particular, CD44-positive patients presented with advanced disease, more often displayed a diffuse pattern of bone marrow infiltration, and had a worse prognosis. 33/61 patients positive for CD44 died within the observation period compared to 7/46 patients negative for CD44 (P = 0.0012). Multivariate analysis emphasized the independent prognostic value of CD44 expression for overall survival (P = 0.022). In contrast, patients positive for CD11c showed a longer survival, with 9/40 patients dying within the observation period compared to 31/67 negative for CD11c (P = 0.0013). Patients lacking CD11c were in advanced Rai and Binet stage. Multivariate analysis confirmed CD11c as a relevant independent prognostic marker (P = 0.033). Moreover, CD11c was able to separate patients with significantly different prognosis in the subgroup of CD44-positive cases. 4/18 patients positive for CD44 and CD11c died before median survival time was reached. Patients positive for CD44 but negative for CD11c had an adverse prognosis: 29/43 patients died, median survival time was 33.4 months. Our results indicate that CD44 positivity and CD11c negativity are associated with more advanced disease and worse prognosis in B-CLL and suggest CD44-positive/CD11c-negative cases represent a more aggressive form of the disease.
Adult↗
Prednimustine, mitoxantrone (PmM) vs cyclophosphamide, vincristine, prednisone (COP) for the treatment of advanced low-grade non-Hodgkin's lymphoma. German Low-Grade Lymphoma Study Group.
The current study was initiated to compare the anti-lymphoma activity and side-effects of prednimustine/mitoxantrone (PmM) vs cyclophosphamide, vincristine, prednisone (COP) in patients with advanced low-grade non-Hodgkin's lymphomas in way of a prospective randomized multicenter trial. Two hundred and forty-six patients with stage III or IV centroblastic-centrocytic (CB-CC (Kiel-classification)) or follicle center lymphoma (FCL (REAL classification)) and centrocytic (CC) or mantle-cell-lymphoma (MCL) were randomized for therapy with either PmM or COP and are fully evaluable for response and toxicity. PmM consisted of prednimustine 100 mg/m2/day on days 1-5 and mitoxantrone 8 mg/m2 /day days 1 and 2, while COP comprised cyclophosphamide 400 mg/m2/day on days 1-5, vincristine 1.4 mg/m2/day on day 1 and prednisone 100 mg/m2/day on days 1-5. Both regimens were repeated for a total of six cycles followed by an additional two courses for consolidation in responding cases and a subsequent second randomization for interferon alpha maintenance vs observation only. Overall response rates were comparable with 83% complete and partial remissions after COP and 84% remissions after PmM. PmM revealed a significantly higher rate of complete remissions (36 vs 18%, P < 0.006), the majority being achieved after four courses. The more rapid and possibly also more effective reduction of the lymphoma cell mass by PmM resulted in a tendency to a longer event-free interval for patients achieving remissions after PmM as compared to COP with estimated median event-free intervals of 31 vs 14 months, respectively (P=0.04). Separate analysis of lymphoma subtypes showed a tendency to a lower rate of complete remission in CC or MCL as compared to CB-CC or FCL (16 vs 30%, P=0.12, NS) while overall response rates were in a similar range (81 vs 85%). In both subtypes, PmM induced a higher rate of complete remission while overall response rates were comparable after PmM or COP. Treatment associated side-effects comprised predominantly myelosuppression and granulocytopenia in particular which was more frequently observed after PmM than COP (43 vs 31 %, P < 0.0001). This difference was clinically irrelevant, however, since serious infectious complications were encountered in less than 3% of cycles after both regimens. COP therapy was associated with a significantly higher incidence and degree of hair loss and complete alopecia (31 vs 2%) as well as of peripheral neurotoxicity (23 vs 2%). These data show that both PmM and COP reveal a high anti-lymphoma activity in patients with advanced stage non-Hodgkin's lymphoma. PmM appears advantageous with a higher rate of complete remissions and a better tolerability with regard to secondary side-effects. A longer follow-up is needed to assess the long-term effects of initial treatment on disease-free and overall survival and the impact on additional maintenance therapy with interferon alpha.
Adult↗
CD44 variant isoforms in non-Hodgkin's lymphoma: a new independent prognostic factor.
Isoforms of the transmembrane glycoprotein CD44, generated by alternative RNA splicing, have been correlated to tumor dissemination. For evaluation of the potential role of CD44 variant isoforms in non-Hodgkin's lymphoma (NHL), the presence of CD44 isoforms was analyzed in a large panel of reactive and neoplastic lymphoid tissues by immunohistochemical staining, as well as detection of CD44 variant RNAs by the reverse transcriptase-polymerase chain reaction. Whereas the CD44 standard or hematopoietic isoform (CD44s), devoid of the variant regions, was expressed in all leukocyte subpopulations, the variant isoforms (CD44v) showed a highly restricted pattern of expression, mainly observed in epithelial layers of lymphoid tissues and subpopulations of leukocytes after stimulation. In addition to a strong expression of CD44s, variant isoforms containing CD44-6v in combination with other variant exons were observed predominantly in aggressive lymphoma and were associated with a shorter overall survival of patients (n = 138; P < .0001). Moreover, multivariate analysis indicated CD44-6v as a new independent prognostic parameter in high grade NHL in comparison with the risk groups defined by the International NHL Lymphoma Prognostic Factors Project (N Engl J Med 329:987, 1993).
Adolescent↗
Are CD44 variant isoforms involved in human tumour progression?
The transmembrane glycoprotein CD44 exists in a variety of isoforms generated by alternative splicing of the pre-mRNA. In a rat metastasis model, certain variant isoforms (containing exon 6v) are causally involved in lung metastasis formation. We have summarized the data obtained to date on the expression of CD44 variant isoforms in human tumour progression. In non-Hodgkin lymphomas, expression of exon 6v containing isoforms is an independent prognostic factor indicating an adverse prognosis. Upregulation of exon 9v containing isoforms in gastric and renal cell carcinomas relates to a poor prognosis of patients. In colorectal carcinomas, CD44-9v isoforms are strongly expressed already in early adenomas; CD44-6v isoforms are upregulated in late adenomas along with ras and TP53 mutations. No expression of variant isoforms has been detectable in neuroblastomas, but significant downregulation of CD44s correlates inversely with tumour progression and N-myc amplification. Only in breast carcinoma has no correlation of CD44 expression with survival or any other prognostic marker been established. Evaluation of CD44 isoform expression by immunohistochemistry in cases of non-Hodgkin lymphoma, gastric, colon and renal cell carcinomas, as well as neuroblastomas, may be a useful diagnostic parameter indicating invasive processes.
Breast Neoplasms↗
Expression and modulation of CD44 variant isoforms in humans.
CD44 is a ubiquitous surface molecule that exists as a number of isoforms, generated by alternative splicing of 10 "variant" exons. Little is known about the expression and function of the variant isoforms, except that certain isoforms may play a role in cancer metastasis. We produced mAbs against CD44 variant regions encoded by exons 4v, 6v, and 9v, by immunizing mice with a fusion protein spanning variant exons 3v to 10v. A comprehensive analysis of human tissues revealed that CD44 variant isoforms were expressed widely throughout the body, principally by epithelial cells. However there was differential expression of CD44 variant exons by different epithelia. Most epithelia expressed exon 9v, but much fewer expressed 6v or 4v. The regions of epithelia that expressed the highest levels of the variant isoforms were the generative cells, particularly the basal cells of stratified squamous epithelium, and of glandular epithelium. CD44 variant isoforms were also expressed differentially by leukocytes, with CD44-9v expressed at very low levels and CD44-6v and 4v virtually absent. However, CD44-9v and CD44-6v were the main variants that were transiently upregulated on T cells after mitogenic stimulation and on myelomonocytic cell lines by TNF alpha and IFN gamma treatment. Some epithelial cell lines could preferentially upregulate CD44-6v upon IFN gamma incubation. These results show that CD44 variant isoforms are expressed much more widely than first appreciated, and that expression of the variant isoforms on some cell types can be modulated by particular cytokines.
Amino Acid Sequence↗