Identification of a Second Acute Promyelocytic Leukemia (APL) Patient with the STAT5b-RARα Fusion Gene among PML-RARα-Negative Eastern Cooperative Oncology Group (ECOG) APL Protocol Registrants.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 3005-3005 ◽  
Author(s):  
Robert E. Gallagher ◽  
Serena Mak ◽  
Elisabeth Paietta ◽  
Brenda Cooper ◽  
W. Christopher Ehmann ◽  
...  
Keyword(s):  
Fusion Gene ◽  
Single Case ◽  
Case Reports ◽  
Eastern Cooperative Oncology Group ◽  
Promyelocytic Leukemia ◽  
Phase Iii ◽  
Chromosome 17 ◽  
Fusion Genes ◽  
Rt Pcr ◽  
First Case

Abstract In addition to the PML-RARα fusion gene, which accounts for >98% of APL cases, a common segment of 5′-truncated RARα has been found to fuse with the following 4 alternative genes: promyelocytic leukemia zinc finger (PLZF-RARα), nucleophosmin (NPM-RARα), nuclear mitotic apparatus protein (NUMA-RARα) and signal transducer and activator of transcription 5b (STAT5b-RARα). While recurrent cases of PLZF-RARα and NPM-RARα have been documented, there are only single case reports of NUMA-RARα and STAT5b-RARα. In two Phase III clinical trials, E2491 and C9710, the ECOG registered 10 and 12 presumptive APL patients, respectively, based on initial clinical and cytological assessment, which were negative for PML-RARα by reverse transcriptase-polymerase chain reaction (RT-PCR) testing. In this study, we tested 20/22 of these PML-RARα-negative protocol patients for the presence of the 4 alternative fusion genes by RT-PCR, using the corresponding normal transcripts for the rearranged genes as RNA transcription controls. All specimens were positive for the control gene, while 1 case each was positive for PLZF-RARα or STAT5b-RARα. The karyotypes for these 2 cases, respectively, were 46, XY, t(11:17)(q23;q21) and 46, XY, t(10;11)(q22:q25), i(17)(q10). None of the X-RARα-negative cases had abnormalities of chromosome 17. Immunophenotypically, the PLZF-RARα case was consistent with APL; the STAT5b-RARα case had all features of APL (negative for CD11a, CD18, CD34, HLA-DR) except for weak CD133 expression. These findings imply that it is the RARα rearrangement that prompts the APL immunophenotype. Sequence analysis of the STAT5b-RARα mRNA disclosed the same break/fusion point of the STAT5b gene as the only previously-reported case of STAT5b-RARα-positive APL (Arnould, et al, Hum Mol Genet8, 1741, 1999). Also like the first case (67 years), our STAT5b-RARα patient was an elderly male (57 years). These results suggest that X-RARα fusion genes will rarely be found in the absence of cytogenetic evidence of chromosome 17 abnormalities and establish that STAT5b-RARα, although rare, is a recurrent pathogenetic factor in APL.

scholarly journals Autologous Bone Marrow Transplantation for Acute Promyelocytic Leukemia in Second Remission: Prognostic Relevance of Pretransplant Minimal Residual Disease Assessment by Reverse-Transcription Polymerase Chain Reaction of the PML/RARα Fusion Gene

Blood ◽  
1997 ◽  
Vol 90 (3) ◽  
pp. 1321-1325 ◽  
Author(s):  
Giovanna Meloni ◽  
Daniela Diverio ◽  
Marco Vignetti ◽  
Giuseppe Avvisati ◽  
Saveria Capria ◽  
...  
Keyword(s):  
Median Time ◽  
Fusion Gene ◽  
Autologous Bone Marrow Transplantation ◽  
Autologous Bone Marrow ◽  
Promyelocytic Leukemia ◽  
Rt Pcr ◽  
Chain Reaction ◽  
Polymerase Chain ◽  
Autologous Bone

Abstract Reverse-transcription polymerase chain reaction (RT-PCR) of the PML/RARα fusion gene may predict relapse in acute promyelocytic leukemia (APL) patients in hematologic complete remission (CR). We have prospectively studied by RT-PCR 15 PML/RARα+ APL patients undergoing autologous bone marrow transplantation (ABMT) in second CR. The median time of first CR duration was 12 months (range, 6 to 40). All patients were reinduced with all-trans retinoic acid (ATRA), followed in 12 of 15 cases by mitoxantrone and Ara-C as consolidation. Fourteen patients received the BAVC (BCNU, Ara-C, m-AMSA, and VP-16) schedule as conditioning regimen. Unpurged marrows were collected immediately before conditioning treatment, analyzed by RT-PCR, and reinfused at median of 2 months (range, 2 to 7) from the achievement of second CR. Seven patients were PCR+ and eight PCR− for PML/RARα in their pretransplant marrows. All seven patients of the former group remained PCR+ during the follow-up and relapsed at a median time of 5 months (range, 2 to 9) from ABMT and 9 months (range, 4 to 14) from second CR. Of the eight PCR− patients, all remained PCR− during the follow-up controls. One patient relapsed at 10 months from ABMT, one died of a secondary (PML/RARα−) leukemia, and six are in hematologic and molecular remission at a median time of 28 months (range, 15 to 60) after ABMT and 32 months (range, 17 to 62) from second CR. Our results indicate that, in APL patients in second CR, ABMT with PML/RARα− marrow cells is likely to result in prolonged clinical and molecular remissions. Conversely, patients who test PCR+ after reinduction necessitate the use of alternative aggressive approaches, including unrelated allogeneic transplant.

scholarly journals Acute Promyelocytic Leukemia during Pregnancy: A Systematic Review of the Literature

Cancers ◽  
2020 ◽  
Vol 12 (4) ◽  
pp. 968 ◽  
Author(s):  
Andrea Santolaria ◽  
Alfredo Perales ◽  
Pau Montesinos ◽  
Miguel A. Sanz
Keyword(s):  
Acute Promyelocytic Leukemia ◽  
Gestational Age ◽  
Remission Rate ◽  
Single Case ◽  
Case Reports ◽  
Pulmonary Hemorrhage ◽  
First Trimester ◽  
Promyelocytic Leukemia ◽  
Eligibility Criteria ◽  
Challenging Situation

The management of pregnant women with acute promyelocytic leukemia (APL) is a challenging situation where limited evidence-based information is available. We performed a systematic literature review to analyze the outcomes reported for both mother and fetus when APL is diagnosed during pregnancy. PubMed, Scopus and Web of Science databases were systematically searched to identify studies reporting cases of APL during pregnancy. Sixty-six articles met the eligibility criteria (53 single case reports). Ninety-two patients were eligible for induction therapy, with most them being treated with all-trans retinoic acid alone (32%) or combined with chemotherapy (43%), while the remaining patients received chemotherapy alone. Three patients were treated with arsenic-based regimens after delivery. Overall complete remission rate was 89%, with no statistically significant differences according to the type of induction and gestational age. During the first trimester, women were more likely to experience spontaneous and induced abortion compared to those during the second trimester (88% vs. 30%) (p < 0.0001), while only one patient diagnosed during the third trimester terminated in stillbirth. Twelve of 16 infants with neonatal complications had respiratory distress syndrome. Except two early deaths (Potter’s syndrome and pulmonary hemorrhage), all neonates evolved favorably. This study confirms that gestational age does not affect the results in the mother, but is closely related to fetal viability. Our results may be useful for the process of decision making that requires the involvement of the patient, hematologist, obstetrician and neonatologist.

scholarly journals Novel PML-RARA Fusion Gene on Chromosome 17 in Acute Promyelocytic Leukemia with Normal Chromosome 15 and 17

2007 ◽  
Vol 42 (3) ◽  
pp. 296 ◽  
Author(s):  
Kyoung-Ha Kim ◽  
Jong-Ho Won ◽  
Ki-Ju Jeung ◽  
Sang-Cheol Lee ◽  
Hyun-Jung Kim ◽  
...  
Keyword(s):  
Acute Promyelocytic Leukemia ◽  
Fusion Gene ◽  
Promyelocytic Leukemia ◽  
Normal Chromosome ◽  
Chromosome 17 ◽  
Chromosome 15

Acute Promyelocytic Leukemia Harboring STAT5b-RARα Fusion Gene and G596V Mutation in the Stat5b SH2 Domain of the Fusion Gene.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 4227-4227 ◽  
Author(s):  
Eisaku Iwanaga ◽  
Miki Nakamura ◽  
Tomoko Nanri ◽  
Toshiro Kawakita ◽  
Naofumi Matsuno ◽  
...  
Keyword(s):  
Dna Repair ◽  
Missense Mutation ◽  
Acute Promyelocytic Leukemia ◽  
Clinical Features ◽  
Fusion Gene ◽  
Sh2 Domain ◽  
Promyelocytic Leukemia ◽  
Response To Therapy ◽  
Chromosome 17 ◽  
Marrow Cells

Abstract Most patients with acute promyelocytic leukemia (APL) exhibit a characteristic t(15;17) translocation that fuses the PML on 15q22 to the RARα on 17q12. In a small subset of APL, RARα fuses to several other genes including the PLZF on 11q23, NPM1 on 5q35, NUMA1 on 11q13, STAT5b on 17q11, and PRKAR1α on 17q23. The STAT5b-RARα chimeric protein was delocalized from the cytoplasm to the nucleus, where it displayed a microspeckled pattern, implicating that this APL might result from dysregulation of the JAK/STAT5 signal transduction pathway. However, only two patients with APL harboring STAT5b-RARα fusion gene have been reported, and clinical features and response to therapy as well as the pathogenesis in this subgroup remain to be determined. We examined 8 PML-RARα-negative APL patients for the presence of the above alternative fusion genes by RT-PCR. We here present the third patient with APL harboring a STAT5b-RARα fusion gene and a missense mutation G596V in the SH2 domain of the STAT5b. A 41-year old Japanese man admitted to our hospital because of petechiae, fever and leukocytosis (77.8 x 109/L). His promyelocytes were relatively mature with dense nuclei and abundant azurophilic granules, while faggot cells were observed. Promyelocytes were positive for CD13 and CD33, but negative for CD34, CD117 or HLA-DR, consistent with APL cells. Karyotype analysis of the bone marrow cells revealed 47, XY,del(9)(q?),add(17)(q12),+mar1[3]/48, XY,idem,+mar1[17]. Activity of α2 plasmin inhibitor was 16%, and FDP was 344.0 μg/mL (< 5.0 μg/mL). The patient was diagnosed to have APL and DIC with fibrinolysis. He achieved a complete remission after one course of chemotherapy and all-trans retinoic acid (ATRA) although the sign of ATRA-induced granulocytic differentiation was not observed. Sequence analysis of the STAT5b-RARα transcript disclosed that the STAT5-RARα fusion gene corresponded to those of previously reported case of STAT5b-RARα-positive APL. Abnormalities of chromosome 17 and resistance to ATRA were commonly observed in 3 patients harboring STAT5b-RARα. Interestingly, there was an additional missense mutation (G596V) within the STAT5b SH2 domain of the STAT5b-RARα gene. Neither STAT5b-RARα fusion gene nor G596V was detected in marrow cells during remission. As the SH2 domain plays an important role in the activation of STAT proteins and the G596 substituted amino acid is highly conserved in the SH2 domain-containing proteins, it would be interesting to analyze the STAT5b and STAT5b-RARα protein harboring G596V mutation. In addition, G596V mutant clone dominate before treatment and wild type subclone was not detected. G596V mutation may occur at an early phase of leukemogenesis or may acquire dominant proliferation during development of APL. STAT5 appears to upregulate DNA repair protein RAD51. One can assume that activated STAT5b-RARα disrupts DNA repair process and results in genomic instability. Further investigations are needed to understand the molecular pathogenesis and clinical features of STAT5b-RARα-positive APL.

scholarly journals Arsenic Trioxide Treatment during Pregnancy for Acute Promyelocytic Leukemia in a 22-Year-Old Woman

2020 ◽  
Vol 2020 ◽  
pp. 1-5 ◽  
Author(s):  
Claire Cochet ◽  
Marion Simonet ◽  
Julie Cattin ◽  
Jean-Patrick Metz ◽  
Ana Berceanu ◽  
...  
Keyword(s):  
Arsenic Trioxide ◽  
Acute Promyelocytic Leukemia ◽  
Animal Studies ◽  
Case Reports ◽  
Fetal Loss ◽  
Promyelocytic Leukemia ◽  
University Hospital ◽  
First Case ◽  
Fetal Complications ◽  
Medical Teams

Acute leukemia during pregnancy is rare (1 for 100000 pregnancies). The association of arsenic trioxide (ATO) and all-trans retinoic acid (ATRA) is known as the best therapy in standard-risk acute promyelocytic leukemia (APL). We describe the first case of a pregnancy with ATRA and ATO reported in the literature. In March 2018 at the University Hospital of Besançon, a 22-year-old woman was diagnosed with APL at 14 weeks of gestation (WG). She received a total of 2160 mg of ATRA and 930 mg of ATO between 14 and 35 WG. The mother’s cytological remission was very fast. No maternal or fetal complications occurred during pregnancy. The pediatrics outcomes were good. Many case reports about ATRA exposure during the second and third trimesters report no serious adverse effect for pregnancy. ATO is teratogenic, genotoxic, and carcinogenic and passes through the placenta. Fetal exposure seems to be associated with bad pregnancy outcomes (preterm delivery, decreased birth weight, and fetal loss) and with lung diseases in young adults. No clinical trial is obviously possible, and the only data available are environmental exposure or animal studies. This case report may help medical teams to make hard decision for a treatment of APL during pregnancy.

scholarly journals Interstitial insertion of retinoic acid receptor-alpha gene in acute promyelocytic leukemia with normal chromosomes 15 and 17

Blood ◽  
1994 ◽  
Vol 83 (10) ◽  
pp. 2946-2951 ◽  
Author(s):  
LR Hiorns ◽  
T Min ◽  
GJ Swansbury ◽  
A Zelent ◽  
MJ Dyer ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
Acute Promyelocytic Leukemia ◽  
Retinoic Acid Receptor ◽  
Promyelocytic Leukemia ◽  
Chromosome 17 ◽  
Chromosome 15 ◽  
Retinoic Acid Receptor Alpha ◽  
Rt Pcr ◽  
Acid Receptor ◽  
Receptor Alpha

Abstract The translocation t(15;17)(q22;q21) is seen exclusively in patients with acute promyelocytic leukemia (APL) and in the promyelocytic blast crisis of chronic myeloid leukemia (CML). This translocation juxta- poses the promyelocytic leukemia (PML) gene on chromosome 15 and the retinoic acid receptor-alpha (RARA) gene on chromosome 17, resulting in the formation of a chimeric mRNA transcript. We describe a patient with the microgranular variant form of APL, with no detectable cytogenetic abnormality of either chromosomes 15 or 17, who nevertheless had juxtaposition of PML and RARA genes and expressed a chimeric transcript. Conventional cytogenetics showed the karyotype 46,XY,d- er(3)t(3;8)(p25;q12). Fluorescent in situ hybridization (FISH) with paints for chromosomes 8, 15, and 17 confirmed the presence of structurally intact chromosomes 15 and 17 and trisomy for chromosome 8q. Nevertheless, FISH using cosmid probes for PML and RARA showed their juxtaposition on one chromosome 15 homolog. Both genes were also present on their normal homologs; in addition, part of the RARA gene was still present on the remaining chromosome 17. DNA analysis by Southern blotting, performed with a variety of probes including PML, RARA and retinoic acid receptor-beta (RARB), showed a rearrangement in PML. Reverse transcriptase polymerase chain reaction (RT-PCR) confirmed the existence of hybrid transcripts of 276, 455 bp and 623 bp, from PML- RARA on the der(15) chromosome, consistent with alternate exon splicing of the long form of the transcript occurring in 50% to 60% of patients with APL. Our results show that APL patients with cytogenetically normal chromosomes 15 and 17 may, nevertheless, have involvement of both PML and RARA genes defining a subgroup of APL, t(15;17)- negative/PML-RARA-positive which is analogous to Philadelphia chromosome-negative/BCR-ABL-positive CML. In this case, the presence of chimeric transcripts suggests that treatment with all-trans RA may be warranted in APL, even in the absence of detectable cytogenetic change, showing the usefulness of RT-PCR or FISH to aid diagnosis.

Early Detection of Relapse by Prospective Reverse Transcriptase-Polymerase Chain Reaction Analysis of the PML/RARα Fusion Gene in Patients With Acute Promyelocytic Leukemia Enrolled in the GIMEMA-AIEOP Multicenter “AIDA” Trial

Blood ◽  
1998 ◽  
Vol 92 (3) ◽  
pp. 784-789 ◽  
Author(s):  
Daniela Diverio ◽  
Vincenzo Rossi ◽  
Giuseppe Avvisati ◽  
Silvia DeSantis ◽  
Alessandra Pistilli ◽  
...  
Keyword(s):  
Polymerase Chain Reaction ◽  
Fusion Gene ◽  
Promyelocytic Leukemia ◽  
Rt Pcr ◽  
Molecular Monitoring ◽  
Chain Reaction ◽  
Trans Retinoic Acid ◽  
All Trans Retinoic Acid ◽  
Polymerase Chain

Abstract Although the majority of patients with acute promyelocytic leukemia (APL) are potentially cured by treatments combining all-trans retinoic acid (ATRA) and chemotherapy (CHT), a sizable proportion (around 30%) will relapse during follow-up. Retrospective molecular monitoring studies using reverse transcriptase-polymerase chain reaction (RT-PCR) for the specific PML/RARα fusion gene, have shown that a positive test usually precedes the occurrence of hematologic relapse. Prospective RT-PCR analyses were performed since 1993 at diagnosis and at preestablished time intervals during follow-up in bone marrow (BM) samples of 163 patients with PML/RARα+ APL enrolled in the multicenter Gruppo Italiano Malattie Ematologiche Maligne dell' Adulto (GIMEMA) trial AIDA (All-trans retinoic acid plus Idarubicin). Treatment consisted of ATRA and idarubicin for induction followed by three polychemotherapy courses as consolidation. The sensitivity level of the RT-PCR assay for PML/RARα, as assessed by serial dilution experiments, was 10−4. All patients were in hematologic remission and tested PCR− at the end of consolidation. Of 21 who converted to PCR-positive thereafter, 20 underwent hematologic relapse at a median time of 3 months (range, 1 to 14) from the first PCR+ result. Seventeen of these 21 (81%) PCR+ conversions were recorded within the first 6 months postconsolidation. Of 142 who tested persistently PCR− in ≥2 tests after consolidation, 8 had hematologic relapse and 134 remained in complete remission (CR) after a median follow-up of 18 months (range, 6 to 38) postconsolidation. Using a time-dependent Cox model, the relative risk of hematologic relapse of patients who converted to PCR+ was 31.8 (confidence limits 95%, 12.9 to 78.3). Our results indicate that conversion to PCR positivity for PML/RARα during remission is highly predictive of subsequent hematologic relapse and highlight the prognostic value of stringent molecular monitoring during the early postconsolidation phase in APL. As a result of the present study, salvage treatment in patients enrolled in the GIMEMA trial AIDA is now anticipated at the time of molecular relapse, defined as the conversion to PCR positivity in two successive BM samplings during follow-up. © 1998 by The American Society of Hematology.

scholarly journals Highly purified primitive hematopoietic stem cells are PML-RARA negative and generate nonclonal progenitors in acute promyelocytic leukemia

Blood ◽  
1995 ◽  
Vol 85 (8) ◽  
pp. 2154-2161 ◽  
Author(s):  
AG Turhan ◽  
FM Lemoine ◽  
C Debert ◽  
ML Bonnet ◽  
C Baillou ◽  
...  
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Acute Promyelocytic Leukemia ◽  
Cell Sorting ◽  
Fusion Gene ◽  
Promyelocytic Leukemia ◽  
Pcr Analysis ◽  
Cell Populations ◽  
Rt Pcr ◽  
Hematopoietic Stem

The hierarchical level of stem cell involvement in acute promyelocytic leukemia (APL) characterized by the pathognomonic PML-RARA fusion gene is unknown. To determine if the cells of the primitive hematopoietic stem cell compartment are involved in the leukemic process, we have used molecular and cell sorting techniques in peripheral blood and bone marrow (BM) cells at diagnosis from three patients with APL and t(15; 17). In two of them, clonality analysis was also possible using the BstXI polymorphic site of the PGK gene. The PML-RARA fusion gene was readily identified by reverse transcriptase-polymerase chain reaction (RT-PCR) analysis of BM cells obtained at diagnosis in all three patients. These same samples were then used to sort CD34+ cells and their CD38+ and CD38-subsets by fluorescence-activated cell sorting. In both female patients, CD34+/CD38+ and CD34+/CD38- cell fractions were polyclonal using PCR, whereas a monoclonal pattern was identified at the BM sample obtained at diagnosis either by Southern blotting or by PCR. Because of the high sensitivity of the PCR analysis, the polyclonal pattern of these cell populations could mask the presence of a minor clone. To detect this clone, we preformed RT-PCR analysis for t(15; 17). In one female patient, the abnormal PML-RAR fusion gene was found only in the more mature CD34+/CD38+ cell fraction using a nested PCR approach, whereas the polyclonal CD34+/CD38- fraction was PML-RARA negative. These findings were confirmed in a third patient with APL in whom the PML-RARA transcripts were absent in the CD34+/CD38- cell fraction. To study the clonality at the level of clonogenic progenitors, we used in one patient PGK analysis by PCR of individual burst-forming units-erythroid and colony-forming units-granulocyte- macrophage obtained from the CD34+/CD38- and CD34+/CD38+ cell populations at diagnosis and from the BM sample obtained during remission. The two highly purified cell populations gave rise to morphologically normal colonies clonal for both the BstXI site containing (A) and the BstXI site lacking (B) PGK allelles, indicating their polyclonal content, a pattern that was also found in clonogenic progenitors obtained at remission. These findings strongly suggest that the primitive hematopoietic stem cells as defined by the CD34+/CD38- antigens are not involved by the neoplastic process in APL. These results may have important implications for autografting strategies of retinoic acid/chemotherapy-resistant or relapsed patients.

scholarly journals Autologous Bone Marrow Transplantation for Acute Promyelocytic Leukemia in Second Remission: Prognostic Relevance of Pretransplant Minimal Residual Disease Assessment by Reverse-Transcription Polymerase Chain Reaction of the PML/RARα Fusion Gene

Blood ◽  
1997 ◽  
Vol 90 (3) ◽  
pp. 1321-1325 ◽  
Author(s):  
Giovanna Meloni ◽  
Daniela Diverio ◽  
Marco Vignetti ◽  
Giuseppe Avvisati ◽  
Saveria Capria ◽  
...  
Keyword(s):  
Median Time ◽  
Fusion Gene ◽  
Autologous Bone Marrow Transplantation ◽  
Autologous Bone Marrow ◽  
Promyelocytic Leukemia ◽  
Rt Pcr ◽  
Chain Reaction ◽  
Polymerase Chain ◽  
Autologous Bone

Reverse-transcription polymerase chain reaction (RT-PCR) of the PML/RARα fusion gene may predict relapse in acute promyelocytic leukemia (APL) patients in hematologic complete remission (CR). We have prospectively studied by RT-PCR 15 PML/RARα+ APL patients undergoing autologous bone marrow transplantation (ABMT) in second CR. The median time of first CR duration was 12 months (range, 6 to 40). All patients were reinduced with all-trans retinoic acid (ATRA), followed in 12 of 15 cases by mitoxantrone and Ara-C as consolidation. Fourteen patients received the BAVC (BCNU, Ara-C, m-AMSA, and VP-16) schedule as conditioning regimen. Unpurged marrows were collected immediately before conditioning treatment, analyzed by RT-PCR, and reinfused at median of 2 months (range, 2 to 7) from the achievement of second CR. Seven patients were PCR+ and eight PCR− for PML/RARα in their pretransplant marrows. All seven patients of the former group remained PCR+ during the follow-up and relapsed at a median time of 5 months (range, 2 to 9) from ABMT and 9 months (range, 4 to 14) from second CR. Of the eight PCR− patients, all remained PCR− during the follow-up controls. One patient relapsed at 10 months from ABMT, one died of a secondary (PML/RARα−) leukemia, and six are in hematologic and molecular remission at a median time of 28 months (range, 15 to 60) after ABMT and 32 months (range, 17 to 62) from second CR. Our results indicate that, in APL patients in second CR, ABMT with PML/RARα− marrow cells is likely to result in prolonged clinical and molecular remissions. Conversely, patients who test PCR+ after reinduction necessitate the use of alternative aggressive approaches, including unrelated allogeneic transplant.

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