Prognostic Significance of Serial Determinations of LDH Levels in Primary (De Novo) Myelodysplastic Syndromes.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 4828-4828
Author(s):  
Friedrich Wimazal ◽  
Wolfgang R. Sperr ◽  
Anja Vales ◽  
Michael Kundi ◽  
Alexandra Boehm ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Lactate Dehydrogenase ◽  
Disease Progression ◽  
Myelodysplastic Syndromes ◽  
Prognostic Value ◽  
De Novo ◽  
Prognostic Significance ◽  
Bone Marrow Examination ◽  
Probability Of Survival

Abstract An increased lactate dehydrogenase (LDH) level at diagnosis is associated with a reduced probability of survival and an enhanced risk of AML development in primary (de novo) myelodysplastic syndromes (MDS). However, so far, little is known about the prognostic value of an increase in LDH levels during the follow up in these patients. We have serially determined LDH levels in 221 patients (102 males, 119 females) with de novo MDS (median age 70 years; FAB-types: RA, n=62; RARS, n=46; RAEB, n=48; RAEBT, n=36; CMML, n=29), and examined the prognostic value of LDH as a follow-up parameter. Confirming previous data, an elevated LDH level at diagnosis was found to be associated with a significantly increased probability of AML evolution and a significantly decreased probability of survival (p<0.05). In the follow up, an increase in LDH (from normal to elevated) was found to be associated with progression of MDS and AML evolution in most cases. Moreover, in those patients who progressed to AML, LDH levels were found to be significantly higher in the two three-months-periods preceding progression compared to the two initial three-months-periods examined (p<0.005). In most patients, the increase in LDH was accompanied or followed by other signs of disease progression, such as the occurrence of thrombocytopenia or an increase in blasts. Together, our data show that LDH can be employed as a prognostic follow-up variable in patients with MDS. In those patients in whom an increase in LDH is noted, a thorough re-evaluation of the progression-status of the disease including a bone marrow examination should be considered.

Quantitative Dynamics of Flow Cytometric Aberrancies during Treatment with Erythropoietin/G-CSF Are Predictive for Responses in LOW/INT-I Risk Myelodysplastic Syndromes.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1661-1661
Author(s):  
Theresia M Westers ◽  
Canan Alhan ◽  
Claudia Cali ◽  
Gert J Ossenkoppele ◽  
Arjan A van de Loosdrecht
Keyword(s):  
Bone Marrow ◽  
Disease Progression ◽  
Myelodysplastic Syndromes ◽  
Progressive Disease ◽  
Median Number ◽  
Response To Therapy ◽  
Disease Monitoring ◽  
Flow Cytometric ◽  
Transfusion Dependency

Abstract Flow cytometry (FCM) in myelodysplastic syndromes (MDS) is recognized as a useful tool in identifying aberrancies in expression of differentiation antigens on immature and mature bone marrow cells of erythroid and myelomonocytic lineages. FCM in MDS correlates significantly to morphology according to WHO and the WHO-based Prognostic Scoring System (WPSS). Moreover, certain aberrancies in pure RA+/−RS patients, i.e. CD7 on myeloid blasts, seemed to predict transfusion dependency and disease progression independent of classical prognostic parameters such as WHO, cytogenetics and IPSS (Van de Loosdrecht et al., Blood 2008, 111). Flow cytometric aberrancies in bone marrow of 29 patients with low or int-I risk MDS were analyzed at diagnosis and after approximately 1 year of treatment with a standardized regimen of Epo (NeoRecormon®) and G-CSF (median: 12 months (range: 4–24) in order to evaluate the value of FCM in disease monitoring. Patients were classified as RA+/−RS (n=11), RCMD+/−RS (n=15), 1 hypoplastic MDS, 1 MDS-U and 1 MDS/MPD. Progression was defined as an increase in WHO subgroup to at least RAEB-1 within 18 months after diagnosis of MDS. Before treatment, median number of aberrancies in the myelomonocytic lineage, as assessed by FCM, was 4 in RA+/−RS (range 1–8) and 5 in RCMD+/−RS (range 3–10); other MDS subgroups were too small. In age-matched normal bone marrow samples the median number of aberrancies was 1 (range 0–3, n=18). Aberrant expression of CD5, CD7 or CD56 was observed on myeloid blasts at diagnosis in 13 out of 18 patients that were transfusion-dependent or suffered from progressive disease during follow-up (4 RA+/−RS, 7 RCMD+/−RS, 1 MDS-U and 1MDS/MPD). Interestingly, expression of these markers was only detected in 1 out of 11 patients that were not or low transfusion dependent. This particular RCMD-RS patient had short response duration. The number of blast aberrancies correlated significantly to transfusion dependency and disease progression (r=0.459, p=0.012). Nine patients showed hematological improvement upon Epo/G-CSF treatment. In most of these patients (4/6 RA+/−RS and 2/3 RCMD+/−RS) the number of flow cytometric aberrancies decreased (median 4 at diagnosis to 2.5 at follow-up in all responders). This decrease was caused by a diminished number of monocytic aberrancies (p=0.028); a stable blast aberrancy was seen in only one patient. In 15 patients with stable disease, no significant changes in the number of flow cytometric aberrancies could be detected (median 5 and 5, at diagnosis and follow-up, respectively); whereas in 4 of the 5 patients with progressive disease during Epo/G-CSF (2/2 RA+/−RS, 1/2 RCMD+/−RS and 1 MDS/MPD) the number of aberrancies increased (median 7 and 9, at diagnosis and follow-up, respectively). This increase was mainly caused by changes in the number of aberrancies in blast and granulocyte subpopulations. The response to therapy seems to depend on the number of blast aberrancies (r=0.351, p=0.062). From these data we hypothesize that FCM can be used as an objective sensitive disease monitoring parameter in low/int-I risk MDS. Furthermore, in a subset of these patients treatment with Epo/G-CSF might have altered disease progression reflected by normalization or stabilization of aberrancies on myelomonocytic cells. This underscores observations that Epo/G-CSF improves overall survival and/or leukemia free survival. Prospective studies are being conducted to validate flow cytometric analysis in the diagnosis, prognostication and disease monitoring of low/int-I risk MDS during Epo/G-CSF and lenalidomide. To conclude, FCM can contribute to the management of low/int-I risk MDS patients as changes in the number of flow cytometric aberrancies reflect response to treatment.

scholarly journals Prognostic significance of serial determinations of lactate dehydrogenase (LDH) in the follow-up of patients with myelodysplastic syndromes

2008 ◽  
Vol 19 (5) ◽  
pp. 970-976 ◽  
Author(s):  
F. Wimazal ◽  
W.R. Sperr ◽  
M. Kundi ◽  
A. Vales ◽  
C. Fonatsch ◽  
...  
Keyword(s):  
Lactate Dehydrogenase ◽  
Myelodysplastic Syndromes ◽  
Prognostic Significance

scholarly journals The Genetics of Myelodysplastic Syndromes: Clinical Relevance

Genes ◽  
2021 ◽  
Vol 12 (8) ◽  
pp. 1144
Author(s):  
Chiara Chiereghin ◽  
Erica Travaglino ◽  
Matteo Zampini ◽  
Elena Saba ◽  
Claudia Saitta ◽  
...  
Keyword(s):  
Disease Progression ◽  
Myelodysplastic Syndromes ◽  
Clinical Relevance ◽  
Driver Mutations ◽  
Significant Information ◽  
Hematopoietic Stem ◽  
Probability Of Survival ◽  
Mutational Status ◽  
Increased Risk ◽  
Risk Of Disease

Myelodysplastic syndromes (MDS) are a clonal disease arising from hematopoietic stem cells, that are characterized by ineffective hematopoiesis (leading to peripheral blood cytopenia) and by an increased risk of evolution into acute myeloid leukemia. MDS are driven by a complex combination of genetic mutations that results in heterogeneous clinical phenotype and outcome. Genetic studies have enabled the identification of a set of recurrently mutated genes which are central to the pathogenesis of MDS and can be organized into a limited number of cellular pathways, including RNA splicing (SF3B1, SRSF2, ZRSR2, U2AF1 genes), DNA methylation (TET2, DNMT3A, IDH1/2), transcription regulation (RUNX1), signal transduction (CBL, RAS), DNA repair (TP53), chromatin modification (ASXL1, EZH2), and cohesin complex (STAG2). Few genes are consistently mutated in >10% of patients, whereas a long tail of 40–50 genes are mutated in <5% of cases. At diagnosis, the majority of MDS patients have 2–4 driver mutations and hundreds of background mutations. Reliable genotype/phenotype relationships were described in MDS: SF3B1 mutations are associated with the presence of ring sideroblasts and more recent studies indicate that other splicing mutations (SRSF2, U2AF1) may identify distinct disease categories with specific hematological features. Moreover, gene mutations have been shown to influence the probability of survival and risk of disease progression and mutational status may add significant information to currently available prognostic tools. For instance, SF3B1 mutations are predictors of favourable prognosis, while driver mutations of other genes (such as ASXL1, SRSF2, RUNX1, TP53) are associated with a reduced probability of survival and increased risk of disease progression. In this article, we review the most recent advances in our understanding of the genetic basis of myelodysplastic syndromes and discuss its clinical relevance.

scholarly journals MBCL-04. 5 – AZACYTIDINE IN TREATMENT OF CHILDREN WITH DE NOVO AND RELAPSED METASTATIC MEDULLOBLASTOMA: RESULTS OF INTERCENTER PILOT STUDY

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii387-iii387
Author(s):  
Andrey Levashov ◽  
Dmitry Khochenkov ◽  
Anna Stroganova ◽  
Marina Ryzhova ◽  
Sergey Gorelyshev ◽  
...  
Keyword(s):  
Gene Amplification ◽  
De Novo ◽  
Prognostic Significance ◽  
N Gene ◽  
Free Survival ◽  
Tumor Bed ◽  
Craniospinal Radiation ◽  
Therapeutic Program ◽  
Grade 3

Abstract The aim of this study was to estimate treatment toxicity and event-free survival (EFS) according to therapeutic program, MYC/MYC-N gene amplification and MGMT/DNMT (1, 3a, 3b) proteins expression in tumor cells. From 2016 to 2018 twenty four patients were included in trial. Children underwent adjuvant therapy: craniospinal radiation (CSI) or local radiation therapy (RT) to the relapsed site up to 23.4Gy with 5-azacytidine, 2 cycles methotrexate/5-azacytidine/cisplatin/etoposide, 3 cycles 5-azacytidine/temozolomide - for relapsed group (arm A, n = 5); for patients with de novo medulloblastoma: arm B, n = 11 – vincristine/cyclophosphamide/cisplatin/etoposide (OPEC) - based induction, CSI 36Gy + local RT to the tumor bed up to 54Gy with 5-azacytidine, 1 cycle OPEC and 2 cycles thiophosphamide/carboplatin with auto stem cell transplantation (auto-SCT); arm C, n = 8 – cyclophosphamide/cisplatin - based induction, CSI 23.4 Gy followed by 2 cycles 5-azacytidine/thiophosphamide/carboplatin with auto-SCT, local RT with 5-azacytidine. The combination of 5-azacytidine with local RT or temozolomide was safety and tolerability. Arm C was discontinued due to severe gastrointestinal grade 3/4 toxicity, hemorrhagic syndrome after combination of 5-azacytidine with thiophosphamide/carboplatin. EFS was 0% in arm A, 53.0 ± 15.5%, 50.0 ± 17.7% in arms B and C, a median follow-up 8.8 ± 1.1 months (arm A), 18.8 ± 2.5 months (arm B), 25.0 ± 4.4 months (arm C). Addition of 5-azacytidine to RT or chemotherapy did not improve EFS of patients with MYC/MYC-N gene amplification positive tumor. There was not determined any prognostic significance of MGMT/DNMT (1, 3a, 3b) proteins expression in this cohort.

Personalized, ctDNA analysis to detect minimal residual disease and identify patients at high risk of relapse with multiple myeloma.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 8029-8029
Author(s):  
Binod Dhakal ◽  
Shruti Sharma ◽  
Svetlana Shchegrova ◽  
Minu Maninder ◽  
Meenakshi Malhotra ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Residual Disease ◽  
Prognostic Significance ◽  
Unmet Need ◽  
Progression Free Survival ◽  
Multiparameter Flow Cytometry ◽  
High Dose ◽  
Blood Samples ◽  
Ctdna Analysis

8029 Background: Despite treatment with high-dose chemotherapy followed by autologous stem cell transplantation (AHCT), MM patients invariably relapse. MRD-negativity post-AHCT has emerged as the most important prognostic marker. Currently, MRD in MM is monitored via bone marrow aspirate sampling. Marrow MRD assays are limited by the spatial heterogeneity of marrow MM localization; extramedullary disease and sampling variability of marrow aspiration. Sensitive, non-invasive blood-based MRD assay is an unmet need. ctDNA as a noninvasive biomarker can be utilized to predict relapse in MM. Here we attempt to evaluate MRD using ctDNA in AHCT recipients with MM. Methods: In this retrospective, single-center study, we analyzed ctDNA MRD in blood samples collected from 28 patients with MM after upfront AHCT. A total of 80 plasma timepoints were available pre and post AHCT with a median follow-up of 92.4 months. Multiparameter flow cytometry (MFC) at 10-4 level was used to assess the MRD from the BM biopsy. Individual bone marrow aspirates or FFPE slides from the time of MM diagnosis and matched normal blood were whole-exome sequenced, and somatic mutations were identified. MRD assessment at 3 months post-AHCT was performed by ctDNA analysis using a personalized, tumor-informed (SignateraTM, bespoke mPCR NGS assay). The prognostic value of ctDNA was evaluated by correlating MRD status with clinical outcomes. Results: Table provides the baseline disease characteristics. Median age was 67 [41-75] years and 16 [57.1%] were males. ctDNA was detectable in 70.8% (17/24) of pre-AHCT, 53.6% (15/28) of ̃3 months post-AHCT, and 39.2% (11/28) of patients during the surveillance phase post-AHCT. Of the 15 ctDNA MRD positive patients, 93.3% (n=14) experienced relapse on follow-up (hazard ratio: 5.64; 95% CI: 1.8-17; p=0.0003). Patients negative for ctDNA at 3 months post-AHCT had significantly superior progression-free survival (PFS) compared to positive (median PFS, 84 months vs. 31 months; p=0.003) The positive predictive value (PPV) for relapse among patients positive for ctDNA at 3 months post-AHCT was 93.3%, and significantly higher than marrow MFC of 68.4%. Conclusions: Our study shows the feasibility that a tumor-informed assay on archival blood samples is predictive of relapse post-AHCT. Future prospective studies with real-time marrow NGS and ctDNA samples are needed to define the role of ctDNA in MM and its prognostic significance.[Table: see text]

Oncogenes and Male Breast Carcinoma: c-erbB-2 and p53 Coexpression Predicts a Poor Survival

2000 ◽  
Vol 18 (16) ◽  
pp. 2948-2956 ◽  
Author(s):  
Achille Pich ◽  
Elena Margaria ◽  
Luigi Chiusa
Keyword(s):  
Breast Carcinoma ◽  
Prognostic Value ◽  
Ductal Carcinoma ◽  
Univariate Analysis ◽  
Prognostic Significance ◽  
Male Breast ◽  
Male Breast Carcinoma ◽  
P53 Immunoreactivity ◽  
Mib 1

PURPOSE: To investigate the prognostic value of biomarkers in male breast carcinoma (MBC). PATIENTS AND METHODS: Fifty patients (mean age, 62.2 years) with invasive ductal carcinoma were retrospectively studied. All patients received surgery; 35 had adjuvant postoperative therapy. The median follow-up was 59 months (range, 1 to 230 months). c-myc, c-erbB-2, p53, and bcl-2 proteins were immunohistochemically detected on sections from formalin-fixed, paraffin-embedded tissues using 9E11, CB11, DO7, and bcl-2 124 monoclonal antibodies (mAbs). Estrogen, progesterone, and androgen receptors were detected using specific mAbs. Cell proliferation was assessed by MIB-1 mAb. RESULTS: In univariate analysis, c-myc, c-erbB-2, and p53 protein overexpression was significantly correlated with prognosis. The median survival was 107 months for c-myc–negative and 52 months for c-myc–positive patients (P = .01), 96 months for c-erbB-2–negative and 39 months for c-erbB-2–positive patients (P = .02), and 100 months for p53-negative and 33 months for p53-positive patients (P = .0008). Tumor histologic grade (P = .01), tumor size (P = .02), patient age at diagnosis (P = .03), and MIB-1 scores (P = .0004) also had prognostic value. In multivariate analysis, only c-erbB-2 and p53 immunoreactivity retained independent prognostic significance. All nine patients who did not express c-erbB-2 and p53 proteins were alive after 58 months, whereas none of the 14 patients expressing both proteins survived at 61 months follow-up (P = .0002). CONCLUSION: Overexpression of c-myc, c-erbB-2, and p53 proteins may be regarded as an additional prognostic factor in MBC. The combination of c-erbB-2 and p53 immunoreactivity can stratify patients into different risk groups.

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