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ABSTRACT: In cancer patients, laboratory parameters that predict venous thromboembolism (VTE) are scarce. Increased platelet count has been found to be a risk factor for VTE in cancer patients receiving chemotherapy (CHT). We have assessed high platelet count as a risk predictor for VTE in patients with cancer undergoing discriminative anti-cancer treatments and investigated whether platelet count correlates with thrombopoietin (TPO) levels.
The Cancer and Thrombosis Study (CATS) is an ongoing prospective observational study of patients with newly diagnosed cancer or progression of disease, which started in October 2003. Occurrence of VTE and information on the patients' anti-cancer treatment during follow-up were recorded.
Between October 2003 and February 2008, 665 patients with solid tumors were included (314 female/351 male, mean age 62 years). VTE occurred in 44 patients (18 female/26 male, mean age 62 years). The cumulative probability of VTE after 1 year was 34.3% in patients with a platelet count (PC) above the 95th percentile representing 443 x 10(9)/L compared with 5.9% in those below 443 x 10(9)/L. High platelet count [hazard ratio (HR): 3.50, 95% confidence interval (CI): 1.52-8.06, P = 0.0032], soluble P-selectin [HR: 2.66, 95% CI: 1.42-4.96, P = 0.0021] and surgery [HR: 4.05, 95% CI: 1.74-9.46, P = 0.0012] were statistically significant risk factors for VTE in multivariable analysis along with leucocyte count, age, gender, radio- and CHT. We found no correlation between platelet count and TPO levels.
High PC is a clinically important, independent risk predictor for VTE in cancer patients. PC was not found to be associated with TPO levels.
Journal of Thrombosis and Haemostasis 11/2009; 8(1):114-20. · 5.73 Impact Factor
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ABSTRACT: The prognosis of chronic lymphocytic leukaemia (CLL) patients is largely determined by the karyotype of the malignant clone. We have investigated the gene expression profile associated with trisomy 12 (+12).
Initially, unselected peripheral blood mononuclear cells of four patients with +12 were compared with 16 CLL controls using microarray analysis.
were validated by quantitative real-time PCR with RNA from 61 patients (29 with +12, 32 CLL controls). Results Seven genes showing the strongest correlation with +12 in microarray analysis were selected for real-time PCR: HIP1R, MYF6, SLC2A6, CD9 (overexpressed); CD200, P2RY14, RASGRP3 (underexpressed). Four genes were significantly associated with +12: HIP1R (P<0.0001), MYF6 (P=0.007), P2RY14 (P=0.014), CD200 (P=0.028). Receiver Operating Characteristic curve analysis revealed that HIP1R expression was a highly sensitive and specific marker for +12 in CLL patients. MYF6 was exclusively expressed in normal or malignant B cells in peripheral blood but was poorly predictive for +12. As expected, a number of overexpressed genes are located on chromosome 12 (HIP1R, MYF6). Interestingly, both significantly underexpressed genes (P2RY14, CD200) reside on the long arm of chromosome 3 pointing to trans-repression in this region.
Analysis of the molecular signature of trisomy 12 in CLL resulted in: (i) identification of a surrogate marker for PCR (HIP1R); (ii) observation of a gene dosage effect; and (iii) detection of specific underexpression of genes located on chromosome 3. These results should help to improve diagnosis and treatment decisions for patients with CLL and trisomy 12.
European Journal of Clinical Investigation 05/2009; 39(7):568-75. · 3.02 Impact Factor
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ABSTRACT: As patients with B-cell lymphomas suffering from an underlying autoimmune condition undergoing therapy with the CD20 antibody rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP) offer the unique possibility of monitoring effects of therapy on various rheumatologic parameters, we have evaluated serologic autoimmune markers and the clinical outcome of patients with autoimmune diseases (ADs) who received lymphoma treatment with R-CHOP during the course of their disease.
We have retrospectively analysed 13 patients with non-Hodgkin's lymphoma who concurrently suffered from ADs and were treated with the R-CHOP regimen. Subjective parameters along with rheumatoid factor (RF) and antinuclear antibodies (ANA) were serially measured.
The median levels of RF were 901 IU/ml [inter-quartile-range (IQR) 189-2520] before and 75 IU/ml (IQR 45-644) after therapy (P = 0.028). The median levels of ANA were 800 (IQR 140-2560) before and 100 (40-1280) after therapy (P = 0.027). Ten (77%) patients showed clinical improvement of their autoimmune symptoms, two (15%) reported no difference and one (7%) patient with rheumatoid arthritis-related worsening symptoms during therapy with R-CHOP. The autoimmune-related symptoms recurred after a median time of 7 weeks (IQR 6-8) in seven patients. In terms of lymphoma response, 11 patients achieved a complete remission and two a partial remission.
This analysis indicates that R-CHOP given for lymphoma treatment is also effective for therapy of concurrent rheumatoid diseases. Both rheumatoid parameters as well as clinical symptoms showed a significant decrease during treatment with this immunochemotherapy. The effects on the rheumatic diseases, however, seem to be of limited duration.
Annals of Oncology 05/2007; 18(4):647-51. · 6.43 Impact Factor
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ABSTRACT: 18F-fluoro-deoxy-glucose positron emission tomography (18F-FDG-PET) has become a routine measure for staging and follow-up of patients with aggressive lymphoma. By contrast, its usefulness to visualize indolent lymphomas characterized by a lower cellular turnover has not clearly been defined. We have investigated accuracy and clinical usefulness of 18F-FDG-PET in patients with follicular lymphoma (FL).
A total of 64 patients with FL WHO grade I - III (48, 5, and 11 patients) were imaged at our institution to assess the value of 18F-FDG-PET for imaging of FL of different gradings. A total of 115 scans (48 before therapy and 67 for response assessment after treatment) were performed, and findings were compared to conventional staging including CT-scan of thorax and abdomen, sonography of lymph nodes and bone marrow biopsy.
Overall, 18F-FDG-PET had a sensitivity of 98%, a specificity of 94%, a positive predictive value of 95% and a negative predictive value of 98%. These results were significantly more accurate (P = 0.023) than the conventional radiology studies. There was no significant difference (P = 0.093) in the accuracy between patients with indolent (WHO grade I and II) versus aggressive FL (WHO grade III).
18F-FDG-PET scan is a reliable method for staging and follow up of patients with nodal FL irrespective of tumor grading.
Annals of Oncology 06/2006; 17(5):780-4. · 6.43 Impact Factor
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ABSTRACT: The prognostic value of the detection of peripheral blood (PB) and/or bone marrow (BM) involvement by polymerase chain reaction (PCR) amplification of rearranged immunoglobulin heavy chain (IgH) and immunoglobulin kappa light chain (Igkappa) genes was evaluated in 155 patients with diffuse large B-cell lymphomas (DLBCL). Immunoglobulin gene rearrangements (IgR) were detected in 35/155 (23%) patients. The presence of IgR in PB/BM was related to clinical stage (CS I-III vs CS IV; P<0.001), histopathological detection of BM involvement (P<0.001), and the International Prognostic Index (P<0.001). IgR-positive cases had a significantly lower complete remission (CR) rate (18/35, 51%) than IgR-negative patients (85/120, 71%; P=0.042), and a significantly poorer overall survival (OAS) at 5 years (25 vs 66%; P<0.001). There was a significant difference in the estimated OAS at 5 years between patients with negative BM histology and negative PCR results (66%), patients with negative BM histology but positive IgR (37%), and patients with positive BM histology (12%). Our results indicate that molecular methods improve the accuracy of staging in patients with DLBCL and define a group of patients with normal bone marrow histology who have a significantly poorer OAS due to molecular detection of PB/BM involvement.
Leukemia 06/2004; 18(6):1102-7. · 9.56 Impact Factor
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I Simonitsch-Klupp,
I Hauser,
G Ott,
J Drach,
J Ackermann,
J Kaufmann,
A Weltermann,
H T Greinix,
C Skrabs,
C Dittrich,
D Lutz,
R Pötter,
C Mannhalter,
K Lechner,
A Chott, U Jaeger
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ABSTRACT: To define reproducible criteria for subgroups of diffuse large B-cell lymphomas (DLBCL), including lymphomas with plasmablastic/plasmacytoid features (PB/PC-Fs), we investigated 66 DLBCL; the samples were categorized as either centroblastic (CB), immunoblastic (IB) or PB/PC-F applying standardized morphologic criteria. Blinded specimens were reviewed by three independent pathologists. The final consensus classification included 44 CB (67%), seven IB (10%) and 15 PB/PC-F (23%). The interobserver agreement between two centers (Vienna, Würzburg) was 93.5%. Most PB/PC-F were CD20+, cIgM+, MUM-1+, CD138+/-, bcl-6-, corresponding to an activated B-cell phenotype. Immunoglobulin-V(H) gene mutation analysis was consistent with a germinal or postgerminal center-cell origin. By fluorescence in situ hybridization analysis, 11/13 (85%) PB/PC-F had a monoallelic TP53 deletion. The pretreatment characteristics of patients with PB/PC-F included a tendency for more B symptoms, extranodal disease and a higher IPI. Importantly, PB/PC-F were resistant to standard chemotherapy (complete remission rate 47%, relapse rate 71%) and even autologous stem-cell transplantation. The median overall survival (OS) (14 months, P<0.002) and disease-free survival (6 months, P=0.02) were significantly shorter compared to patients with CB and IB. The OS difference was pronounced within the low and low-intermediate IPI risk group (P<0.001). Our data indicate a strong association of plasmablastic/plasmacytoid morphology with TP53 deletions, poor response to chemotherapy and short survival.
Leukemia 01/2004; 18(1):146-55. · 9.56 Impact Factor
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ABSTRACT: Lymphomas have represented an indication for nuclear medicine investigations for 30 years. Gallium-67 scintigraphy has been shown to be a valuable complementary method in Hodgkin's disease and non-Hodgkin lymphoma for detecting viable residual lesions after chemotherapy and for diagnosis of a relapse. Thallium-201 is of interest in differentiating cerebral lymphomas from infectious lesions in AIDS patients but less useful in extra-cerebral lymphomas. PET with fluorine-18-FDG is more accurate than 67Ga in lymphoma. In patients with a positive PET scan after chemotherapy an early relapse occurs in up to 100%, while more than 80% of patients with a negative PET will have a long-term remission. Most studies show that FDG-PET is significantly correlated with patient outcome whereas there is much weaker or even no correlation for CT. The main reason is that PET is not bound to morphological criteria like lymph node size while CT is often not able to differentiate between residual tumour and post-therapeutic fibrosis. Therefore, based on a considerable number of clinical studies, FDG-PET gains increasing significance for staging, restaging and therapy monitoring in malignant lymphomas.
The quarterly journal of nuclear medicine: official publication of the Italian Association of Nuclear Medicine (AIMN) [and] the International Association of Radiopharmacology (IAR) 04/2003; 47(1):14-21.
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ABSTRACT: Detection of minimal residual disease (MRD) by polymerase chain reaction (PCR) has become an essential tool for molecular monitoring of acute myeloid leukemia (AML). Currently, specific translocation markers are available for 40-50% of AMLs. Expression markers may widen this spectrum to 70-90%. Quantitative PCR (Q-PCR, real-time PCR) is now as sensitive as conventional two-step PCR and could improve as well as facilitate clinical decision-making. Q-PCR has been applied to a variety of molecular markers, delineating threshold levels early after induction therapy, for postinduction monitoring, as well as for the detection of relapse. For most markers, lack of decline of transcript levels by less than 2 logs after chemotherapy has been established as a poor prognostic sign. Moreover, increases in transcript levels are almost invariably associated with relapse. However, the predictive value of PCR negativity after chemotherapy is not as clear. The major tasks for the future will be standardization of Q-PCR techniques, exact definition of threshold levels, and monitoring schedules in bone marrow (BM) and peripheral blood (PB), as well as investigation of novel markers found by microarray analysis.
Annals of Hematology 04/2003; 82(3):139-47. · 2.62 Impact Factor
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O Parolini,
B Kagerbauer,
I Simonitsch-Klupp,
P Ambros, U Jaeger,
G Mann,
O A Haas,
M Morra,
H Gadner,
C Terhorst,
W Knapp,
W Holter
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ABSTRACT: Mutations or deletions in the SH2D1A (src homology 2 domain protein 1A) gene result in a severe immunodeficiency called X-linked lymphoproliferative (XLP) disease. XLP is primarily characterized by a defective immune response against the Epstein-Barr virus (EBV), resulting in an unusually severe and often fatal clinical course following EBV infection. The second major cause of death is the development of B cell lymphomas, both in EBV-infected and EBV-negative patients. To study whether the clinical manifestation of XLP gene defects and/or polymorphisms extends beyond the classically recognized phenotype, we analyzed patients for the presence of SH2D1A gene alterations who presented with fatal or nonfatal, yet unusually severe or chronic EBV infections, and other possibly EBV-associated diseases, such as Hodgkin's lymphomas or nonendemic Burkitt's lymphomas and Burkitt-type leukemias. We identified mutations of the SH2D1A gene only in the majority of patients presenting with fatal mononucleosis or an XLP family history, but not in any of the other patients studied. The only alteration determined was a polymorphism in the 5' region of the SH2D1A gene both in patient groups as well as in controls.
Annals of Hematology 09/2002; 81(8):441-7. · 2.62 Impact Factor
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ABSTRACT: We have determined the predictive value of [18F]2-fluoro-2-deoxy-glucose (FDG-PET) in patients with Hodgkin's disease (HD) and aggressive non-Hodgkin's lymphoma (NHL) scheduled for high-dose therapy with stem cell transplantation (HDT/SCT). Inclusion criteria were the presence of an FDG-PET scan after chemotherapy (ChT) within 8 weeks prior to HDT/SCT and available follow-up data. Sixteen patients (10 NHL and six HD) were observed during a follow-up period of 4 to 28 months (median 13 months). Before SCT, five patients had a negative PET, three were weakly positive, two moderately positive, and six strongly positive. None of the five patients with a negative PET before HDT/SCT relapsed and two of three patients with a weakly positive scan are still in remission after HDT/SCT. Of eight patients with a moderate or high positive PET before HDT/SCT, seven relapsed and one died of early HDT/SCT related complications (P< 0.01). Three of eight relapsing patients died of lymphoma 5 to 10 months after SCT and in one additional patient not responding to HDT/SCT, the main cause of death was chronic toxicity 4 months after transplantation. After 12 months, in PET-negative patients the overall and relapse-free survival was 100%, in PET-positive patients 55% and 18%, respectively. In NHL, two patients with negative PET, but with an age-adjusted international prognostic index (AaIPI) of 2 and one with AaIPI = 1 are still in remission. In the seven PET-positive subjects, one patient with AaIPI = 0, three with AaIPI = 1, and two with AaIPI = 2 relapsed. We conclude that FDG-PET is accurate in the prediction of relapse prior to HDT/SCT in patients with lymphoma. It provides additional information when compared with the AaIPI.
Leukemia 03/2002; 16(2):260-7. · 9.56 Impact Factor
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ABSTRACT: T(14;18) chromosomal translocation is assumed to result from illegitimate rearrangement between the BCL2 proto-oncogene and the IGH locus during the D(H) to J(H) joining phase of V(D)J recombination in early B cells. Analysis of the breakpoint junctions suggests that translocation derives from the fusion between normal V(D)J recombination intermediates at the IGH locus and non-V(D)J-mediated broken-ends at the BCL2 locus. So far, BCL2 broken-ends have only been observed fused to coding-ends, raising questions concerning the molecular constraints of the illegitimate joining process. Using a combination of genome walking and long-range PCR assays, we describe in this report that in 4.5% (2/44) of the t(14;18), one of the BCL2 broken-ends is fused to a signal-end. The formation of these J(H)RSS/BCL2 junctions provides direct evidence that BCL2 broken-ends are capable of joining to both products of V(D)J recombination, suggesting their presence in the RAG-mediated post-cleavage complex. In addition, junctions generated by this alternative end-joining do not involve deletion of the chromosome 14 intervening sequences generally lost in the standard translocation, providing a unique opportunity to investigate the rearrangement status of this region in the translocated IGH allele. In both cases, a DJ(H) rearrangement could be detected 5' of the J(H)-RSS/BCL2 junction. These findings, together with the previously reported bias towards the most external D(H) and J(H) segments in standard breakpoints, strongly suggest that t(14;18) preferentially occurs during an attempted secondary D(H) to J(H) rearrangement. This unusual and restricted window of differentiation opens intriguing questions concerning the etiology of the translocation.
Leukemia 02/2002; 16(1):120-6. · 9.56 Impact Factor
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M Mitterbauer,
P Neumeister,
P Kalhs,
S Brugger,
G Fischer,
K Dieckmann,
P Hoecker,
W Hinterberger,
W Linkesch,
I Simonitsch, U Jaeger,
K Lechner,
C Mannhalter,
G Mitterbauer,
H T Greinix
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ABSTRACT: From 1987 to 1999 35 patients with poor prognosis non-Hodgkin's lymphoma (NHL) underwent allogeneic stem cell transplantation (SCT) at the University Hospitals of Vienna and Graz. Initial biopsy specimens were reclassified according to the Revised European-American Classification of Lymphoid Neoplasms (REAL). All patients surviving 28 days engrafted. Twenty-eight of them (93%) attained clinical remission. At the last follow-up 14 patients were alive and disease-free at a median of 5.0 (range, 2.3-12.9) years after allogeneic SCT. The actuarial overall survival is 35%. Five patients relapsed 1.8 to 27.6 months after transplant, the probability of relapse is 23%. Of the 21 deaths following SCT, seven were due to relapse/refractory disease and 14 due to transplant-related causes. The probability of treatment-related mortality is 48%. After SCT, minimal residual disease (MRD) was monitored by polymerase chain reaction (PCR) in seven patients with a BCL-2/IgH translocation and in 13 with a clonal immunoglobulin heavy chain (IgH) rearrangement. All 20 patients attained clinical remission rapidly and converted to PCR negativity. In the follow-up nine of these patients are in long-term clinical and molecular remission, six PCR-negative patients died of transplant-related causes and five patients relapsed. In summary, allogeneic stem cell transplantation has a curative potential for patients with refractory and recurrent non-Hodgkin's lymphoma. In our series long-term disease-free survival was associated with molecular disease eradication after SCT. Treatment-related mortality rate was high, thus earlier referral of selected patients to allogeneic SCT should be considered.
Leukemia 05/2001; 15(4):635-41. · 9.56 Impact Factor
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N Welzel,
T Le,
R Marculescu,
G Mitterbauer,
A Chott,
C Pott,
M Kneba,
M Q Du,
R Kusec,
J Drach,
M Raderer,
C Mannhalter,
K Lechner,
B Nadel, U Jaeger
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ABSTRACT: The t(11;14)(q13;q32) between the BCL-1 and immunoglobulin heavy chain gene (IgH) loci in mantle cell lymphoma (MCL) are believed to be mediated by the mechanism of V(D)J recombination similar to the t(14; 18) in follicular lymphoma (FL). We have recently shown that the t(14;18) event creates staggered double-strand breaks in the BCL-2 locus, and that the t(14;18) junctions contain templated nucleotide insertions (T-nucleotides; U. Jäger et al., Blood, 95: 3520-3529, 2000). Reasoning that the earlier (pregerminal center) B-cell origin of MCL might be reflected in a different molecular structure of the chromosomal breakpoints, we PCR-amplified diagnostic samples from 93 patients. Thirty-six samples (39%) were positive for the direct (BCL-1/J(H)) and 23 for both direct and reciprocal (D(H)/BCL-1) junctions. The breaks on chromosome 14 exhibited features of V(D)J-mediated recombination as shown by D(H) and J(H) coding end processing. However, duplications of BCL-1 sequences in 39% of the 23 patients indicate staggered double-strand breaks in the major translocation cluster region (MTC). This is incompatible with V(D)J recombination and indicates a different mechanism of cleavage. The use of J(H)6 in the junctions (39%) was similar to that in the immunoglobulin genes of normal B cells and B-CLL, but considerably less than in FL. Only 2 of 36 samples contained a BCL-1/DJ(H) rearrangement, which was indicative of a previous DJ(H) rearrangement. Most importantly, 19% of the BCL-1/IgH junctions with inserts of > or =5 nucleotides contained error-prone copies (T-nucleotides) of 8-12 nucleotides originating from the surrounding BCL-1 or IgH regions, a lower rate than in FL. No correlation was found between the addition of T-nucleotides and the rate of somatic mutation in the immunoglobulin genes. We conclude that the t(11;14) and t(14;18) use the same basic mechanism of translocation including V(D)J-mediated recombination, double-strand staggered breaks, and template-dependent, error-prone DNA-synthesis. However, the distinct differences in the utilization of J(H) regions suggest that the t(11;14) occurs predominantly during an attempted primary D(H)-J(H) rearrangement in early B cells, whereas the t(14;18) mostly occurs during secondary rearrangement. This is in agreement with the pregerminal center B-cell origin of MCL.
Cancer Research 03/2001; 61(4):1629-36. · 7.86 Impact Factor
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B Stoiser,
P Knöbl,
C Fonatsch,
O A Haas,
G Mitterbauer,
A Weltermann,
K Geissler,
P Valent,
W Sperr,
I Pabinger,
K Lechner, U Jaeger
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ABSTRACT: Recurrence of the disease is the major problem in the treatment of acute myeloid leukemia (AML). The majority of patients who achieve a second remission will ultimately relapse. In this retrospective single-center study, we have analyzed the outcome of patients with a second relapse and tried to define the prognostic factors in intensively treated patients. Of 534 patients with AML, 62 had a second relapse. Thirty-three received further intensive chemotherapy (CT). Eighteen patients (55%) achieved a third complete remission (CR). The early death (ED) rate was only 9%. The overall survival (OS) of treated vs untreated patients was 6.9 vs 1.3 months, respectively (P = 0.01). The major selection criteria for a third CT were a favourable (t(15;17),t(8;21),inv(16)) or normal karyotype, long (>11 months) second CR (P < or = 0.005) and no previous bone marrow transplantation (BMT)(P < 0.01). Favorable or normal karyotype, second CR >11 months, as well as no previous BMT (P < 0.01) were associated with the achievement of a third CR. Favorable (P < 0.005) or normal karyotype (P < 0.01), as well as a second CR >11 months (P < 0.005) were associated with prolonged survival after CT. The median OS for patients receiving CT with favorable or normal cytogenetics, a second CR > 11 months, but no previous BMT was 26.5 months. Five patients with favorable or normal karyotype achieved a fourth or fifth remission. We conclude that intensive CT is associated with a survival benefit and good quality of life if patients are properly selected.
Leukemia 12/2000; 14(12):2059-63. · 9.56 Impact Factor
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ABSTRACT: Drug resistance of non-Hodgkin's lymphomas may involve mechanisms of the multidrug resistance phenotype including the lung resistance protein (LRP) and the multidrug resistance protein (MRP1). To determine the clinical relevance of these multidrug resistance factors in previously untreated diffuse large B-cell lymphomas (n = 48), we studied LRP and MRP1 expression in lymphoma cells and their impact on clinical outcome. LRP and MRP1 expression were immunohistochemically assessed by means of the monoclonal antibodies LRP-56 and MRPr1, respectively. LRP was positive in 23% and MRP1 in 44% of the samples. LRP expression was associated with higher tumor stage (P = 0.03), elevated serum lactate dehydrogenase levels (P = 0.01), and the International Prognostic Index (P = 0.0001). LRP-positive patients had a lower complete response rate to polychemotherapy than LRP-negative patients (18 versus 65%; P = 0.006). Patients with LRP expression had a shorter overall survival than those without LRP expression (median of 0.9 years versus median not reached; P = 0.001). MRP1 expression was independent of clinical and laboratory parameters and had no impact on the outcome of chemotherapy or survival of the patients. These data suggest that LRP expression but not MRP1 expression is an important mechanism of drug resistance associated with worse clinical outcome in previously untreated diffuse large B-cell lymphomas. Thus, the reversal of LRP-mediated drug resistance may improve clinical outcome in diffuse large B-cell lymphoma in the future.
Clinical Cancer Research 10/2000; 6(9):3417-23. · 7.74 Impact Factor
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A Borkhardt,
S Bojesen,
O A Haas,
U Fuchs,
D Bartelheimer,
I F Loncarevic,
R M Bohle,
J Harbott,
R Repp, U Jaeger,
S Viehmann,
T Henn,
P Korth,
D Scharr,
F Lampert
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ABSTRACT: We have isolated the human GRAF gene (for GTPase regulator associated with the focal adhesion kinase pp125(FAK)). This gene was fused with MLL in a unique t(5;11)(q31;q23) that occurred in an infant with juvenile myelomonocytic leukemia. GRAF encodes a member of the Rho family of the GTPase-activating protein (GAP) family. On the protein level, it is 90% homologous to the recently described chicken GRAF gene that functions as a GAP of RhoA in vivo and is thus a critical component of the integrin signaling transduction pathway. The particular position of the human GRAF gene at 5q31 and the proposed antiproliferative and tumor suppressor properties of its avian homologue suggest that it also might be pathogenetically relevant for hematologic malignancies with deletions of 5q. To investigate this possibility, we sequenced 4-5 individual cDNA clones from 13 cases in which one allele of GRAF was deleted. We found point mutations within the GAP domain of the second GRAF allele in one patient. In two additional patients we found an insertion of 52 or 74 bp within the GRAF cDNA that generates a reading frame shift followed by a premature stop codon. GRAF maps outside the previously defined commonly deleted 5q31 region. Nevertheless, inactivation of both alleles in at least some cases suggests that deletions and mutations of the GRAF gene may be instrumental in the development and progression of hematopoeitic disorders with a del(5q).
Proceedings of the National Academy of Sciences 09/2000; 97(16):9168-73. · 9.68 Impact Factor
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E Reiter,
H Greinix,
W Rabitsch,
F Keil,
I Schwarzinger, U Jaeger,
K Lechner,
N Worel,
B Streubel,
C Fonatsch,
G Mitterbauer,
P Kalhs
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ABSTRACT: Structural rearrangements of the long arm of chromosome 3 involving bands 3q21 and 3q26 and leading either to a paracentric inversion inv (3)(q21q26) or a translocation between both homologous chromosomes--t(3;3)(q21q26)-- have been reported in patients with acute myelogenous leukemia (AML), myelodysplastic syndromes, myeloproliferative disorders, and chronic myelogenous leukemia in blast crisis. We describe three patients with de novo AML with these structural abnormalities who received multiple courses of conventional chemotherapy followed by unrelated donor (n=2) and autologous (n = 1) bone marrow transplantation (BMT). All three patients had early relapse: patients 1 and 2 had relapse 69 days and 306 days after BMT, respectively, and patient 3 immediately after autologous BMT. Despite further chemotherapy, they died without achieving another remission. These findings, together with other recorded similar cases, show that AML with structural abnormalities of the long arm of chromosome 3 as described has an extremely poor prognosis even with the most potent anti-leukemic treatment modalities.
Annals of Hematology 08/2000; 79(7):374-7. · 2.62 Impact Factor
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M Mitterbauer,
K Laczika,
M Novak,
G Mitterbauer,
B Hilgarth,
H Pirc-Danoewinata,
I Schwarzinger,
O A Haas,
C Fonatsch,
K Lechner, U Jaeger
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ABSTRACT: Identification of the inversion 16 in patients with acute myeloid leukemia (AML) is of great practical value since these patients have a relatively favorable prognosis, especially when treated with high-dose cytarabine. We compared the results of cytogenetic analysis and reverse transcriptase-polymerase chain reaction (RT-PCR) for core binding factor (CBF) beta/myosin heavy chain (MYH11) in 241 unselected cases of AML. In contrast with other studies, we found a high concordance between these 2 methods. Eighteen of 241 patients showed a cytogenetic anomaly of the chromosome 16. We detected the fusion transcript by RT-PCR in all 18 cases and in 2 additional patients with AML without any cytogenetic anomaly of chromosome 16. One patient had a normal diploid karyotype, and the second patient showed a trisomy 22 in karyotype analysis, which often is associated with inv(16). Only 8 of 20 CBF beta/MYH11-positive patients had M4Eo morphologic features. The much higher discrepancy between cytogenetic analysis and RT-PCR in other studies, especially in AMLs other than M4Eo, possibly indicates the necessity for PCR screening regardless of the French-American-British classification.
American Journal of Clinical Pathology 04/2000; 113(3):406-10. · 2.60 Impact Factor
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ABSTRACT: The benefit of all-trans-retinoic acid (ATRA) in the front line therapy of acute promyelocytic leukemia (APL) is well established, but its role in postremission therapy and in the treatment of relapse is currently under investigation. Moreover, the impact of cytosine arabinoside (Ara-C) in the therapy of APL has been questioned in recent studies. We report a prolonged third molecular remission (MR) in a patient with hyperleukocytotic APL after induction with ATRA, consolidation chemotherapy (CT) with intermittent intermediate dose Ara-C and maintenance therapy with intermittent ATRA. While the first two remissions were relatively short (8 months and 11 months, resp.), the duration of the third continuous CR (49+ months) is more than twice as long as the length of the two previous remissions combined. In this case Ara-C followed by intermittent ATRA maintenance was a safe and effective therapy for relapsed disease. A third molecular remission of such duration and quality is unusual.
Leukemia and Lymphoma 03/2000; 36(5-6):625-9. · 2.58 Impact Factor
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ABSTRACT: Twenty-seven patients with AML and MLL gene rearrangement were analyzed by a reverse transcriptase polymerase chain reaction (RT-PCR) for the MLL-AF9 translocation. The MLL-AF9 fusion transcript was detected in six patients. In five patients, the breakpoint of the AF9 gene was located within the recently described site A; in one patient, a novel breakpoint (AF9 site D) mapped to a position 377 bp 3' of site A. Five patients could be serially monitored for a period of 4-23 months. Two patients became two-step PCR negative in bone marrow and peripheral blood. Molecular remission was achieved rapidly after one cycle of induction chemotherapy. Both patients are in continuous complete remission (CR) at 22 and 15 months, respectively. Two patients who had achieved hematological CR did not become PCR negative and MLL-AF9 fusion transcripts were detectable in all samples after induction and consolidation chemotherapy. One patient relapsed 5 months after achieving CR. The other patient received allogeneic bone marrow transplantation from an HLA-identical sibling 2 months after achieving hematological CR and became PCR negative 4 weeks after transplantation. In the fifth patient, hematological CR could not be achieved with two cycles of intensive induction chemotherapy, and MLL-AF9 transcripts were present in all samples tested. Our data indicate that MLL-AF9 RT-PCR is specific for the t(9;11) translocation. PCR negativity can be achieved in responding patients already 1 month after induction chemotherapy. The fast reduction of MLL-AF9 positive blast cells below the detection limit of RT-PCR seems to be a prerequisite for long-term CR. The results of RT-PCR may be useful for treatment decisions (eg BMT).
Leukemia 11/1999; 13(10):1519-24. · 9.56 Impact Factor
