Discovery of 6 Novel Translocations Involving the Imatinib Responsive Genes PDGFRB and PDGFRB from Screening 29,047 Abnormal Bone Marrow Specimens.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 2902-2902
Author(s):  
Rhett P. Ketterling ◽  
Ryan A. Knudson ◽  
Heather C. Flynn Gilmer
Keyword(s):  
Bone Marrow ◽  
Mayo Clinic ◽  
Kinase Inhibitor ◽  
Hypereosinophilic Syndrome ◽  
Myeloproliferative Disorders ◽  
Fish Analysis ◽  
Disease Response ◽  
Pdgfra Gene ◽  
Abnormal Bone Marrow ◽  
Mast Cell Disease

Abstract BACKGROUND: DNA rearrangements that result in the inappropriate activation of the PDGFRA gene at 4q12 and the PDGFRB gene at 5q31-q33 occur rarely in patients with chronic myeloproliferative disorders. Approximately 10% of patients with systemic mast cell disease/hypereosinophilic syndrome have a unique mutational mechanism resulting in PDGFRA overexpression due to a novel microdeletion of the CHIC2 region resulting in the juxtaposition of FIP1L1 and PDGFRA. PDGFRB activation has been observed in patients with chronic myelomonocytic leukemia/atypical chronic myeloid leukemia and has been associated with 11 translocation partners. Since patients with demonstrable breakpoints in the PDGFRA and PDGFRB genes often have a dramatic disease response to the tyrosine kinase inhibitor imatinib, we searched the Mayo Clinic Cytogenetic database to identify additional translocation partners involving these regions. METHODS: Homebrew dual-color FISH probes were created which flank the PDGFRA gene at 4q12 and the PDGFRB gene at 5q31-q33. Archived bone marrow karyotypes analyzed in the Mayo Clinic Cytogenetics laboratory from a 15 year period (1989-2004) were reviewed to determine the frequency of specimens with breakpoints at 4q12 and 5q31-33. Of the 29,047 abnormal specimens, 64 possessed a 4q12 breakpoint and 164 possessed a 5q31-q33 breakpoint (excluding simple deletions). Of these 228 patients, residual bone marrow specimens were available from 170 patients for FISH analysis. RESULTS: Eleven of 50 patients with a 4q12 breakpoint yielded a break with the PDGFRA FISH probe. Eight patients had the previously described t(4;12)(q12;p13) which results in a reciprocal exchange between the TEL oncogene and has a break near, but not within, the PDGFRA gene. Three patients had breaks within the PDGFRA gene and had novel translocation partners including 1q44, 3q25 and 17q23. Twelve of 120 patients with a 5q31-q33 anomaly had a break detected with the PDGFRB FISH probe. Nine patients had the classic t(5;12)(q33;p13) involving PDGFRB and TEL. Three patients had novel PDGFRB translocation partners, including 1q21, 14q32 and 16p13.1. CONCLUSIONS: Breakpoints involving the PDGFRA and PDGFRB genes appear to be quite uncommon as only 23 patient samples were abnormal in our series of 29,407 abnormal bone marrow samples. With the description of three new translocations involving PDGFRB, at least 14 unique translocation partners have been identified with this gene. With the exception of the recurrent t(5;12) between PDGFRB and TEL, most translocations involving PDGFRB appear to be unique. The microdeletion of CHIC2 at 4q12 resulting in the juxtaposition of FIP1L1 and PDGFRA has been the sole mechanism thus far described resulting in the activation of this gene. The identification of the three translocations involving the PDGFRA gene represent the first classic cytogenetically visible rearrangements involving this novel gene region. While rare, we propose that all chromosome anomalies identified with breakpoints in the 4q12 and 5q31-q33 regions should receive appropriate FISH testing to determine the potential involvement of the PDGFRA and PDGFRB genes.

Alemtuzumab (CAMPATH-1H™) Is Effective Therapy for Hypereosinophilic Syndrome (HES).

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 4902-4902
Author(s):  
Alfonso Quintas-Cardama ◽  
Ayalew Tefferi ◽  
Jorge Cortes ◽  
Animesh Pardanani ◽  
Farhad Ravandi-Kashani ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Partial Response ◽  
Tyrosine Kinase ◽  
Kinase Inhibitor ◽  
Hypereosinophilic Syndrome ◽  
Response Duration ◽  
Complete Response ◽  
Clinical Results ◽  
Small Subset ◽  
Weekly Cycles

Abstract Idiopathic HES is a myeloproliferative disorder (MPD) characterized by persistent overproduction of eosinophils resulting in organ damage. In a small subset of patients (pts), the disease is caused by the FIP1L1-PDGFR-α fusion tyrosine kinase. Its expression has been associated with complete clinical responses to therapy with tyrosine kinase inhibitor (TKI) imatinib mesylate. In contrast, there is no specific therapy for pts with HES lacking FIP1L1-PDGFR-α expression and corticosteroids are used for palliation. Alemtuzumab (Campath-1H™) is a humanized rat monoclonal antibody directed against the CD52 antigen. Since CD52 is expressed on eosinophils, we evaluated its efficacy in pts with FIP1L1-PDGFR-α-negative symptomatic HES. A total of 9 pts (5 male, 4 female) received alemtuzumab in weekly cycles at the dose of 30 (8 pts) or 10 (1 pt) mg 3 times a week intravenously or subcutaneously. During the first week alemtuzumab was given in escalating doses (3→10→30mg) to assure tolerance. Median age was 53 years (range 24–70), time from HES diagnosis to alemtuzumab therapy 34 months (range 4–195), median WBC 17×109/L (range 6.9–82.4), absolute eosinophil count (AEC) 9×109/L (range 0.7–30), and bone marrow eosinophils 23% (range 10–68). Three pts had abnormal cytogenetics: del11(q23), +8, and t(5;6). Pts had received a median of 3 prior therapies (range 2–6), including corticosteroids (prednisone; n=9), imatinib (n=7), dasatinib (n=3), interferon-alpha (n=3), hydroxyurea (n=3), nilotinib (n=2), and cladribine (n=2). A total of 121 weekly cycles have been administered (median 13 cycles) thus far. A complete hematologic response (CHR; i.e. AEC normalization) was observed in 8 pts (89%) within 4 weeks of therapy; peripheral blood eosinophils were undetectable in 6 of 8 CHR pts. Follow-up bone marrow specimens were available in 3 pts while in CHR (after a median of 5.5 weekly alemtuzumab cycles) showing complete response in 2 and partial response in 1 pt. In addition, 3 pts that were on prednisone and 2 on hydroxyurea at the start of alemtuzumab discontinued them within 2 weeks into therapy. One pt had a remarkable partial response with reduction of AEC from 47.5 to 1×109/L after 8 weekly cycles of alemtuzumab; this patient was on 3g of hydroxyurea and 80mg of prednisone at the start of alemtuzumab and was able to discontinue hydroxyurea and decrease prednisone to 10mg while on alemtuzumab. Five pts who stopped alemtuzumab experienced relapse after a median time of 3.5 weeks (range, 1 to 10) and 1 relapsed while receiving alemtuzumab after 14 weekly cycles. Three pts are currently on alemtuzumab: 2 receiving 30 mg weekly as maintenance while in CHR after 8+ and 19+ weeks, respectively, and 1 with partial response is receiving 30mg 3 times a week. One relapsed pt was rechallenged with alemtuzumab and normalized AEC again. Alemtuzumab was generally well tolerated. Grade 3–4 drug-related toxicities occurred in 2 pts, 1 with neutropenia and 1 with infusion-related fever, which led to transient and complete alemtuzumab discontinuation, respectively. Two pts experienced CMV reactivation that required therapy. In summary, alemtuzumab was well tolerated and has remarkable activity in pts with FIP1L1-PDGFR-α-negative HES. Different dose schedules of alemtuzumab that include prolonged maintenance therapy are warranted to improve the response duration. Updated clinical results will be presented.

scholarly journals Severe Eosinophilia Associated with FIP1L1/PDGFRA Rearrangement Presenting with Yamaguchi Syndrome

2021 ◽  
Vol 8 (1) ◽  
Author(s):  
Aamir Z ◽  
◽  
Hanif HM ◽  
Keyword(s):  
Bone Marrow ◽  
Peripheral Blood ◽  
Low Dose ◽  
Kinase Inhibitor ◽  
Organ Damage ◽  
Left Ventricular ◽  
Fish Analysis ◽  
Chronic Eosinophilic Leukemia ◽  
Organ Tissue ◽  
Apical Hypertrophy

FIP1L1/PDGFRA is a rare genetic rearrangement, presenting most commonly as Chronic Eosinophilic Leukemia (CEL), but may also be associated with other myeloid and lymphoid neoplasms. The peripheral blood and bone marrow exhibit a striking eosinophilia, often associated with an increased number of mast cells on trephine biopsy. Tissue infiltration by eosinophils and release of cytokines from eosinophilic granules mediate multi-organ tissue damage. The tyrosine kinase inhibitor Imatinib has been shown to induce rapid and complete clinical and haematological responses in patients harboring the mutation. We present the case of a young patient with CEL associated with PDGFRA rearrangement, presenting with severe eosinophilia and evidence of multi-organ damage (cardiac, renal, endocrine and respiratory). The peripheral blood and bone marrow displayed a striking eosinophila, and FISH analysis for FIP1L1/PDGFRA revealed a positive fusion signal in 92% of the nuclei examined. Echocardiography showed left ventricular apical hypertrophy (Yamaguchi syndrome), which has previously not been reported in this subset of patients. He was managed with supportive care, along with low-dose imatinib (100mg/day initially), to which he achieved a rapid clinical and haematological response. Currently, five months from the initial diagnosis, he is doing well on low dose imatinib (100 mg) twice a week.

Evaluation of Mast Cells in Myeloproliferative Disorders and Myelodysplastic Syndromes

2005 ◽  
Vol 129 (2) ◽  
pp. 219-222 ◽  
Author(s):  
Cherie H. Dunphy
Keyword(s):  
Bone Marrow ◽  
Mast Cell ◽  
Mast Cells ◽  
Myelodysplastic Syndromes ◽  
Bone Marrow Cells ◽  
Myeloproliferative Disorders ◽  
Systematic Evaluation ◽  
Malignant Neoplasms ◽  
Hematologic Disorder ◽  
Mast Cell Disease

Abstract Context.—Mast cells may be increased as a reactive mastocytosis in various hematologic disorders and malignant neoplasms, as well as in systemic mast cell disease (SMCD). There are no statistical differences in mast cell numbers in reactive mastocytosis and SMCD; however, SMCD usually reveals dyspoietic mast cells and other dyspoietic bone marrow elements. In addition, SMCD is frequently (45%) associated with myeloproliferative disorders (MPDs) (17%) and myelodysplastic syndromes (MDSs) (28%). Thus, it has been suggested that SMCD may represent one aspect of a hematologic disorder that involves multiple bone marrow lineages. Objective.—To perform a systematic evaluation of MPDs and MDSs without SMCD for dyspoietic mast cells. Design.—A total of 55 MPDs or MDSs were reviewed, including 20 cytogenetically proven chronic myeloid leukemias, 6 essential thrombocythemias, 2 polycythemia veras, 21 cytogenetically proven MDSs, and 6 chronic myelomonocytic leukemias. Cases of idiopathic myelofibrosis were not included due to lack of spicules. The bone marrow aspirates were reviewed for an increase in mast cells (1+ to 3+), dyspoietic features within mast cells (decreased cytoplasmic granularity, uneven granule distribution), and a predominance of fusiform mast cells. Results.—All cases, except 2 MDSs, had evaluable bone marrow spicules. Of interest, the MPDs were significantly more associated with increased and dyspoietic mast cells (57% and 61%, respectively) than were the MDSs (11% and 4%, respectively). The 2 polycythemia veras and 6 chronic myelomonocytic leukemias did not reveal increased or dyspoietic mast cells. Conclusions.—These findings indicate that MPDs (chronic myeloid leukemia and essential thrombocythemia) frequently contain neoplastic mast cells as the spectrum of abnormal bone marrow cells. This feature, in conjunction with other parameters, may possibly be useful in the differential diagnosis of MPDs and MDSs. Our findings, compared with the previously reported findings in SMCD, suggest that SMCD may be more closely related to MPDs than to MDSs.

FIP1L1-PDGFRA fusion: prevalence and clinicopathologic correlates in 89 consecutive patients with moderate to severe eosinophilia

Blood ◽  
2004 ◽  
Vol 104 (10) ◽  
pp. 3038-3045 ◽  
Author(s):  
Animesh Pardanani ◽  
Stephanie R. Brockman ◽  
Sarah F. Paternoster ◽  
Heather C. Flynn ◽  
Rhett P. Ketterling ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Mast Cell ◽  
Bone Marrow Cells ◽  
Systemic Mastocytosis ◽  
Hypereosinophilic Syndrome ◽  
Growth Factor Receptor ◽  
Oncogenic Mutation ◽  
Mast Cell Disease ◽  
Bone Marrow Mast Cell

Abstract A novel oncogenic mutation (FIP1L1-PDGFRA), which results in a constitutively activated platelet-derived growth factor receptor-α (PDGFRA), has been invariably associated with a primary eosinophilic disorder. The current study examines both the prevalence and the associated clinicopathologic features of this mutation in a cohort of 89 adult patients presenting with an absolute eosinophil count (AEC) of higher than 1.5 × 109/L. A fluorescence in situ hybridization (FISH)–based strategy was used to detect FIP1L1-PDGFRA in bone marrow cells. None of 8 patients with reactive eosinophilia displayed the abnormality, whereas the incidence of FIP1L1-PDGFRA in the remaining 81 patients with primary eosinophilia was 14% (11 patients). None (0%) of 57 patients with the hypereosinophilic syndrome (HES) but 10 (56%) of 19 patients with systemic mast cell disease associated with eosinophilia (SMCD-eos) carried the specific mutation. The bone marrow mast cell infiltration pattern in FIP1L1-PDGFRA+ SMCD-eos was distinctly diffuse with loose tumoral aggregates. Treatment with low-dose imatinib (100 mg/d) produced complete and durable responses in all 8 FIP1L1-PDGFRA+ cases treated. In contrast, only 40% partial response rate was seen in 10 HES cases. FIP1L1-PDGFRA is a relatively infrequent but treatment-relevant mutation in primary eosinophilia that is indicative of an underlying systemic mastocytosis.

BAALC and WT1 Transcript Amount Discriminates Secondary or Reactive Eosinophilia from Idiopathic Hypereosinophilic Syndrome or Chronic Eosinophilic Leukemia

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 5222-5222
Author(s):  
Jiannong Cen ◽  
Zixing Chen ◽  
Xiaofei Qi ◽  
Li Yao ◽  
Jun He ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Mononuclear Cells ◽  
Fusion Gene ◽  
Hypereosinophilic Syndrome ◽  
Myeloproliferative Disorders ◽  
Hematopoietic Stem ◽  
Chronic Eosinophilic Leukemia ◽  
Relative Expression Level ◽  
Clinical Conditions ◽  
Transcript Amount

Abstract Idiopathic hypereosinophilic syndromes (HES) or chronic eosinophilic leukemia (CEL) comprise a spectrum of indolent to aggressive diseases characterized by persistent hypereosinophilia. Hypereosinophilia can result from the presence of a defect in the hematopoietic stem cell giving rise to eosinophilia, it can present in many myeloproliferative disorders or alternatively it may be a reactive form, secondary to many clinical conditions. The fusion gene FIP1L1-PDGFR alpha was identified in a subset of patients presenting with HES/CEL. In spite of this, the majority of HES/CEL patients do not present detectable molecular lesions and for many of them the diagnosis is based on exclusion criteria and sometimes it remains doubt. CD34-positive progenitor cells from bone marrow (BM) express BAALC and WT1. Overexpression of BAALC and WT1 were seen in patients with AML and ALL. In a subset of AML it marked poor prognosis, suggesting a role for BAALC or WT1 overexpression in acute leukemia. To explored the possibility to distinguish between HES/CEL and reactive hypereosinophilia based on the measurement of BAALC and WT1 transcript amount. Twenty-two patients with hypereosinophilia were characterized at the molecular level and analyzed for BAALC and WT1 expression. The transcription of FIP1L1-PDGFRalpha fusion gene was detected by nested RT-PCR. The relative transcript amount of BAALC and WT1 were determined by real time PCR analyses. The FIP1L1-PDGFRalpha fusion gene expressed has been identified in bone marrow mononuclear cells of 4 cases. The relative expression level of BAALC and WT1 in these 4 cases with positive FIP1L1-PDGFRalpha fusion gene expression were 2.27(0.27–6.8) and 0.39(0.002–0.90), respectively. Whereas the relative amount of transcripts of BAALC and WT1 in 18 patients with negative FIP1L1-PDGFRalpha fusion gene were 0.069(0.015–0.11) and 0.054(0–0.34) respectively. The relative amount of transcripts of BAALC and WT1 in patients with HES/CEL were 32 times and 7 times than that in those with negative FIP1L1-PDGFRalpha fusion gene, respectively. These results clearly demonstrates that BAALC and WT1 quantitative assessment allows to discriminate between HES/CEL and reactive eosinophilia and represents a useful tool for disease monitoring especially in the patients lacking a marker of clonality.

Simultaneous Supression of CML and GIST by Imatinib in Single Patient.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 4660-4660
Author(s):  
Yuko Mishima ◽  
Yasuhito Terui ◽  
Kengo Takeuchi ◽  
Masahiro Yokoyama ◽  
Eijiro Nagasaki ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Kinase Inhibitor ◽  
Submucosal Tumor ◽  
Smooth Muscle Actin ◽  
S100 Protein ◽  
Chronic Phase ◽  
Simultaneous Occurrence ◽  
Fish Analysis ◽  
Gastric Submucosal Tumor ◽  
Kit Mutation

Abstract Background: Imatinib mesylate, that is tyrosine kinase inhibitor, is highly effective drug for chronic myeloogenous leukemia(CML). Imatinib induces cytogenetical and molecular remission for CML without bone marrow transplantation. Imatinib is effective for not only CML but Gastrointestinal Tumor (GIST). Imatinib targets mutation of c-kit or platelet derived growth factor receptor alpha (PDGF-alpha) in GIST. Before these days, the case of double cancer of CML with GIST has not been reported yet. Clinical Course: A 43-year-old man, who admitted our hospital, had leukocytosis, thrombocytosis, and melaena. His white blood cell (WBC) count was 65×10 4 /μL, hemoglobin level was 13.5 g/dl, and platelet count was 114.2×10 4/μL. The WBC fraction was as follows: blast 1%; promyelocyte 1.5%; myelocyte 13.5%; metamyelocyte 2.5%; band 5.5%; segment 46.5%; lymphocyte 16.5%; monocyte 4.5%; basophil 3.0% and eosinophil 5.5%. The bone marrow aspiration demonstrated the hypercellular bone marrow and blast cells did not increase and metaplasia of cells was not observed. Karyotypic FISH analysis revealed the chromosome of t(9;22)(q34:q11) and he was diagnosed as CML in chronic phase. He had no splenomegaly. At this time, gastric submucosal tumor was detected by endoscopy of the upper gastrointestinal tract. The tumor located lesser curvature of the mid-stomach and had no mobility. Under the fiberscopic ultrasonography, the submucosal tumor had low and heterogenous echogenic pattern. The computed tomography showed that the tumor, which size was six cm, was solid mass and associated with calcification. For the therapy, in the first, Imatinib (400mg) was started against CML. His WBC and platelet was slowly decreased and after four months he reached at morphological remission. FISH showed the presence of 30% bcr/abl+ transcript in his bone marrow. In this period, although the size of his submucosal tumor did not change on the CT, it seemed that the elevation of mucosa was decreased under the gastrointestinal fiberscopy. After nine months from start of Imatinib, he received surgical resection of gastric submucosal tumor. The size of removed tumor was about six cm and the tumor associated with broad necrotic lesion. Histological analysis indicated from limited alive lesion. Microscopically, fibrotic and hyalinized lesions cover approximately 99% of the area examined. The residual tumor consists of spindle cells with mild nuclear atypia. Immunohistochemically, the tumor is positive for KIT/CD117 and CD34, and negative for muscle specific actin (HHF35), smooth muscle actin (1A4), desmin and S100 protein. These features are characteristic of GIST. The c-kit mutation was studied by PCR. And we identified the tumor was gastrointestinal stromal tumor (GIST). Discussion: That is first report of simultaneous occurrence CML and GIST in one patient. We selected that after the remission of CML with Imatinib, resection of GIST was performed. That was very curative therapy for him.

Increased Response to Arachidonic Acid and U-46619 and Resistance to Inhibitory Prostaglandins in Patients with Chronic Myeloproliferative Disorders

1988 ◽  
Vol 59 (01) ◽  
pp. 073-076 ◽  
Author(s):  
Sergio Cortelazzo ◽  
Monica Galli ◽  
Donatella Castagna ◽  
Piera Viero ◽  
Giovanni de Gaetano ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Arachidonic Acid ◽  
Platelet Aggregation ◽  
Myeloproliferative Disorders ◽  
Bone Marrow Stem Cell ◽  
Healthy Controls ◽  
Aggregation Response ◽  
Thrombotic Complications ◽  
Cyclic Endoperoxide ◽  
Marrow Stem Cell

SummaryIn patients with myeloproliferative disorders (MPD) a group of related diseases of the bone marrow stem cell and recurrent haemorrhagic and/or thrombotic complications, the production of aggregating prostaglandins (PGs) may be normal or slightly reduced, while PGI2 production is normal. However, MPD platelet sensitivity to antiaggregatory PGs is still unknown.We studied the potency of PGD2, PGI2 and PGEi as inhibitors of platelet aggregation induced by threshold aggregating concentrations of arachidonic acid and U-46619-analogue of the cyclic endoperoxide PGH2 in 20 patients with MPD in comparison with healthy controls, with the aim of evaluating the sensitivity of MPD platelets to antiaggregatory PGs. In these patients platelet prostanoid metabolism was normal. However, the functional response of platelets to aggregating and antiaggregating prostanoids was shifted towards potentially increased platelet aggregation response. These findings could have a clinical relevance in view of the haemostatic and thrombotic complications so frequent in MPD.

Eosinophilic fasciitis associated with hypereosinophilia, abnormal bone-marrow karyotype and inversion of chromosome 5

2013 ◽  
Vol 39 (2) ◽  
pp. 150-153 ◽  
Author(s):  
J. S. Ferguson ◽  
J. Bosworth ◽  
T. Min ◽  
J. Mercieca ◽  
C. A. Holden
Keyword(s):  
Bone Marrow ◽  
Eosinophilic Fasciitis ◽  
Chromosome 5 ◽  
Abnormal Bone Marrow ◽  
And Inversion

scholarly journals A review of current knowledge of myeloproliferative disorders in the horse

2021 ◽  
Vol 63 (1) ◽  
Author(s):  
Katy Satué ◽  
Juan Carlos Gardon ◽  
Ana Muñoz
Keyword(s):  
Bone Marrow ◽  
Myeloid Leukemia ◽  
Current Knowledge ◽  
Myeloproliferative Neoplasms ◽  
Myeloproliferative Disorders ◽  
World Health ◽  
Chronic Granulocytic Leukemia ◽  
Current State ◽  
Multiple Cell ◽  
Health Organization

AbstractMyeloid disorders are conditions being characterized by abnormal proliferation and development of myeloid lineage including granulocytes (neutrophils, eosinophils and basophils), monocytes, erythroids, and megakaryocytes precursor cells. Myeloid leukemia, based on clinical presentation and proliferative rate of neoplastic cells, is divided into acute (AML) and myeloproliferative neoplasms (MPN). The most commonly myeloid leukemia reported in horses are AML-M4 (myelomonocytic) and AML-M5 (monocytic). Isolated cases of AML-M6B (acute erythroid leukemia), and chronic granulocytic leukemia have also been reported. Additionally, bone marrow disorders with dysplastic alterations and ineffective hematopoiesis affecting single or multiple cell lineages or myelodysplastic diseases (MDS), have also been reported in horses. MDSs have increased myeloblasts numbers in blood or bone marrow, although less than 20%, which is the minimum level required for diagnosis of AML. This review performed a detailed description of the current state of knowlegde of the myeloproliferative disorders in horses following the criteria established by the World Health Organization.

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