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  • 1
    In: Blood, American Society of Hematology, Vol. 138, No. Supplement 1 ( 2021-11-05), p. 2384-2384
    Abstract: Background KMT2A-rearranged acute lymphoblastic leukemia (KMT2A-r ALL) is a rare and dismal disease in infants. Despite restriction of the indication of allogeneic hematopoietic stem cell transplantation to the high-risk group (patients aged & lt;180 days with KMT2A-r ALL or central nervous system involvement), adoption of an Interfant-06-based induction therapy with stricter age-related dosing followed by COG AALL0631-based post-remission chemotherapy with additional administration of high-dose cytarabine in the early intensification phase led to rapid clearance of minimal residual disease (MRD) in the Japanese Pediatric Leukemia/Lymphoma Study Group (JPLSG) MLL-10 trial. The MLL-10 trial demonstrated an improved outcome of 66.2% in 3-year event-free survival (EFS) among infants with KMT2A-r ALL (Tomizawa D. Blood 2021). As the Interfant-06 study showed an association between the expression levels of myeloid markers (MM) and poor MRD clearance at end of induction (EOI) and a high relapse rate (Stutterheim J, J Clin Oncol.2021), we analyzed the significance of MM expression in the MLL-10 cohort and its association with prognosis. Methods We analyzed and compared the MM expression (defined as at least one positive marker [with a positive blast subset ≥ 10%] among CD117, CD13, CD33, and CD65/CD15) by using flow cytometry (FCM) in infants with KMT2A-r ALL who were registered in the JPLSG MLL-10 trial. We also compared the results of immunoglobulin/T-cell receptor (Ig/TCR) gene-based polymerase chain reaction (PCR)-MRD analyses or 4-color FCM-MRD assay between the MM-positive and MM-negative groups at EOI and end of early consolidation. The Ig/TCR-MRD results were classified as negative if & lt;5 × 10 −4 and positive if ≥5 × 10 −4, while the FCM-MRD results were classified as negative if & lt;0.01% and positive if ≥0.01%. We prioritized PCR-MRD and used FCM-MRD when we could not make a primer for PCR-MRD. The presence of MRD was not used as a basis for choosing the appropriate therapy. Results and Discussion Among the patients with KMT2A-rALL, 74 were included in this study, excluding one who was not evaluated with FCM at diagnosis. Of these patients, 42 were MM-positive and 32 were MM-negative. The 3-year EFS rates of the MM-positive and MM-negative patients were 62.3% (95% confidence interval [CI], 45.5-75.3) and 70.0% (95% CI, 50.3-83.1), respectively (p = 0.61). Their 3-year overall survival rates were 80.6% (95% CI, 65.0-89.8) and 87.5% (95% CI, 70.0-95.1), respectively (p = 0.74). The numbers of MM-positive and MM-negative patients according to age group are summarized in Table 1, and the difference in age distribution between the two groups was not significant. The MRD statuses of the patients at EOI in the two groups are also summarized in Table 1. No significant difference in MRD clearance was found between the MM-positive and MM-negative groups. Conclusion In this study, we found no significant difference in survival rate between the MM-positive and MM-negative groups. The MM expression was not a prognostic marker in the infants with KMT2A-r ALL in the MLL-10 cohort. We believe that rapid MRD clearance in the early phase of treatment with enhanced chemotherapy would have the greatest contribution to the improvement of prognosis. In this study, the MM-positive patients from the MLL-10 cohort might have benefited from early-phase treatment intensification in terms of MRD clearance. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2021
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  • 2
    In: Blood, American Society of Hematology, Vol. 135, No. 24 ( 2020-06-11), p. 2146-2158
    Abstract: Immunomodulatory drugs (IMiDs) are key agents for the treatment of multiple myeloma and myelodysplastic syndrome with chromosome 5q deletion. IMiDs exert their pleiotropic effects through the recruitment of neosubstrates to cereblon, a substrate receptor of the E3 ubiquitin ligase complex; therefore, identification of cell-specific neosubstrates is important to understand the effects of IMiDs. In clinical practice, IMiDs induce thrombocytopenia, which frequently results in the discontinuation of IMiD treatment. In the current study, we sought to identify the molecular mechanism underlying thrombocytopenia induced by IMiD treatment. We found that IMiDs strongly impaired proplatelet formation, a critical step in functional platelet production, through the inhibition of autocrine estradiol signaling in human megakaryocytes. Furthermore, we identified aromatase, an indispensable enzyme for estradiol biosynthesis, as a novel neosubstrate of cereblon. IMiDs promoted the recruitment of aromatase to cereblon, resulting in the degradation of aromatase in a proteasome-dependent manner. Finally, aromatase was significantly degraded in the bone marrow of patients with multiple myeloma who developed thrombocytopenia with IMiD treatment. These data suggest that aromatase is a neosubstrate of cereblon that is responsible for IMiD-induced thrombocytopenia.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2020
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  • 3
    In: Blood, American Society of Hematology, Vol. 140, No. Supplement 1 ( 2022-11-15), p. 9094-9095
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2022
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  • 4
    In: Blood, American Society of Hematology, Vol. 134, No. Supplement_1 ( 2019-11-13), p. 3854-3854
    Abstract: Introduction. Elderly patients aged 65 or older with acute myeloid leukemia (AML) are often ineligible for hematopoietic stem cell transplantation (HSCT) and generally have a poor prognosis. The prognostic risk classification based on NCCN Guidelines Version3. 2017; NCCN 2017 (O'Donnell MR, JNCCN. 2017) is widely performed; however, the impact of this classification on the prognosis of such elderly AML patients is unclear. While nutritional status assessment using controlling nutritional status (CONUT score) based on serum level of albumin (Alb), total-cholesterol (T-chol) and total lymphocyte count (TLC) predicts prognosis of elderly patients with solid tumor (Liu X, BMC Cancer. 2018), the prognostic significance of nutritional status in elderly patients with AML remains to be clarified. Methods. Hokkaido Leukemia Net (HLN) is prospective cohort study collecting AML samples from hospitals of North Japan Hematology Study Group (NJHSG). In this study, we focused on newly diagnosed AML patients aged 65 or older treated without HSCT, and investigated cytogenetic and molecular abnormality of leukemic cells including FLT3-ITD, NPM1, CEBPA, and KIT. We stratified the patients into favorable, intermediate, and adverse risk group based on NCCN 2017. In order to adjust the assessment of nutritional status for hematopoietic malignancy, we modified the CONUT score eliminating TLC from evaluation criteria (modified-CONUT score, Table) and defined patients with score 3 or more at diagnosis as high group. We evaluated the impacts of NCCN 2017 and modified-CONUT scores on overall survival (OS) in these patients. The study procedures were in accordance with the Helsinki Declaration and institutional ethical guidelines, conducted under the auspices of the institutional ethics committee, and approved by the institutional review boards. Results. Overall, 181 patients with newly diagnosed AML patients aged 65 or older enrolled in HLN between April 2010 and March 2018. Seven patients undergone HSCT were excluded and 174 patients were reviewed (Age 65-93, median 71; male 104, female 70). In this cohort, classification based on NCCN 2017 successfully divided the prognosis of the patients for 2-year and 5-year OS [2-year OS; favorable group, 59.9%; intermediate group, 43.8%; adverse group, 8.1%, 5-year OS; favorable group, 41.5%, intermediate group, 19.7%; adverse group, 4.1%, P=0.00258, Figure A]. On 112 patients who had available records of serum Alb levels and T-chol levels at diagnosis, OS in patients with high modified-CONUT score was significantly lower than the low score group [2-year OS; low score group, 50.3%; high score group, 18.5%; 5-year OS; low score group, 23.5%; high score group, 9.24%, P=0.00203, Figure B] . In a univariate analysis, adverse group in NCCN 2017 and high modified-CONUT score were associated with poor 2-year OS. A multivariate analysis demonstrated that adverse group in NCCN 2017 and high modified-CONUT score were independently associated with poor 2-year OS (adverse group in NCCN 2017; HR, 2.464 ; 95% CI, 1.514 to 4.012, P=0.0002854, high modified-CONUT score; HR, 1.664 ; 95% CI, 1.051 to 2.635, P=0.02976; log-rank). Altogether, we demonstrated that risk stratification based on NCCN 2017 and modified-CONUT score are both effective for predicting prognosis in elderly patients with newly diagnosed AML. Conclusion. The prognostic risk classification based on AML disease status using NCCN Guidelines 2017 effectively stratify prognosis of elderly patients with AML. Moreover, new assessment scoring of patients' nutrition status based on modified-CONUT score can easily stratify elderly patients with newly diagnosed AML. Figure Disclosures Teshima: Novartis: Honoraria, Research Funding.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2019
    detail.hit.zdb_id: 1468538-3
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  • 5
    In: Blood, American Society of Hematology, Vol. 130, No. Suppl_1 ( 2017-12-07), p. 841-841
    Abstract: Adoptive cell transfers of receptor gene-engineered T cells include chimeric antigen receptor-gene transduced T (CAR-T) cell therapy and TCR-gene transduced T (TCR-T) cell therapy. In CD19-CAR-T cell therapy, high incidence of cytokine release syndrome (CRS) is associated with in vivo CAR-T cell proliferation and its clinical efficacy. In human TCR-T cell therapies, there have not been well known about CRS and its association with in vivo T cell kinetics or tumor responses. We have been developing a novel-type affinity-enhanced NY-ESO-1-specific TCR, and an original retrovirus vector that encodes siRNA to silence endogenous TCR creation. The NY-ESO-1 TCR is mutated for high affinity with replacements of G50A and A51E in CDR2 region, which is restricted with HLA-A*02:01 and A*02:06. We extensively examined potential cross-reactivities to different antigen-peptides in preclinical studies, and the high-affinity NY-ESO-1 TCR did not recognize analogous peptides. The new generation retroviral TCR-vector provides enhanced expression of transduced tumor-specific TCRs and an inhibition effect of formations of self-reactive TCRs. This is a first-in-man clinical trial of the novel NY-ESO-1-specfic TCR-T cell transfer to evaluate the safety, in vivo cell kinetics and clinical responses. It is designed as a cell-dose escalation from 5 x108 to 5 x109 cells. NY-ESO-1-expressing refractory cancer patients were enrolled, with 3+3 cohort design. Cyclophosphamide with/without fludarabine were administered prior to the TCR-T cell transfer as pre-conditioning. Six patients were treated with the NY-ESO-1 TCR-T cell transfer, and evaluated for the safety and in vivo cell kinetics. The TCR-T cells appeared in peripheral blood with a dose-dependent manner, associated with in vivo proliferation in an early phase. In three patients given 5x108 cells, no toxicities were seen. Two patients receiving 5x109 cells developed early-phase CRS (G2), with elevations of serum IL-6 and IFN-gamma. They were managed the treatment of anti-IL-6 receptor monoclonal antibody, tocilizumab. In a patient who developed CRS, an event of lung injury (G3) occurred, which was associated with marked infiltration of the NY-ESO-1 TCR-T cells. It was successfully treated with steroid. Two synovial sarcoma patients exhibited tumor responses of PRs. In one patient, progression-free survival lasted more than 8 months. In summary, the affinity-enhanced NY-ESO-1 TCR-T cell transfer exhibited CRSs in association with in vivo cell proliferation and sequential tumor responses. Disclosures No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2017
    detail.hit.zdb_id: 1468538-3
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  • 6
    In: Blood Advances, American Society of Hematology, Vol. 3, No. 21 ( 2019-11-12), p. 3266-3277
    Abstract: The cost of TKI for treatment of CML can be substantially saved by treatment discontinuation in patients who achieved DMR. Starting treatment with imatinib is the most cost-effective strategy even after incorporation of treatment discontinuation.
    Type of Medium: Online Resource
    ISSN: 2473-9529 , 2473-9537
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2019
    detail.hit.zdb_id: 2876449-3
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  • 7
    In: Blood, American Society of Hematology, Vol. 140, No. Supplement 1 ( 2022-11-15), p. 9207-9208
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2022
    detail.hit.zdb_id: 1468538-3
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  • 8
    In: Blood, American Society of Hematology, Vol. 138, No. Supplement 1 ( 2021-11-05), p. 3388-3388
    Abstract: Introduction. Older patients aged over 65 with acute myeloid leukemia (AML) are often ineligible for hematopoietic stem cell transplantation (HSCT) and generally have a poor prognosis. The personalized strategy for appropriate treatment for these patients has not yet been completely established. While C-reactive-protein (CRP) to albumin ratio (CAR) based on serum level of CRP and albumin (Alb) predicts prognosis of patients with hematological malignancies treated with HSCT (Miyashita E, BBMT. 2019), the prognostic significance of this inflammatory and nutritional assessment in transplant-ineligible elderly patients with AML remains to be clarified. Methods. Hokkaido Leukemia Net (HLN) is prospective cohort study collecting AML samples from hospitals of North Japan Hematology Study Group (NJHSG). In this study, we focused on older (≥65 years) patients with newly diagnosed AML treated without HSCT and investigated cytogenetic and molecular abnormality of leukemic cells including FLT3-ITD, NPM1, CEBPA, and KIT. We stratified the patients into favorable, intermediate, and adverse risk group based on NCCN 2017. Based on the result of blood sample test, we assessed CAR [CRP (mg/dL) / Alb (g/dL)] at diagnosis for each patient. Since the median CAR at diagnosis was 0.52 in this cohort, we defined CAR & lt; 0.52 and ≥ 0.52 as CAR low and CAR high, respectively. We evaluated the impacts of NCCN 2017 and CAR on overall survival (OS) in these patients. The study procedures were in accordance with the Helsinki Declaration and institutional ethical guidelines, conducted under the auspices of the institutional ethics committee, and approved by the institutional review boards. Results. In total, 197 patients with newly diagnosed AML patients aged 65 or older enrolled in HLN between April 2010 and March 2019. Nine patients undergone HSCT were excluded, and 188 patients were reviewed (Age 65-93, median 72; male 119, female 69). In this cohort, classification based on NCCN 2017 successfully divided the prognosis of the patients for 2-year and 5-year OS [2-year OS; favorable group, 58.1%; intermediate group, 29.4%; adverse group, 12.6%, 5-year OS; favorable group, 33.7%, intermediate group, 8.74%; adverse group, 9.44%, P=0.000079, Figure A]. OS in patients with CAR 0.52 or more was significantly lower than the low score group [2-year OS; CAR low group, 43.4%; CAR high group, 21.5%; 5-year OS; CAR low group, 21.0%; CAR high group, 9.96%, P=0.00013, Figure B] . In a univariate analysis, higher age, adverse group in NCCN 2017, high CAR, and not reached complete remission (CR) after first induction chemotherapy were associated with poor 2-year OS. A multivariate analysis demonstrated that adverse group in NCCN 2017 and high CAR were independently associated with poor 2-year OS (adverse group in NCCN 2017; HR, 1.671; 95% CI, 1.157 to 2.421, P=0.007, high CAR; HR, 1.572; 95% CI, 1.093 to 2.276, P=0.01618; log-rank). Combined with NCCN 2017, while there were no significant prognostic impacts of CAR at diagnosis in patients with favorable or adverse risk groups (Figure C, E), we found that in intermediate risk group the patients with high CAR had poorer prognosis than patients with low CAR [2-year OS; CAR low group, 43.7%; CAR high group, 15.9%, P=0.0000658; Figure D]. Altogether, we demonstrated that high CAR predicts poor prognosis in the transplant-ineligible elderly patients with newly diagnosed AML and improves risk stratification of the patients with NCCN 2017 intermediate risk group. Conclusion. CAR is a simple and easily evaluable parameter for predicting outcomes of transplant-ineligible elderly patients with newly diagnosed AML, independently from NCCN disease risk classification. Moreover, CAR can further stratify the prognosis of patients with NCCN 2017 intermediate risk group and improve the predictive risk stratification for elderly AML patients. Figure 1 Figure 1. Disclosures Kondo: SANWA KAGAKU KENKYUSHO CO.,LTD.: Consultancy; Astellas Pharma Inc.: Consultancy, Honoraria; Otsuka Pharmaceutical Co., Ltd.: Honoraria, Research Funding; Novartis Pharma KK: Honoraria; Bristol-Myers Squibb Company: Honoraria; Sumitomo Dainippon Pharma Co., Ltd.: Honoraria. Teshima: Merck Sharp & Dohme: Membership on an entity's Board of Directors or advisory committees; Nippon Shinyaku Co., Ltd.: Research Funding; Pfizer Inc.: Honoraria; Fuji pharma CO.,Ltd: Research Funding; Kyowa Kirin Co.,Ltd.: Honoraria, Research Funding; TEIJIN PHARMA Limited: Research Funding; Bristol Myers Squibb: Honoraria; Janssen Pharmaceutical K.K.: Other; CHUGAI PHARMACEUTICAL CO., LTD.: Research Funding; Astellas Pharma Inc.: Research Funding; Takeda Pharmaceutical Company: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis International AG: Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; Gentium/Jazz Pharmaceuticals: Consultancy; Sanofi S.A.: Research Funding.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2021
    detail.hit.zdb_id: 1468538-3
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  • 9
    In: Blood, American Society of Hematology, Vol. 128, No. 22 ( 2016-12-02), p. 4070-4070
    Abstract: [Background] Mixed lineage leukemia (MLL also called KMT2A) rearrangement-positive leukemia is one of the most aggressive types of leukemia. It is diagnosed predominantly in infants and typically shows a multi-lineage phenotype. Since current chemotherapy fails in more than 50% of infantile acute lymphoblastic leukemia (ALL) with MLL-rearrangement, a better understanding of biological features of the disease is important in order to develop more specific and successful treatment strategies. Despite the evident biological and clinical significance of MLL-rearrangement, it has also been shown in vitro and in vivo that MLL-rearrangement is not sufficient to induce full leukemic transformation, indicating additional hits are required for complete leukemogenesis. Recently, sequencing-based genome-wide studies have suggested collaborative involvement of RAS-PI3K pathway in infant leukemogenesis through identification of recurrent mutations affecting RAS-PI3K pathway genes, in infant ALL with or without MLL-rearrangement. However, genetic basis of infant ALL with MLL-rearrangement are not fully elucidated. [Materials and Methods] Here, we performed whole exome sequencing in leukemia samples with matched peripheral blood T lymphocyte from 46 cases of infant ALL including 3 cases with germline MLL. Our cohort included samples from the Infant Leukemia Sub-committee, Japan Children's Cancer Group. For mapping and mutation calling, we used publicly available "Genomon Pipeline". [Results] In total, 198 somatic non-silent mutations (4.3 mutations per case) were identified, including 125 missense, 4 nonsense, 8 splice site mutations, 49 frameshift indels, and 12 in-frame indels. Thirteen genes were recurrently affected, among which RAS-PI3K pathway mutations were the most frequent: KRAS (10/46 cases, 21.7%), NRAS (4/46 cases, 8.7%) and PTPN11 (3/46 cases, 6.5%). In addition, novel recurrent mutations were detected in HSP90AB1 (5/46 cases, 10.9%), MAPRE3 (2/46 cases, 4.3%) and SRCAP (2/46 cases, 4.3%), as well as known candidate driver mutations in FLT3 (7/46 cases, 15.2%), TP53 (3/46 cases, 6.5%), CHD4 (2/46 cases, 4.3%) and PAX5 (2/46 cases, 4.3%). HSP90AB1 is a member of Heat shock protein90 (Hsp90) family that encodes a group of molecular chaperones involved in stabilization and activation of multiple oncogenic proteins and pathways. Overexpression of Hsp90 is observed in ALL, chronic myeloid/lymphocytic leukemia and several non-hematological malignancies. Another recurrently mutated gene, SRCAP, encodes the core component of chromatin-remodeling Snf2-related CREBBP activator protein complex. Recurrent mutations in this gene have recently been reported in FLT3-ITD positive acute myeloid leukemia with significantly high co-occurrence of MLL3 mutations. Overall, RAS-PI3K pathway mutations were detected in 19/46 cases of infant ALL (41.3%). In our cohort, none of 3 germline MLL cases contained RAS-PI3K pathway mutations; one case had a PAX5 mutation, another had a SRCAP mutation, and the other had no candidate driver mutations. In the germline MLL case without candidate drivers, G-banding had identified a structural abnormality, t(5;15)(p15;q11.2), that is rare but reported to be predominant in infant ALL rather than other hematological/non-hematological malignancies. [Conclusion] Our results demonstrated that aberrations of cell proliferation signaling, transcription factors, as well as cell cycle/epigenetic regulators are co-operative oncogenic events in MLL-rearrangement cases. The mutation spectrum is similar to myeloid malignancies rather than lymphoid cancers. Intriguingly, we identified novel recurrent mutations in the oncogenic proteins, such as HSP90AB1, MAPRE3, and SRCAP,suggesting that these are potentially targetable by small-molecule therapy. In addition, we also illustrated the genetic differences between MLL-rearrangement and germline MLL. Thus, our mutational landscape provides a novel insight into the molecular mechanisms of infant ALL and may contribute to improving the clinical outcome of infant patients suffering from the intractable ALL. Disclosures Ogawa: Kan research institute: Consultancy, Research Funding; Takeda Pharmaceuticals: Consultancy, Research Funding; Sumitomo Dainippon Pharma: Research Funding.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2016
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  • 10
    In: Blood, American Society of Hematology, Vol. 140, No. Supplement 1 ( 2022-11-15), p. 3210-3211
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2022
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