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Year : 2016  |  Volume : 12  |  Issue : 2  |  Page : 620-626

Characterization of immunophenotypic aberrancies in adult and childhood acute lymphoblastic leukemia: A study from Northern India

1 Department of Pathology, Dr Rajendra Prasad Government Medical College Kangra at Tanda (Himachal Pradesh); Department of Hematology, Post Graduate Institute of Medical Education and Research, Chandigarh, India
2 Department of Hematology, Post Graduate Institute of Medical Education and Research, Chandigarh, India
3 Department of Internal Medicine, Post Graduate Institute of Medical Education and Research, Chandigarh, India
4 Department of Pediatrics, Post Graduate Institute of Medical Education and Research, Chandigarh, India

Date of Web Publication25-Jul-2016

Correspondence Address:
Manupriya Sharma
Senior Resident (Pathology), Dr Rajendra Prasad Government Medical College Kangra at Tanda (Himachal Pradesh), Ex- Junior Resident Department of Hematology, Post Graduate Institute of Medical Education and Research, Chandigarh, Set No.- 112, Vivekanand Hostel, Kangra at Tanda - 176 001, Himachal Pradesh
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/0973-1482.147716

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 > Abstract 

Background: Identification of aberrant antigen expression is important in characterizing neoplastic population among non.neoplastic bone marrow counterparts and further in the detection of minimal residual disease. (MRD). Flow cytometry (FCM) is an important tool in identifying aberrant phenotypes. Incidence of aberrant phenotypes varies considerably in independent studies and its association with prognostic factors is still debatable.
Aim: To identify the prevalence of aberrant phenotypes on immunophenotyping in a large series of de novo acute lymphoblastic leukemia (ALL) and to evaluate any association with initial clinical and hematological features.
Materials and Methods: In the current study, 303 patients of de novo ALL were included from the Department of Hematology, PGIMER, Chandigarh during the time period (July 2010 to June 2012). The immunophenotype of all cases of ALL was studied using FCM.
Results: Aberrant myeloid antigen expression was seen in 42.5% cases. Most frequent aberrant myeloid antigen was CD13 (32.2% cases), followed by CD33 (27.2% cases) and CD117 (18.5% cases). The expression of CD117 was relatively frequent in comparison to earlier reports which describe its rare expression. Adult T- ALL showed higher expression of CD33 and CD117 than pediatric T-ALL (P = 0.032 and 0.043, respectively). Myeloid antigen expression in ALL was associated with lower WBC count (P < 0.05) and lower number of peripheral blasts (P < 0.05). Expression of CD34 was higher in My + ALL group (P < 0.05) than My- ALL group.
Conclusion: In summary, CD117 is a relatively frequently expressed myeloid marker contrary to earlier reports which describes its rare expression. Pediatric and adult ALL cases with low blast count and CD34 positivity are more likely to express aberrant myeloid markers. Current study also supports that myeloid antigen expression in both adult and pediatric ALL is not associated with adverse presenting clinical and biological features.

Keywords: Aberrant phenotype, acute lymphoblastic leukemia, flow cytometry, immunophenotyping

How to cite this article:
Sharma M, Sachdeva MU, Varma N, Varma S, Marwaha R K. Characterization of immunophenotypic aberrancies in adult and childhood acute lymphoblastic leukemia: A study from Northern India. J Can Res Ther 2016;12:620-6

How to cite this URL:
Sharma M, Sachdeva MU, Varma N, Varma S, Marwaha R K. Characterization of immunophenotypic aberrancies in adult and childhood acute lymphoblastic leukemia: A study from Northern India. J Can Res Ther [serial online] 2016 [cited 2020 Jul 14];12:620-6. Available from: http://www.cancerjournal.net/text.asp?2016/12/2/620/147716

 > Introduction Top

Aberrant phenotypes in acute leukemia are defined as patterns of antigen expression on neoplastic cells different from the process of normal hematopoietic maturation. In ALL, these aberrancies include: Cross-lineage antigen expression (expression of myeloid antigens in ALL, B-lineage antigens in T- ALL or T- lineage antigens in B-ALL); asynchronous antigen expression where early antigens are co- expressed with mature ones.[1] Immunopheno typing plays a major role in identifying these aberrant phenotypes. The importance of identifying these aberrant phenotypes is to generate sufficient data about their incidence as well as to know about their clinical and prognostic significance. This data can guide further in making alternate treatment decisions, if required. Even though immunopheno typing is an important tool in leukemia diagnosis, many centers in India do not have the availability of flow cytometry. Diagnosis is made on morphology and cytochemistry alone at these centers. Hence, proper lineage characterization and identification of any aberrant phenotypes is missed in all those cases which do not reach higher centers. Many studies, mainly from the west, have evaluated the expression of aberrant phenotypes in ALL. The expression of aberrant myeloid antigen (MyAg) has varied between 5 and 86% in various studies.[2],[3],[4],[5],[6],[7] The prognostic significance of MyAg expression in ALL is still controversial because of contradictory reports. Some studies have reported worse prognosis for MyAg + ALL patients;[3],[8],[9],[10] however, certain other studies with varied treatment protocols based on high-dose chemotherapies have failed to confirm any prognostic correlation.[4],[11],[12] CD34 is a stem cell marker of hematopoietic progenitors and its expression decreases with normal developmental process. In ALL, expression of CD34 might be associated with immaturity due to developmental arrest or asynchronous expression with mature antigens. Studies have evaluated the clinical significance of expression of CD34 in ALL with favorable features in childhood ALL,[13],[14] but in adult ALL, the expression of CD34 is associated with poor prognostic features.[15],[16] This wide variation in expression of aberrant markers could be due to differences in the FCM instruments, reagents and the criteria for antigen positivity used. Further, there is a large variation in the incidence and prognosis of ALL patients in Indian population compared to that of west. Hence, this study was planned for a span of two years to identify various immunophenotypic aberrancies in a large series of ALL cases from Indian population which were uniformly characterized using flow cytometry. Initial clinical and hematological features were studied in relation to the expression of aberrant markers.

 > Materials and Methods Top

A prospective study was conducted in the Department of Hematology, PGIMER, Chandigarh. All consecutively diagnosed cases of ALL for a period of 2 years (July 2010 to June 2012) were included in the study. Written informed consents were obtained from all the patients. During this study period, 303 patients of ALL were diagnosed [Pediatric cases (<15 years); 207, Adult cases (>15 years); 96]. The diagnosis of acute leukemia was made on routinely stained bone marrow aspiration/peripheral blood smears and was evaluated according to French- American- British (FAB) criteria.[17] Final lineage assignment of all acute leukemia cases was based on FCM. The study was approved by the Institutional Review Board of the tertiary hospital.

Bone marrow examination

Bone marrow examination was done preferably from the posterior iliac crest area using Jamshidi bone marrow aspiration needle (No. 16 for adults and No. 18 for pediatric patients). One to two milliliters of bone marrow aspirate was taken for making smears and in EDTA vials for FCM. Bone marrow biopsy was taken in all cases with Jamshidi trephine biopsy needle (No. 11 for adults and no. 13 for pediatric cases). It was fixed in 10% buffered formalin. Smears were examined using May-Grunwald Giemsa (MGG) and special stains: Myelo-peroxidase (MPO), Periodic acid Schiff (PAS). Each case was evaluated morphologically based on FAB criteria.[17]


Two to three milliliters of peripheral blood/bone marrow sample was collected in EDTA vials. Samples were analyzed within 24 hours of collection. Imunophenotypic analysis was performed in all cases based on a pre- defined diagnostic panel of fluorescein isothiocyanate (FITC), phycoerythrin (PE) and allophycocyanin (APC) conjugated monoclonal antibodies (Moab): CD13-PE, CD33-APC, CD117-APC, CD19-FITC, CD10-PE, CD20-APC, CD22-PE, CD2-FITC, CD3-PE, CD4-PE, CD8-FITC, CD5-PE, CD7-FITC, CD14-FITC, CD11b-PE, CD1a-PE, CD34-PE, HLA-DR-FITC on the surface of leukemic cells and intra-cytoplasmic Igµ chain-PE/FITC, cytoplasmic CD3-FITC/APC, CD79a-PE, myeloperoxidase (MPO)-FITC antigens and nuclear TdT. All antibodies were purchased from BD biosciences, California, USA. Briefly, the whole blood sample (50 µl) was processed with red blood cell lysing solution and washed with phosphate-buffered saline (PBS). A cell count of (approximately 1 × 106 cells/tube) was adjusted. The sample was incubated with 5 μl of specific fluorochrome conjugated Moab in dark for 30 minutes at room temperature. Unbound Moabs were removed with PBS washings and cell button was resuspended in 500 ml of PBS. For detection of cytoplasmic/nuclear antigens, 'BD FACS Permealizing solution 2' was used. Flow cytometric analysis was performed on flow cytometer (BD FACS caliber/BD FACS Canto II) and analyzed with cell quest/FACS Diva, respectively. Results were obtained by gating the blast cells with side scatter (SSC) versus forward scatter (FSC) followed by SSC versus CD45 gating. Doublets were excluded based on 'area versus width' or 'area versus height' plotting. FCM data was analyzed based on dot plots. Negative controls were simultaneously run in every case. For surface antigens, marker positivity was considered when more than 20% of blast cells were positive and more than 10% blast cell positivity was considered for cytoplasmic antigens.

Statistical analysis

SPSS-17 was used for statistical analysis. Continuous variables were assessed with independent t-test and categorical variables with Fischer's exact test. Significance was assessed at P ≤ 0.05.

 > Results Top

Patient characteristics

A total of 303 pretreatment cases of ALL were analyzed in the study. Patient age range was wide (range <1-65 years; median 10.0 years). Majority of cases (207/303; 68.3%) were in pediatric age group with a median age of 6.0 years. Adult ALL cases were (96/303; 31.7%) with a median age of 30.5 years. Overall male/female ratio was 2.5:1. The ratio was slightly higher in children (M: F =2.7:1) than in adults (2.1: 1). Physical examination revealed hepatomegaly in 69% of the cases, splenomegaly in 56.5% and lymphadenopathy (LAP) in 62.3% of the cases. Hematological parameters showed hemoglobin (range 2.3-15.8 g/dl; median 7.5 g/dl), white blood cell count of (range 1.0-436.0 × 109/L; median 10.3 × 109/L) and platelet count of (range 2.0-508.0 × 109/L; median 28.0 × 109/L).

Eighty-five percent (257/303) of patients were classified as B-lineage ALL (pro-B ALL 8%, common-B ALL 74%, pre-B ALL 18%). Fifteen percent (46/303) patients were identified as T-lineage ALL (pro-T ALL 29%, pre-T ALL 11%, cortical- T ALL 44%, mature-T ALL 16%).

Aberrant phenotype in ALL cases

Immunophenotypic aberrancies are defined as patterns of antigen expression on neoplastic cells that are different from what is seen during the normal maturation process. Among aberrant patterns, expressions of myeloid antigens (CD13/CD33/CD117) in ALL cases, T-cell antigen in B-ALL cases, B-cell antigen in T-ALL cases and aberrant patterns in CD34 expression were evaluated.

Aberrant expression of myeloid antigens in ALL

A total of 42.5% cases examined showed expression of at least one myeloid antigen. CD13 was the most frequently expressed antigen (32.2% of cases), followed by CD33 (27.2% of cases) and CD117 (18.5% of cases). All these aberrancies along with their frequencies- overall and separately in adult and pediatric age groups are listed in [Table 1]. [Figure 1] shows a case of B-ALL with aberrant myeloid antigen expression on FCM. Expression of myeloid lineage antigens was more in adult ALL cases as compared to children. In adult T-ALL cases, the expression of myeloid markers (CD33/CD117) was statistically more significant as compared to the paediatric T- ALL cases [Table 1].
Table 1: Myeloid antigens expressed in acute lymphoblastic leukemia

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Figure 1: Case of B- ALL showing aberrant expression of myeloid markers CD13, CD117 and dim CD33. (•) Blasts are identified on SSc-A/CD45 perCP-A as dim CD45 positive. (•) Majority of gated blasts are positive for B-cell specific marker, i.e., CD19 (95.5%), CD79a (82.9%) and CD10 (96.4%). Myeloid markers: CD13 (71.8%), CD117 (74.9%) and dim CD33 (28%) are positive. Blasts are negative for MPO

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There was no statistically significant difference in expression of myeloid lineage antigens between B- ALL and T-ALL.

In 226 out of 256 B-lineage ALL cases, all three myeloid markers- CD13, CD33 and CD117 were analyzed. The expression of one myeloid antigen was seen in 28.3% cases and that of two myeloid antigens in 12% and all three myeloid antigens were expressed in 14 cases (6.2%) [Table 2]. Out of 14 cases showing expression of three myeloid antigens, 11 cases met European Group for the Immunologic Classification of the Leukemias (EGIL) criteria for biphenotypic leukemia.[18] However, only two cases were diagnosed as Acute leukaemia of ambiguous lineage (ALAL) based on the more stringent WHO 2008 criteria.[1] Similarly, in 38 out of 46 T-lineage ALL cases, all three myeloid markers were evaluated. Out of these, one myeloid antigen was expressed in 18.4%cases, two antigens in 15.8% and all three myeloid antigens were expressed in only two T-ALL cases (5.3%), as shown in [Table 2].
Table 2: Myeloid antigen expression in B-lineage ALL and T-lineage ALL

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Based on the positivity of at least one of the two myeloid markers (CD33 and/or CD13), patients were stratified into two groups: My + ALL and My-ALL. Prognostic factors were studied separately in the two groups in adults and children.

Adult ALL cases

The clinical and biological characteristics of My + ALL and My- ALL groups are compared as summarized in [Table 3]. Among adult ALL cases (n = 96) hemoglobin (range, 2.4-15.8 g/dl; median 7.45 g/dl), white blood cell count (range, 1.0-436.0 × 109/L; median 20.85 × 109/L) and platelet count of (range, 2-282.0 × 109/L; median 55.7 × 109/L) were seen. Overall anemia (Hb < 10.0 g/dl) was seen in 87.5% cases.
Table 3: Distribution of CD13 and/or CD33 expression according to clinical and biological features in adult and pediatric ALL cases

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In both My + ALL group and My- ALL group, 48 cases each were identified. Statistically significant difference was seen with regard to the median white blood cell count (P = 0.001) and the number of peripheral blasts (P = 0.003), as both were lower in My + ALL group. No statistically significant differences were found between My + ALL and My-ALL group with regard to gender, median age, clinical features, median hemoglobin, median platelet count, bone marrow findings (percentage of bone marrow blasts, FAB subtype) and immunophenotyping (B- ALL and T- ALL), as shown in [Table 3]. Expression of CD34 was significantly higher in My + ALL group (62%) as compared to My-ALL group (13%) (P = 0.001).

Pediatric ALL cases

Among pediatric ALL cases (n = 207), hematological parameters showed hemoglobin (range, 2.3-13.8 g/dl; median 7.6 g/dl), white blood cell count (range, 1-410 × 109/L; median 8.70 × 109/L) and platelet count (range, 2-508 × 109/L; median 28.0 × 109/L). Anemia (hemoglobin < 10.0g/dl) was seen in 81.6% cases. There were 81 cases in My + ALL group and 126 cases in My-ALL group. Based on clinical features, LAP was statistically significant in My + ALL group (P = 0.048). The number of peripheral blasts was significantly lower in My + ALL (P = 0.0028). My + ALL were significantly more frequent with B- lineage ALL (42%) than with T- ALL (17%) (P = 0.004) Other factors like gender, median age, clinical and hematological factors did not show any significant differences. Expression of CD34 was found in 50% of My + ALL and 10% of My- ALL (P = 0.0004), as shown in [Table 3].

Expression of CD34 in ALL

CD34 expression was seen in 67.3% of all ALL cases. The expression was more frequent in B- ALL (70.3%) as compared to T- ALL (51%). CD34 is a stem cell marker and normally its expression should decrease according to phenotypic maturation. In T- ALL, expression of CD34 decreased from early T- cell phenotype (78%) to intermediate stage (20%). However, no clear loss of antigen was observed further with advancing thymocyte maturation though the expression of CD34 increased again in late T- cell stage (42%). Normally, the immature B- cells express CD34, TdT and slightly bright CD10 but are entirely negative for CD20. With maturity, they lose CD34, TdT, become less bright for CD10 and gradually express CD20 and dim surface immunoglobulin. In B- ALL, we observed asynchronous dual expression of CD34 and CD20 in 12% cases. CD34 showed a statistically significant correlation with expression of myeloid markers in ALL cases [Table 3].

Aberrant expression of T-Cell antigens in B-ALL

Expression of T- cell antigens was observed in 17 cases (7%). Most common antigen was CD4, expressed in 11 cases (4.5%). However, CD4 is not T- lineage specific and is also expressed on myelomonocytic cells. CD7 was expressed in five cases (2%). No single case expressed more than one T- cell antigen [Table 4]. Expression of CD3 was not seen.
Table 4: Aberrant T-lineage and B-lineage antigens expression in B-ALL and T-ALL

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Aberrant expression of B-Cell antigens in T-ALL

B- Lineage antigens were expressed in seven T-ALL cases (15%). The most common of these was CD79a, expressed in 5 cases (16%) and CD19 was expressed in three cases (6.5%). None of the cases expressed CD20 [Table 4].

 > Discussion Top

In the current study of 303 patients of pre-treatment acute leukemia, multiple immunophenotypic aberrancies were seen. Most common immunophenotypic aberrancy was expression of myeloid associated antigens (My + ALL) seen in 42.5% of all cases. Reports on the degree of myeloid antigen expression vary widely from 5% to 86%. This wide variation in the antigen expression can be attributed to different thresholds for antigen positivity, different FCM methods, variation in the binding patterns of different monoclonal antibody clones, instruments and reagents.[19],[20] In the present study, we followed a uniform flow cytometry method for characterization of all acute leukemia cases. Prior to 2008 WHO diagnostic criteria for identifying ALAL (Acute Leukemia of Ambiguous Lineage), cases were identified as biphenotypic acute leukemia (BAL) based on EGIL scoring system. According to this scoring system, a case was considered as biphenotypic when point values were greater than two for myeloid and one of the lymphoid lineages.[18] As a result, many cases of acute leukemia with aberrant marker expression were over diagnosed as BAL and put on more intensive therapeutic regimens. The WHO 2008 criteria for ALAL are stringent and based on the expression of more specific cytoplasmic markers for identifying a particular lineage.[1] Only two cases (0.6%) in the current study fulfilled the WHO 2008 criteria for ALAL as compared to 14 cases of BAL based on EGIL scoring system.

WHO states myeloid markers CD33 and CD13 are often expressed in ALL cases and expression of CD117 is rare. Rare expression of CD117 is considered to be associated with activating mutations of FLT3.[21] Our study upheld the WHO suggestion in relation to CD13 and CD33 where the expression of these markers was found in 32.2% and 27.2% cases, respectively. Similar to earlier reports, CD13 was the most frequently expressed antigen in our study.[6],[7] In various studies, the expression of CD13 has varied between 25 and 55% and of CD33 between 23-45%. However, instead of CD117 as a rarely expressed marker, we found its expression in 18.5% of all ALL cases. Adult ALL cases showed relatively higher expression of myeloid markers than pediatric cases. The difference was statistically significant in T- ALL cases where the expression of CD33 and CD117 was much higher in adults than in pediatric cases (P = 0.032 and 0.043, respectively). Similar findings were seen in studies by Bhushan et al. and Suggs et al.[22],[23] In the current study, the expression of aberrant myeloid antigens in ALL was studied in relation to clinical and hematological factors. Among adult ALL cases, expression of myeloid markers was significantly associated with lower white blood cell count (P = 0.001) and lower peripheral blast count (P = 0.003). Similar results were seen in a study by Vitale et al., which evaluated 377 adult ALL cases for expression of myeloid antigens.[7] However, Bhushan et al. did not find any significant difference in clinical and hematological features between My + and My- phenotypes of ALL.[22] Yenerel et al. showed higher expression of myeloid antigen in adult B- Lineage ALL than in T- lineage ALL; though this difference was not supported in our study.[24] Among pediatric ALL cases in our study, myeloid antigen expression was associated with significant presence of LAP (P = 0.048), lower peripheral blast count (P = 0.0028), more association with B- lineage ALL (P = 0.004) and higher expression of CD34 (P = 0.0004).

CD34 is normally expressed on hematopoietic stem cells and early thymic T- cell precursors. Expression of CD34 on leukemic blast cells might be associated with developmental arrest at an immature stage or a continuous spectrum of expression. CD34 expression was higher in B- ALL (70.3%) than in T- ALL (51%). This is in agreement with previous reports in both adult and pediatric series.[14],[15],[16],[25] This could be due to a relatively immature haematopoietic cell involvement in B- ALL than in T- ALL. In the present study, CD34 expression was associated with early T-cell phenotype (78%). There was a sharp fall in CD34 expression with phenotypic maturation to intermediate stage (20%). However, there was no further decrease as CD34 appeared again in late T- cell stage (42%). CD34 expression in ALL has been evaluated in various studies and similar aberrant phenotypes have been reported.[14],[26] In the present study, expression of CD34 showed statistically significant relation with myeloid expression in both adult and pediatric ALL cases (P = 0.001 and 0.0004). The results are in agreement with a previous study by Vitale et al., where CD34 expression was significantly associated with myeloid- associated markers.[7] Aberrant myeloid expression in adult and pediatric ALL cases has controversial results regarding its clinical significance in relation to event-free survival or overall survival.[3], 4, [8],[9],[10],[11] However, in present study correlation with treatment response parameters has not been carried out to definitely comment upon the overall prognostic significance of expression of myeloid markers in ALL. The incidence of ALL in Asian and African countries is approximately one half the incidence in western world. This geographic variation could be attributed to differences in the environmental and lifestyle factors as well as potential genetic differences. Hence, it is important to perform such studies in the developing countries to have sufficient data for better understanding of the disease process and its biological significance. Further, overall prognosis of ALL cases in developing countries like India remains poor. One of the prominent reasons for poor prognosis is lack of sufficient resources in the existing health care system. Flow cytometry is very important for the diagnosis and proper lineage classification of acute leukemias. Many hospitals in India do not have the facility of flow cytometer and other centers do not use wide antibody panel and cytoplasmic markers. This often leads to delay in proper diagnosis, identification of adverse prognostic factors; which may influence the tumor burden and treatment outcome. This reflects the importance of referral of these patients to higher centers for diagnostic techniques like flow cytometry for proper diagnosis and prognostication of the patients.

In summary, we conclude that the present study is novel in relation to a large sample size studied and how it further adds to our information regarding the controversial association of myeloid marker expression with underlying clinical and biological factors. Multiple immunophenotypic aberrancies were identified in ALL cases in the current study. Most common was aberrant myeloid antigen expression in ALL cases (42.5%). CD 13 was the most common aberrant myeloid antigen in ALL (32.2%). The present study highlighted CD117 as a relatively frequently expressed myeloid marker in ALL, contrary to earlier studies which describe its rare expression. Majority of ALL cases expressed single myeloid antigen. Myeloid antigen expression was relatively more in adult ALL cases than in children. This difference was statistically significant in T- ALL cases. We found that pediatric and adult ALL cases with low blast count at presentation and CD34 positivity are more likely to express aberrant myeloid markers. Pediatric B- ALL cases show significantly higher expression of aberrant myeloid markers than pediatric T- ALL. Current study also supports that myeloid antigen expression in both adult and pediatric ALL is not associated with adverse presenting clinical and hematological features except LAP which is frequently associated with pediatric My + ALL cases. Nonetheless, evaluation of the expression of immunophenotypic aberrancies remains valuable for a more precise characterization of leukemic population in each individual case. These aberrant phenotypes can be useful for making alternate therapeutic decisions (e.g. anti- CD33 treatment) and for monitoring minimal residual disease during the course of the disease.

 > References Top

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  [Figure 1]

  [Table 1], [Table 2], [Table 3], [Table 4]


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