N-Cadherin Immunoexpression In Patients With Acute Myeloid Leukemia

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 4976-4976
Author(s):  
Rahul D Pawar ◽  
Tara L. Lin ◽  
Wei Cui ◽  
Omar S. Aljitawi
Keyword(s):  
Bone Marrow ◽  
Bone Marrow Biopsy ◽  
Myeloid Leukemia ◽  
Statistical Difference ◽  
Culture Conditions ◽  
Bone Marrow Biopsies ◽  
Biopsy Specimens ◽  
Control Bone ◽  
Grade 3 ◽  
Acute Myeloid

Abstract Introduction N-cadherin is a member of the cadherin family which is involved in calcium ion dependent adhesion between cells by interaction with catenin on other cells. In our previous work, we have shown differential patterns of N-cadherin expression in acute myeloid leukemia (AML) cell lines when cultured in traditional 2-dimensional (2-D) culture conditions (over monolayer of stromal cells) compared to 3-D culture conditions.  In addition, we have observed that AML cell lines which are more resistant to chemotherapy in vitro had higher expression of N-cadherin, suggesting potential translational applications to patients with AML.  In order to further examine the role of N-cadherin in AML, we studied patterns of N-cadherin immunoexpression in bone marrow samples taken from patients with untreated AML and compared them to control bone marrow samples. Methods In this retrospective study, we evaluated bone marrow biopsy specimens of 10 AML patients for N-cadherin expression by immunohistochemistry. Bone marrow biopsy specimens from 10 negative staging lymphoma patients were used as control. Automated Cellular Imaging system (ACIS) was used to quantify and grade N-cadherin immunoexpression in the nucleus as well as in the cytoplasm of evaluated cells. ACIS uses advanced color detection software in order to evaluate N-cadherin positive cells and measure the intensity of staining. Grades of N-cadherin positivity were subclassified as grade 0 (no staining) 1+, 2+, 3+. 10 different areas of each sample were evaluated in order to estimate the median intensity of staining per slide. Student’s t-test was used to compare the generated medians and a P-value of <0.05 was considered statistically significant. Results Nuclear N-cadherin staining was graded and compared between bone marrow biopsy specimens of patients with AML and control bone marrow biopsies from patients with negative staging bone marrow examinations for lymphoma.  Interestingly, the percentage of N-cadherin grade 0 (negative) cells was higher in controls than AML samples (54% vs. 37%, p=0. 01). Also, the percentage of grade 1 and grade 2 expressing cells was significantly higher in AML cases compared to controls (grade 1: 39% vs. 29%, p=0.005; grade 2: 21% vs. 13%, p=0.029).  However, there was no statistical difference seen in between AML cases and controls in terms of levels of grade 3 expression. Similarly, cytoplasmic N-cadherin staining was quantified. Grade 0 expressing cells were significantly higher in control samples compared to AML samples (34% vs. 16%, p=0.01). There was no statistical difference seen in terms of levels of grade 1 expression. However, grade 2 and 3 expression levels quantifying the higher levels of N-cadherin expression were significantly higher in bone marrow biopsies from patients with AML versus those from negative staging bone marrows (grade 2: 26% vs. 9%, P=0.01; grade 3:  4% vs. 1%, p=0.04). Conclusion Based on these results, we conclude that cytoplasmic N-cadherin expression is significantly increased in AML bone-marrow samples compared to control samples. These results should be further evaluated in the future to determine the prognostic significance of N-cadherin expression in AML. Disclosures: No relevant conflicts of interest to declare.

scholarly journals N-Cadherin Immunoexpression in Patients with Acute Myeloid Leukemia

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 4944-4944 ◽  
Author(s):  
Rahul D Pawar ◽  
Wei Cui ◽  
Tara L. Lin ◽  
Omar S. Aljitawi
Keyword(s):  
Bone Marrow ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Risk Groups ◽  
Culture Conditions ◽  
Response To Chemotherapy ◽  
Significant Difference ◽  
Control Bone ◽  
Grade 3 ◽  
Acute Myeloid

Abstract Introduction: N-cadherin (NCAD) is a member of the cadherin family which is involved in calcium ion dependent adhesion between cells by interaction with catenin on neighboring cells. In our previous work, we have shown differential patterns of N-cadherin expression in acute myeloid leukemia (AML) cell lines when cultured in traditional 2-dimensional (2-D) culture conditions (over monolayer of stromal cells) compared to 3-D culture conditions. In addition, we observed that AML cell lines which were more resistant to chemotherapy in vitro had higher expression of N-cadherin. In order to further examine the role of NCAD in AML, we studied patterns of NCAD immuno-expression in bone marrow samples taken from AML patients prior to induction therapy and compared them to control bone marrow samples. We then compared patterns of NCAD immuno-expression among different AML cytogenetic risk groups as well as by their response to treatment. Methods: Bone marrow aspirate/biopsy sections of leukemia patients and controls comprising of lymphoma patients were stained for NCAD by immunohistochemistry. The percentage of NCAD positive cells and the intensity of nuclear and cytoplasmic NCAD staining were determined using Automated Cellular Imaging system. A four-tier grading system from grade 0 (negative) to grade 3(highest) was used. Control bone marrow biopsies were chosen from lymphoma patients with negative staging bone marrow. Results: A total of 33 AML bone marrow samples were examined and compared with 16 controls. The percentage of nuclear NCAD expression was significantly higher in AML compared to controls (58.36% vs 39.75%, p=0.000636). Though grade 1 and grade 2 NCAD expression was statistically significantly higher in AML samples compared to controls (grade 1: 38.10% vs 27.13%, p=0.000044; grade 2: 17.40% vs 10.38%, p=0.034), there was no statistically significant difference in grade 3 expression between AML cases and controls (2.91% vs 2.25%, p=0.607). Similarly, cytoplasmic NCAD staining was quantified. The percentage of cytoplasmic NCAD expression was significantly higher in AML samples compared to controls (84.30% vs 65%, p=<0.00001). In the case of cytoplasmic NCAD expression, grade 2 and grade 3 immuno-expression was significantly higher in AML cases compared to controls (grade 2: 24.70% vs 7.38%, p=0.000142; grade 3: 2.79% vs 0.81%, p=0.023), while grade 1 NCAD cytoplasmic immuno-expression was not significantly different between AML cases and controls (56.67% vs 56.81%, p=0.9692). NCAD expression between different cytogenetic risk categories (favorable vs intermediate, intermediate vs poor, favorable vs poor) was compared; no significant difference in NCAD expression between different cytogenetic risk groups was detected. Similarly when we compared NCAD expression between AML cases and the response to chemotherapy, there was no significant difference in NCAD expression between AML cases that achieved complete remission with chemotherapy and AML cases that did not achieve complete remission. Conclusion. Based on these results, we conclude that nuclear and cytoplasmic N-cadherin expression is significantly higher in AML patients than control bone marrow samples. We did not see a difference in level of NCAD expression among different AML cytogenetic risk groups or by response to chemotherapy. These results should be further evaluated in a larger cohort to determine the significance of N-cadherin expression in AML. Disclosures No relevant conflicts of interest to declare.

Acute myeloid leukemia: Immunohistologic findings in paraffin-embedded bone marrow biopsy specimens

1990 ◽  
Vol 21 (6) ◽  
pp. 648-655 ◽  
Author(s):  
Hans-Peter Horny ◽  
Margaret Campbell ◽  
Berthold Steinke ◽  
Edwin Kaiserling
Keyword(s):  
Bone Marrow ◽  
Acute Myeloid Leukemia ◽  
Bone Marrow Biopsy ◽  
Myeloid Leukemia ◽  
Biopsy Specimens ◽  
Acute Myeloid

scholarly journals Immunohistochemistry Can Be Used to Subtype Acute Myeloid Leukemia in Routinely Processed Bone Marrow Biopsy Specimens

2000 ◽  
Vol 113 (6) ◽  
pp. 814-822 ◽  
Author(s):  
Elizabeth J. Manaloor ◽  
Richard S. Neiman ◽  
Douglas K. Heilman ◽  
Maher Albitar ◽  
Thomas Casey ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Myeloid Leukemia ◽  
Bone Marrow Biopsy ◽  
Myeloid Leukemia ◽  
Biopsy Specimens ◽  
Acute Myeloid

scholarly journals BCOR Mutations in Acute Myeloid Leukemia: Clonal Evolution and Prognosis

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 4-4
Author(s):  
Ashley Zhang ◽  
Yuntao Liu ◽  
Shuning Wei ◽  
Benfa Gong ◽  
Chunlin Zhou ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Myeloid Leukemia ◽  
Risk Stratification ◽  
Myeloid Leukemia ◽  
Statistical Difference ◽  
Tp53 Mutation ◽  
Clonal Evolution ◽  
Normal Karyotype ◽  
Abnormal Karyotype ◽  
Acute Myeloid

Background BCOR gene is a transcription repressor that may influence normal hematopoiesis and is associated with poor prognosis in acute myeloid leukemia (AML) with normal karyotype. However, due to the rare mutation frequency in AML (3.8%-5%), clinical characteristics and prognosis of AML patients with BCOR mutation including abnormal karyotype are still unknown. In addition, the clonal evolution of AML patients with BCOR mutation has not been fully investigated. Methods By means of next generation of sequencing, we performed sequencing of 114 genes related to hematological diseases including BCOR on 509 newly diagnosed AML patients (except for acute promyelocytic leukemia) from March 2017 to April 2019. The 2017 European Leukemia Net (ELN) genetic risk stratification was used to evaluate prognosis. Overall survival (OS) was defined as the time from diagnosis to death or last follow-up. Relapse-free survival (RFS) was measured from remission to relapse or death. Clonal evolution was investigated through analyzing bone marrow samples at diagnosis, complete remission (CR) and relapse from the same patient. Result Among 509 AML patients, we found BCOR mutations in 23 patients (4.5%). BCOR mutations were enriched in patients with mutations of RUNX1 (p = 0.008) and BCORL1 (p = 0.0003). Patients with BCOR mutation were more at adverse ELN risk category compared to patients without BCOR mutation (p = 0.007). Besides, there was a larger proportion of patients with normal karyotype in BCOR mutation group but it had not reached statistical difference (62.5% vs 45.5%, p = 0.064). The abnormal karyotype in patients with BCOR mutations included trisomy 8, t(9;11), inv(3), -7 and complex karyotype.There were no significant differences in age, sex, white blood cell count, hemoglobin or platelet count between the two groups. More patients died during induction (13.0% vs 3.5%, p = 0.56) and fewer patients achieved CR after 2 cycles of chemotherapy when patients had BCOR mutations (69.6% vs 82.5%, p = 0.115) but the difference had not reached statistical difference . Patients with BCOR mutations had inferior 2-year OS (52.1% vs 70.7%, p = 0.0094) and 2-year RFS (29.8% vs 61.1%, p = 0.0090). After adjustment for ELN risk stratification, BCOR mutation was still remain a poor prognostic factor. However, the adverse prognostic impact of BCOR mutation is overcome by hematopoietic stem cell transplantation (HSCT), in which there was no difference between BCOR mutation group and wild type group (p = 0.474) (Figure 1). Through analysis of paired bone marrow sample at diagnosis, remission and relapse, we revealed the clonal evolution that BCOR mutation was only detected at diagnosis sample as a subclone and diminished at CR and relapse while TP53 mutation was only detected at relapse with a variant allele frequency (VAF) of 25.5%. We also found BCOR mutation at another patient's diagnosis and relapse sample while TP53 mutation was detected at relapse with VAF of 11.8%. Conclusion BCOR is associated with RUNX1 mutation and higher ELN risk. AML patients with BCOR mutation including normal and abnormal karyotype conferred a worse impact on OS that can be overcome by HSCT. BCOR mutation is a subclone at diagnosis or relapse in some patients, in which TP53 mutation clone occurred at relapse. Disclosures No relevant conflicts of interest to declare.

scholarly journals Immunoistochemical expression of PD-1 and PD-L1 in bone marrow biopsies of patients with acute myeloid leukemia

2020 ◽  
Vol 12 (1) ◽  
Author(s):  
Francesco Romano ◽  
Antonino Giulio Giannone ◽  
Sergio Siragusa ◽  
Rossana Porcasi ◽  
Ada Maria Florena
Keyword(s):  
Bone Marrow ◽  
Immune Response ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Immune Escape ◽  
Medical Community ◽  
Immune Checkpoints ◽  
Bone Marrow Biopsies ◽  
Underlying Mechanisms ◽  
Acute Myeloid

tumor immunotherapy is a rapidly evolving field. The discovery of the ability of neoplasms to evade the immune response has shifted the attention of the medical community to the underlying mechanisms of the immune response to tumors, highlighting the importance of so-called immune check points, including CTLA4, TIM-3 and PD-1.  an immune escape mechanism is the activation of the immune checkpoint pathway that contributes to the creation of an immunosuppressive microenvironment and therefore to tumor proliferation.although immune checkpoints have been extensively investigated in solid tumors, the same is not true for hematologic neoplasms, particularly for myeloid malignancies. our study is based on the evaluation of the activation of the PD-1 and PD-L1 pathway in the context of the bone marrow tumor microenvironment of patients with acute myeloid leukemia. To do so we evaluated  34 bone marrow biopsies of patients with acute myeloid leukemia comparing them to 10 controls using immunohistochemical methods.

Expression of Angiopoietins and Their Receptor Tie2 in the Bone Marrow of Patients with Acute Myeloid Leukemia.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 1894-1894
Author(s):  
Christoph Schliemann ◽  
Ralf Bieker ◽  
Teresa Padro ◽  
Torsten Kessler ◽  
Heike Hintelmann ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Critical Role ◽  
Angiogenic Factor ◽  
Term Survival ◽  
Bone Marrow Biopsies ◽  
Cox Regression Analysis ◽  
The Impact ◽  
Acute Myeloid

Abstract Angiopoietin-1 (Ang-1) and its natural antagonist Angiopoietin-2 (Ang-2), both ligands for the receptor tyrosine kinase Tie2, are known to play an essential role in normal and pathological angiogenesis. However, the importance of angiopoietin signaling in the pathophysiology of hematologic neoplasias such as acute myeloid leukemia (AML) remains to be elucidated. We investigated the expression of Ang-1, Ang-2 and Tie2 by immunohistochemical analyses in bone marrow biopsies of 64 adult patients with newly diagnosed AML and correlated angiogenic factor expression with clinicopathological variables and long-term survival. Expression of Ang-2 was significantly increased in the bone marrow of AML patients (median [interquartile ranges]: 4.7 [3.3 – 5.7] AU [arbitrary units]) as compared with 16 control patients (1.5 [1.5 – 1.8] AU; P < 0.0001). In contrast, Ang-1 expression levels in AML patients did not differ from those found in controls. Thus, we observed a reversal of the Ang-1 and Ang-2 expression balance in the neoplastic bone marrow (Ang-2:Ang-1 ratio: 1.73) as compared with normal bone marrow (0.51; P < 0.0001). Furthermore, the angiopoietin receptor Tie2 was significantly overexpressed in leukemic blasts (3.8 [2.8 – 4.9] AU vs. 1.8 [1.6 – 2.3] AU; P < 0.0001). Patients expressing high levels of Ang-2 showed significantly longer overall survival (OS) than those with low Ang-2 levels (52.7 vs. 14.7 months; P = 0.039). The impact of Ang-2 expression on OS was especially evident in AML patients simultaneously expressing low levels of Ang-1 (P = 0.0298). Multivariate Cox regression analysis revealed karyotype and Ang-2 expression as independent prognostic factors for OS (hazard ratio [CI]: 3.06 [1.39 – 6.70] and 0.31 [0.14 – 0.69], respectively; P < 0.01). In conclusion, these data provide evidence that the alteration of angiopoietin balance in favor of Ang-2 may play a critical role in the pathophysiology of AML. Furthermore, high pre-therapeutic bone marrow Ang-2 levels indicate a favorable prognosis in polychemotherapy treated AML by a yet unknown mechanism.

Overall Survival in Acute Erythroleukemia According to Pathologic Features.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2597-2597
Author(s):  
Xiaohui Zhang ◽  
Alan F List ◽  
Rami Komrokji ◽  
Jeffrey E Lancet ◽  
Lynn Moscinski ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Overall Survival ◽  
Myeloid Leukemia ◽  
Median Overall Survival ◽  
De Novo ◽  
High Grade ◽  
Bone Marrow Biopsies ◽  
Pathologic Features ◽  
Marrow Cellularity ◽  
Acute Myeloid

Abstract Abstract 2597 Background: Acute erythroleukemia (AEL) is a rare subtype of acute myeloid leukemia (AML), comprising less than 5% of all AML, with a historically poor prognosis. According to the 2008 World Health Organization (WHO) classification, it is characterized by the presence of more than 50% erythroid precursors in the entire cellularity and more than 20% myeloblasts in the non-erythroid cell population. The clinical and pathologic features of this subtype have not been clearly defined, and due to the lack of sufficient clinical data, there are concerns that the current categorization might not truly reflect the differences among the cases and the distinction from myelodysplastic syndromes (MDS) and acute myeloid leukemia with myelodysplasia-related changes (AML-MRC). We reviewed ten years of AEL cases from the Moffitt Cancer Center (MCC), as well as high grade MDS and AML-MRC with erythroid predominance (>50% of marrow cells), and compared outcome of these cases according to disease subcategory. Methods: Cases from the MCC data base from 2001 to 2011 were reviewed, identifying 77 cases with a bone marrow aspirate fulfilling the WHO criteria for AEL, and 23 cases of high grade MDS with erythroid predominance of more than 50% of cellularity. Pure erythroid leukemia cases were excluded. Upon further review, of the 77 AEL cases, 22 cases (28.5%) were de novo AEL, 27 cases (35%) evolved from antecedent MDS (MDS-AEL), and 28 cases (36.4%) were re-categorized into AML-MRC as shown by subsequent bone marrow biopsies. Pathological data of serial bone marrow biopsies and clinical data were collected. Patient survival was analyzed with Kaplan-Meier method from the date of diagnosis until death from any cause or last follow up visit. Survival curves were compared by the logrank test. Results: The median overall survival of 22 cases of de novo AEL is 25 months, while the median overall survival of 27 cases of MDS-AEL and 28 cases of AML-MRC are both 14 months. Patients with de novo AEL had better prognosis than those with AML-MRC (p=0.03). There were no significant statistical differences in overall survival between de novo AEL and MDS-AEL, or between MDS-AEL and AML-MRC (p=0.49 and 0.2, respectively). The 23 cases of high grade MDS with erythroid predominance have a median survival of 51 months, compared to 26 months for all the analyzed cases of AML with myelodysplastic features, including MDS-AEL and AML-MRC, when the survival durations were calculated from the date of initial MDS diagnosis. When comparing this group of high grade MDS with MDS-AEL or AML-MRC, the differences were not statistically different (p=0.34). We next analyzed survival of the AEL patients according to blast percentage. In this study, an arbitrary myeloblast count threshold of 10% of the overall marrow cellularity was used. Although myeloblast count did not significantly impact survival, when the cases were subcategorized based on the blast counts of serial bone marrow biopsies including those that did not meet the criteria for AEL, survival was significantly better in the patients with blast counts consistently lower than 10% of all bone marrow cellularity (p=0.03). In addition, patients with normal karyotype had significantly better survival than those with complex karyotypes (p=0.0017). Conclusion: Our findings suggest that there are overlapping features among high grade MDS, AEL and AML-MRC. Serial bone marrow biopsies are more critical in establishing a diagnosis and predicting prognosis than blast percentage calculations on a single marrow. Indicators such as complex cytogenetic changes and appropriate blast percentage threshold are necessary to further refine the classification. Disclosures: No relevant conflicts of interest to declare.

Increased angiogenesis in the bone marrow of patients with acute myeloid leukemia

Blood ◽  
2000 ◽  
Vol 95 (8) ◽  
pp. 2637-2644 ◽  
Author(s):  
Teresa Padró ◽  
Sandra Ruiz ◽  
Ralf Bieker ◽  
Horst Bürger ◽  
Martin Steins ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Myeloid Leukemia ◽  
Complete Remission ◽  
Induction Chemotherapy ◽  
Microvessel Density ◽  
Myeloid Leukemia ◽  
Remission Induction ◽  
Bone Marrow Biopsies ◽  
Acute Myeloid

The importance of angiogenesis for the progressive growth and viability of solid tumors is well established. In contrast, only few data are available for hematologic neoplasms. To investigate the role of angiogenesis in acute myeloid leukemia (AML), bone marrow biopsies from 62 adults with newly diagnosed, untreated AML (day 0) were evaluated. Further studies were done after the completion of remission induction chemotherapy (day 16 of induction chemotherapy, n = 21; complete remission, n = 20). Microvessels were scored in at least 3 areas (×500 field, 0.126 mm2) of the highest microvessel density in representative sections of each bone marrow specimen using immunohistochemistry for von Willebrand factor and thrombomodulin. Microvessel counts were significantly higher in patients with AML (n = 62) compared with control patients (n = 22): median (interquartile range) 24.0 (21.0-27.8)/×500 field vs 11.2 (10.0-12.0)/×500 field, respectively (P < .001). On day 16 of induction chemotherapy, microvessel density was reduced by 60% (44-66) (P < .001) in hypoplastic marrows without residual blasts, in contrast to only 17% (0-37) reduction in hypoplastic marrows with ≥ 5% residual blasts (P < .001 for the difference between both groups). Bone marrow biopsies taken at the time of complete remission displayed a microvessel density in the same range as the controls. In conclusion, there is evidence of increased microvessel density in the bone marrow of patients with AML, which supports the hypothesis of an important role of angiogenesis in AML. Furthermore, these findings suggest that antiangiogenic therapy might constitute a novel strategy for the treatment of AML.

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