Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.10.2 (focal adhesion kinase)
44,029 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Results for adult ALL have improved, with CR rates of 68% to 91% and a cure rate of 25% to 41%. The outcome for patients with T-ALL has especially improved, and the major drugs responsible are C and ara-C. Outcome for B-ALL has improved by using short intensive cycles including, among other drugs, C and high-dose MTX. The inferior outcome of adult ALL compared with childhood ALL seems related to the high proportion of Ph1/BCR-ABL positive ALL patients, which constitute about 30% in adults versus less than 5% in children. The major prognostic factors for survival in adult ALL are age, time to achieve CR, cytogenetic abnormalities, immunologic subtype, and WBC; these may serve as a guide for BMT in first CR. New approaches in the treatment of adult ALL include the use of HGFs, the use of biologic response modifiers, and the detection of MRD to tailor treatment decisions.
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PMID:Therapy of the newly diagnosed adult with acute lymphoblastic leukemia. 844 56

We sequentially performed cytogenetic analysis and RT-PCR analysis of BCR-ABL transcripts in 17 cases of Ph1-positive ALL who had achieved hematological complete remission (CR) with intensive chemotherapy (CT). Sixteen cases were studied prospectively. All but one of the patients had reached cytogenetic CR, but cytogenetic has low sensitivity in predicting relapse. Twelve patients relapsed, three died in first CR and two were alive in first CR. Two of five, two of four, and five of nine patients who were allografted (in first or second CR), autografted and received consolidation CT, respectively, achieved negative two-round PCR in the bone marrow (BM): three died in CR, three remained in CR with negative two-step PCR in the BM and three relapsed after 22 to 28 months. In all cases, relapse was preceded by switch to PCR positivity in the BM by 4 to 6 months. The remaining nine patients remained PCR-positive in the BM and relapsed after 2 to 16 months. In the four autografted cases, PCR was positive at the time of bone marrow harvest. The two patients who received a purged transplant achieved negative PCR and prolonged CR, whereas the two patients who received an unpurged transplant remained PCR positive and relapsed. In 34% of the samples where analysis was concomitant, sensitivity of PCR proved lower in the blood than in the BM. These findings show that RT-PCR is a useful tool in the monitoring of MRD in Ph1 positive ALL.
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PMID:Good correlation between RT-PCR analysis and relapse in Philadelphia (Ph1)-positive acute lymphoblastic leukemia (ALL). 900 95

Chronic myeloid leukaemia (CML) can be treated successfully with allogeneic bone marrow transplantation (BMT) leading to long-term disease-free survival. Leukemia relapse, however, remains a significant clinical problem. Relapse following BMT presumably results from the expansion of small numbers of recipient leukaemic cells which have survived the conditioning therapy. In order to define patients who are at a high risk of leukaemia relapse, a variety of techniques have been employed to detect persistence of host haemopoiesis (mixed chimaerism, MC) or residual leukaemia (minimal residual disease, MRD). However, the precise relationship between the detection of MC and MRD post-BMT is unknown. We have investigated chimaerism and MRD status in 22 patients who were in clinical and haematological remission post-allogeneic BMT for chronic phase CML. Chimaerism was assessed using short tandem repeat PCR (STR-PCR) while BCR-ABL mRNA detection using reverse transcriptase polymerase chain reaction (RT-PCR) was performed to detect the presence of MRD. Seventeen patients received unmanipulated marrow (non-TCD) while in five patients a T cell-depleted transplant (TCD) was performed as additional GVHD prophylaxis. Chimaerism was evaluated in 18 patients (14 non-TCD, four TCD). Mixed chimaerism was an uncommon finding in recipients of unmanipulated BMT (21%) when compared to TCD BMT (100%). No evidence of MRD, as identified using the BCR-ABL mRNA RT-PCR assay, was detected in those patients who were donor chimaeras. Early and transient MC and MRD was detected in four patients (two non-TCD, two TCD) who have subsequently converted to a donor profile. One patient has stable low-level MC but remains MRD negative 4 years post-BMT. Late MC and MRD was observed in two patients who relapsed >6 years after TCD BMT for CML. We conclude that mixed chimaerism is a rare event in recipients of unmanipulated BMT and that donor chimaerism as detected by STR-PCR assay is consistent with disease-free survival and identifies patients with a low risk of leukaemic relapse post-BMT for CML.
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PMID:Persistent donor chimaerism is consistent with disease-free survival following BMT for chronic myeloid leukaemia. 925 92

The detection of BCR-ABL specific RNA by RT-PCR has been shown to predict relapse when positive 6 months after allogeneic stem cell transplantation (SCT) for chronic myelogenous leukemia (CML). In the present study, the focus was on evaluation of residual disease during the first weeks following SCT. In this study, 177 blood or marrow samples were obtained from 33 patients who received allogeneic (20 patients) or autologous (13 patients) SCT on day 0, day 30 and every 3 months for 1 year. T-cell depletion (TCD) was performed in 4 cases. On day 0 (day of graft infusion), 10/30 evaluable patients had negative RT-PCR (33%) regardless of pretransplant characteristics. On day 30, 14/18 patients (77%) from the allogeneic group had negative RT-PCR versus 0% in the autologous group. 2/4 patients who received TCD allogeneic grafts had day 30-positive PCR. Five patients in the allogeneic group had at least one positive RT-PCR sample between day 30 and day 90: 3 of them subsequently relapsed suggesting possible correlation between early positivity and relapse. Our results show that disappearance of MRD can be achieved within 3 months after transplantation in the majority of patients treated with allogeneic but not after autologous SCT. This suggests that the GVL effect might be operational early during the first weeks following transplantation.
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PMID:Survey of early disapearance of BCR/ABL fusion transcript after allogeneic or autologous stem cell transplantation for chronic myelogenous leukemia. 1169 49

The accuracy of cytogenetic diagnosis in the management of hematological malignancies has improved significantly over the past 10 years. Fluorescence in situ hybridization (FISH), a technique of molecular cytogenetics, has played a pivotal role in the detection of unique sub-microscopic chromosomal rearrangements that helped in the identification of chromosomal loci, which contain genes involved in leukemogenesis. We studied the feasibility and sensitivity of the FISH technique for molecular analysis of translocations markers, t(9;22) and t(15;17) for accurate molecular diagnosis and for monitoring the disease in 21 patients with chronic myeloid leukemia (CML) who received interferon-alpha and/or chemotherapy (7 patients), bone marrow transplantation (14 patients), and 14 patients with acute promyelocytic leukemia (APL) who received all-trans-retinoic acid (ATRA) and/or chemotherapy. We also applied conventional karyotyping (CK) for identification of t(9;22) and t(15;17) at diagnosis. All CML cases had a Ph; t(9;22) and except for two cases all APL had t(15;17). The FISH studies on CML marrows in complete cytogenetic remission (CCR) (100% Ph- by CK) achieved by IFN-alpha, showed 0-2.5% of cells with BCR-ABL fusion in first cytogenetic remission (Controls, range 0.5-1.5%). Repeat follow-up FISH studies could be done in two cases in remission, which demonstrated 0-10% of cells with BCR-ABL fusion. Evaluation of Ph positive status of CML marrow at diagnosis by CK (100% Ph+ cells) and FISH (80-92% BCR-ABL fusion) pointed the existence of dormant clone of normal residual hematopoietic cells along with actively proliferating clones of Ph positive cells. Fluorescence in situ hybridization analysis of post-BMT CML marrows in CCR (0% Ph+ mitoses) could detect MRD with range of 1-6%. Among 14 patients, 9 who showed percentage of BCR-ABL positive cells (0.0-1.5%) almost similar to normal controls, 6 patients had comparatively good prognosis (disease-free survival 7-14 months). Of five patients with residual leukemic cells in the range of 2-6%, 4 relapsed within a period of 3-24 months. Fourteen APL patients in CCR [100% t(15;17) negative cells by CK] were evaluated by FISH to check the presence of residual leukemic cells. In these patients FISH could efficiently detect 1-14.5% of residual cells with PML-RARA (patients mean MRD 5%, controls mean MRD 3.5%, P=.02). Since the time of FISH analysis, 5 to 7 patients with higher fraction of leukemic cells (5-11%) relapsed within a short period (1-7 months). On the contrary, 5 of 7 patients with either absence or low percentage of PML-RARA positive cells remained in complete remission for 11-24 months. Our data show that FISH has a potential to detect and measure the fraction of aberrant malignant cells in remission marrows, induced by BMT in CML and chemotherapy in APL. These findings encourage the investigations on a large scale to merit its potential for identification of patients at high risk. In the present studies, FISH on interphase cells also demonstrated its efficiency in the molecular diagnosis by its ability to detect BCR-ABL and PML-RARA fusion in CML with masked/variant Ph and t(15;17) negative APL, respectively. The efficiency of technique in molecular diagnosis was also proved in one of the CML patients who progressed to myeloid blastic phase where interphase FISH could identify an extra BCR-ABL fusion on both chromosomes 9 indicating insertion of BCR into ABL and its duplication.
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PMID:Fluorescence in situ hybridization: a highly efficient technique of molecular diagnosis and predication for disease course in patients with myeloid leukemias. 1175 52

The fusion transcript AML1/ETO corresponding to translocation t(8;21)(q22;q22) can be found in approximately 7-12% of childhood de novo AML. Despite the favorable prognosis, some of these patients relapse. Most of MRD studies so far were performed on adults treated not uniformly. Therefore, we analyzed the follow-up of 15 AML1/ETO-positive children using real-time quantitative reverse transcription PCR (RQ-RT-PCR), all enrolled in the multicenter therapy trial AML-BFM 98. AML1/ETO copy numbers were normalized to the control gene ABL and the results were expressed in copy numbers AML1/ETO per 10 000 copies ABL. At diagnosis, a median of 10 789 copies AML1/ETO was found. A linear decrease to about 10 copies (2-4 log) could be seen in most of the children by the start of consolidation. In the majority of cases they remained positive at this low level during the ongoing therapy. Four children relapsed and two of them had a decrease of less than 2 log before starting consolidation. Three of the relapsed children showed, prior to relapse, an increase of the AML1/ETO fusion transcript at 6, 9, and 11 weeks, respectively. These results suggest that monitoring of minimal residual disease using RQ-RT-PCR could be helpful in detecting patients with a higher risk of relapse.
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PMID:Monitoring of minimal residual disease (MRD) by real-time quantitative reverse transcription PCR (RQ-RT-PCR) in childhood acute myeloid leukemia with AML1/ETO rearrangement. 1276 80

We report a 39-year-old female patient who underwent HLA-identical sibling allogeneic BMT for CML in accelerated phase. Severe pancytopenia refractory to G-CSF associated with progressive splenomegaly and RBC/platelet transfusion dependency were present from day +60 after BMT. MRD assessed by FISH and RT-PCR multiplex for BCR-ABL rearrangement was negative, and complete chimerism was documented by VNTR on days +100, +180, +360 and 2 years after BMT. Splenectomy was performed on day +225 and pancytopenia resolved but chronic extensive graft-versus-host disease developed, with hepatic cholestasis, diffuse scleroderma and sicca-like syndrome. She was sequentially and progressively treated with different immunosuppressive therapy combinations with no clear benefit. On day +940, she presented with infection over the previously present ulcers on both limbs, which culminated in septic shock and death on day +1041. We conclude that, although splenectomy may reverse poor graft function after allogeneic BMT, hyposplenism may trigger or worsen chronic extensive GVHD leading to increased morbidity and mortality.
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PMID:Refractory chronic GVHD emerging after splenectomy in a marrow transplant recipient with accelerated phase CML. 1285 7

We carried out sequential molecular monitoring of different markers on two BCR-ABL positive ALL patients receiving a standard dose induction regimen, which was followed by a maintenance therapy that alternated imatinib and chemotherapy administration. Molecular study was performed at diagnosis, at the end of the induction phase, and then every three months during maintenance therapy. Each marrow sample underwent BCR-ABL analysis (p210 and p190 expression by RT-PCR and Real-time PCR) and monoclonal JH rearrangement analysis, while WT1 gene expression was detected by Real-time PCR. At diagnosis we detected high WT1 expression associated with the presence of both BCR-ABL transcripts and monoclonal JH rearrangement in both patients. Hematological remission, as well as a molecular status characterized by undetectable BCR-ABL expression, normal levels of WT1 expression, and persistence of monoclonal JH rearrangement, were achieved by both patients post-therapy. Follow up of patient 1 showed a progressive increase in WT-1 and in p-190 transcript, which was followed by cytogenetic and hematological relapse. We observed a progressive increase in the p210 transcript without a concomitant increase in WT-1 levels in patient 2. JH rearrangement was detected in all the samples analyzed. The molecular results may indicate the persistence of JH rearranged clonal cells with undetectable BCR-ABL. From a clinical point of view, our preliminary experience suggests that simultaneous analysis of BCR-ABL, JH and WT-1 expression may improve the study of MRD in Ph+ ALL.
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PMID:Monitoring molecular response by BCR-ABL, JH and WT-1 in Ph+ all treated with imatinib containing regimen: preliminary report of two cases. 1716 71

The study was aimed to investigate the relation between the expression level of TEL-AML1 (translocation ETS leukemia-acute myeloid leukemia 1) fusion gene and clinical characteristics as well as early response to treatment in children with ALL (acute lymphoblastic leukemia). With real-time quantitative polymerase chain reaction (RQ-PCR), the expression level of TEL-AML1 at diagnosis and MRD (minimal residual disease) at the end of induction of remission were detected in 35 children with ALL, including 20 SR (standard risk) and 15 IR (intermediate risk) patients. The expression level of TEL-AML1 and clinical characteristics at diagnosis were compared between MRD negative and MRD positive patients. The relation between TEL-AML1 expression levels at diagnosis, MRD level and clinical characteristics as well as early response to treatment were also explored. The results indicated that the expression levels of TEL-AML1 at diagnosis were 1.63 x 10(4) copies/10(4) copies ABL (median). At the end of induction of remission, 16 patients (10 SR and 6 IR patients) did not achieve molecular remission, whose MRD levels were 0.84 - 282.93 copies/10(4) copies ABL. No relation was found between expression levels of TEL-AML1 at diagnosis and clinical characteristics as well as MRD level. There was a significant relation between MRD level and blast count in peripheral blood (PB) at day 8 after prednisone trial induction. Significant relations between MRD level and presenting leukocyte count, blast percentage in PB were also found in the patients with presenting leukocyte count < 25 x 10(9)/L. TEL-AML1 expression level at diagnosis of MRD negative patients was lower than that of MRD positive ones. It is concluded that therapy after induction of remission is of importance by the fact that 45.71% children with TEL-AML1(+) ALL did not achieve molecular remission at the end of induction of remission. The effectiveness of prednisone trial predicts the MRD level. In addition, presenting leukocyte count, blast percentage in PB and TEL-AML1 expression level at diagnosis may have an effect on MRD level to some extent.
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PMID:[Relation between TEL-AML1 expression level and clinical characteristics as well as early response to treatment in children with acute lymphoblastic leukemia]. 1760 58

Wilms' tumor gene 1 (WT1) gene expression was analyzed in 32 patient with acute myeloid leukemia (AML) and 18 with acute lymphoblastic leukemia (ALL) to investigate whether it could serve as a MRD marker. Ninety-four percent of patients with acute leukemia showed high WT1 expression at presentation. WT1 expression as a MRD marker was evaluated in 36 patients. The rise of WT1 expression preceded the hematological relapse by approximately 4 months (mean time 129 days; range 6-298). The prognostic significance of WT1 expression was analyzed in 30 patients with AML. WT1 expression higher than 20 WT1 copies /10(4)ABL copies after induction and consolidation chemotherapy was associated with shorter OS. WT1 expression analysis could be a useful tool for MRD monitoring in acute leukemia.
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PMID:Wilms' tumor gene 1 expression analysis by real-time quantitative polymerase chain reaction for monitoring of minimal residual disease in acute leukemia. 1981 33


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