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1.
Oncologist ; 29(10): 894-903, 2024 Oct 03.
Article in English | MEDLINE | ID: mdl-38937977

ABSTRACT

INTRODUCTION: Immune checkpoint inhibitor (ICI) combinations extend overall survival (OS) while anti-PD-1/L1 monotherapy is non-inferior to sorafenib in treatment-naïve, patients with advanced hepatocellular carcinoma (HCC). Clinicogenomic features are posited to influence patient outcomes. METHODS: The primary objective of this retrospective study was to define the clinical, pathologic, and genomic factors associated with outcomes to ICI therapy in patients with HCC. Patients with histologically confirmed advanced HCC treated with ICI at Memorial Sloan Kettering Cancer Center from 2012 to 2022 were included. Association between clinical, pathological, and genomic characteristics were assessed with univariable and multivariable Cox regression model for progression-free survival (PFS) and OS. RESULTS: Two-hundred and forty-two patients were treated with ICI-based therapy. Patients were predominantly male (82%) with virally mediated HCC (53%) and Child Pugh A score (70%). Median follow-up was 28 months (0.5-78.4). Median PFS for those treated in 1st line, 2nd line and ≥ 3rd line was 4.9 (range: 2.9-6.2), 3.1 (2.3-4.0), and 2.5 (2.1-4.0) months, respectively. Median OS for those treated in 1st line, 2nd line, and ≥ 3rd line was 16 (11-22), 7.5 (6.4-11), and 6.4 (4.6-26) months, respectively. Poor liver function and performance status associated with worse PFS and OS, while viral hepatitis C was associated with favorable outcome. Genetic alterations were not associated with outcomes. CONCLUSION: Clinicopathologic factors were the major determinates of outcomes for patients with advanced HCC treated with ICI. Molecular profiling did not aid in stratification of ICI outcomes. Future studies should explore alternative biomarkers such as the level of immune activation or the pretreatment composition of the immune tumor microenvironment.


Subject(s)
Carcinoma, Hepatocellular , Immune Checkpoint Inhibitors , Immunotherapy , Liver Neoplasms , Humans , Carcinoma, Hepatocellular/pathology , Carcinoma, Hepatocellular/drug therapy , Carcinoma, Hepatocellular/genetics , Carcinoma, Hepatocellular/therapy , Carcinoma, Hepatocellular/mortality , Liver Neoplasms/genetics , Liver Neoplasms/drug therapy , Liver Neoplasms/pathology , Liver Neoplasms/therapy , Male , Female , Middle Aged , Aged , Retrospective Studies , Adult , Immune Checkpoint Inhibitors/therapeutic use , Immunotherapy/methods , Aged, 80 and over
2.
Oncologist ; 20(7): 789-97, 2015 Jul.
Article in English | MEDLINE | ID: mdl-25956405

ABSTRACT

BACKGROUND: RAF inhibitors are an effective therapy for patients with BRAF-mutant melanoma and brain metastasis. Efficacy data are derived from clinical studies enriched with physiologically fit patients; therefore, it is of interest to assess the real-world experience of vemurafenib in this population. Tumor-specific genetic variants that influence sensitivity to RAF kinase inhibitors also require investigation. METHODS: Records of patients with BRAF-mutant melanoma and brain metastases who were treated with vemurafenib were reviewed. Clinical data were extracted to determine extracranial and intracranial objective response rates, progression-free survival (PFS), overall survival (OS), and safety. A bait-capture, next-generation sequencing assay was used to identify mutations in pretreatment tumors that could explain primary resistance to vemurafenib. RESULTS: Among patients with intracranial disease treated with vemurafenib, 27 were included in survival analyses and 22 patients were assessable for response. The extracranial and intracranial objective response rates were 71% and 50%, respectively. Discordant responses were observed between extracranial and intracranial metastatic sites in 4 of 19 evaluable patients. Median PFS was 4.1 months (95% confidence interval [CI]: 2.6-7.9); median intracranial PFS was 4.6 months (95% CI: 2.7-7.9), median OS was 7.5 months (95% CI: 4.3-not reached), with a 30.4% 1-year OS rate. Outcomes were influenced by performance status. Vemurafenib was tolerable, although radiation-induced dermatitis occurred in some patients who received whole-brain radiotherapy. Adequate samples for next-generation sequencing analysis were available for seven patients. Melanomas categorized as "poorly sensitive" (≥20% tumor growth, new lesions, or ≤50% shrinkage for <4 months) harbored co-occurring mutations in genes predicted to activate the phosphatidylinositol 3-kinase-AKT (PI3K-AKT) pathway. CONCLUSION: Vemurafenib is highly active in BRAF-mutant melanoma brain metastases but has limited activity in patients with poor performance status. The safety and efficacy of concurrent radiotherapy and RAF inhibition requires careful clinical evaluation. Combination strategies blocking the MAPK and PI3K-AKT pathway may be warranted in a subset of patients. IMPLICATIONS FOR PRACTICE: Vemurafenib is active for BRAF-mutant intracranial melanoma metastases in an unselected patient population typical of routine oncologic practice. Patients with poor performance status appear to have poor outcomes despite vemurafenib therapy. Preliminary data indicate that co-occurring or secondary alterations in the phosphatidylinositol 3-kinase-AKT (PI3K-AKT) pathway are involved in resistance to RAF inhibition, thus providing a rationale for dual MAPK and PI3K-AKT pathway inhibition in this patient population.


Subject(s)
Brain Neoplasms/drug therapy , Indoles/therapeutic use , Melanoma/drug therapy , Proto-Oncogene Proteins B-raf/genetics , Sulfonamides/therapeutic use , Adult , Aged , Aged, 80 and over , Antineoplastic Agents/adverse effects , Antineoplastic Agents/therapeutic use , Brain Neoplasms/genetics , Brain Neoplasms/mortality , Brain Neoplasms/secondary , Female , Humans , Indoles/adverse effects , Kaplan-Meier Estimate , Male , Melanoma/genetics , Melanoma/mortality , Melanoma/pathology , Middle Aged , Mutation , Retrospective Studies , Sulfonamides/adverse effects , Treatment Outcome , Vemurafenib
3.
JCO Glob Oncol ; 10: e2400090, 2024 Oct.
Article in English | MEDLINE | ID: mdl-39388662

ABSTRACT

PURPOSE: Gallbladder cancer (GBC) is a biliary tract malignancy characterized by its high lethality. Although the incidence of GBC is low in most countries, specific areas such as Chile display a high incidence. Our collaborative study sought to compare clinical and molecular features of GBC cohorts from Chile and the United States with a focus on ERBB2 alterations. METHODS: Patients were accrued at Memorial Sloan Kettering Cancer Center (MSK) or the Pontificia Universidad Católica de Chile (PUC). Clinical information was retrieved from medical records. Genomic analysis was performed by the next-generation sequencing platform MSK-Integrated Mutation Profiling of Actionable Cancer Targets. RESULTS: A total of 260 patients with GBC were included, 237 from MSK and 23 from PUC. There were no significant differences in the clinical characteristics between the patients identified at MSK and at PUC except in terms of lithiasis prevalence which was significantly higher in the PUC cohort (85% v 44%; P = .0003). The prevalence of ERBB2 alterations was comparable between the two cohorts (15% v 9%; P = .42). Overall, ERBB2 alterations were present in 14% of patients (8% with ERBB2 amplification, 4% ERBB2 mutation, 1.5% concurrent amplification and mutation, and 0.4% ERBB2 fusion). Notably, patients with GBC that harbored ERBB2 alterations had better overall survival (OS) versus their ERBB2-wild type counterparts (22.3 months v 11.8 months; P = .024). CONCLUSION: The prevalence of lithiasis seems to be higher in Chilean versus US patients with GBC. A similar prevalence of ERBB2 alterations of overall 14% and better OS suggests that a proportion of them could benefit from human epidermal growth factor receptor type 2-targeted therapies. The smaller cohort of Chile, where the disease prevalence is higher, is a reminder and invitation for the need of more robust next-generation sequencing analyses globally.


Subject(s)
Gallbladder Neoplasms , Receptor, ErbB-2 , Humans , Gallbladder Neoplasms/genetics , Gallbladder Neoplasms/epidemiology , Gallbladder Neoplasms/pathology , Gallbladder Neoplasms/mortality , Chile/epidemiology , Receptor, ErbB-2/genetics , Female , Male , Middle Aged , Aged , United States/epidemiology , Mutation , Cohort Studies , Adult , Genomics , Aged, 80 and over , High-Throughput Nucleotide Sequencing
4.
Cancer Res Commun ; 4(3): 682-690, 2024 03 07.
Article in English | MEDLINE | ID: mdl-38363156

ABSTRACT

Sorafenib blocks nonstructural protein 5A (NS5A)-recruited c-Raf-mediated hepatitis C virus (HCV) replication and gene expression. Release of Raf-1-Ask-1 dimer and inhibition of Raf-1 via sorafenib putatively differ in the presence or absence of doxorubicin. Cancer and Leukemia Group B (CALGB) 80802 (Alliance) randomized phase III trial of doxorubicin plus sorafenib versus sorafenib in patients with advanced hepatocellular carcinoma (HCC), showed no improvement in median overall survival (OS). Whether HCV viral load impacts therapy and whether any correlation between HCV titers and outcome based on HCV was studied. In patients with HCV, HCV titer levels were evaluated at baseline and at multiple postbaseline timepoints until disease progression or treatment discontinuation. HCV titer levels were evaluated in relation to OS and progression-free survival (PFS). Among 53 patients with baseline HCV data, 12 patients had undetectable HCV (HCV-UN). Postbaseline HCV titer levels did not significantly differ between treatment arms. One patient in each arm went from detectable to HCV-UN with greater than 2 log-fold titer levels reduction. Aside from these 2 HCV-UN patients, HCV titers remained stable on treatment. Patients who had HCV-UN at baseline were 3.5 times more likely to progress and/or die from HCC compared with HCV detectable (HR = 3.51; 95% confidence interval: 1.58-7.78; P = 0.002). HCV titer levels remained unchanged, negating any sorafenib impact onto HCV titer levels. Although an overall negative phase III study, patients treated with doxorubicin plus sorafenib and sorafenib only, on CALGB 80802 had worse PFS if HCV-UN. Higher levels of HCV titers at baseline were associated with significantly improved PFS. SIGNIFICANCE: Sorafenib therapy for HCC may impact HCV replication and viral gene expression. In HCV-positive patients accrued to CLAGB 80802 phase III study evaluating the addition of doxorubicin to sorafenib, HCV titer levels were evaluated at baseline and different timepoints. Sorafenib did not impact HCV titer levels. Despite an improved PFS in patients with detectable higher level HCV titers at baseline, no difference in OS was noted.


Subject(s)
Antineoplastic Agents , Carcinoma, Hepatocellular , Hepatitis C , Liver Neoplasms , Humans , Sorafenib/therapeutic use , Carcinoma, Hepatocellular/drug therapy , Liver Neoplasms/drug therapy , Niacinamide/therapeutic use , Phenylurea Compounds/therapeutic use , Doxorubicin/therapeutic use , Hepatitis C/complications , Hepacivirus/genetics
5.
NPJ Precis Oncol ; 7(1): 29, 2023 Mar 23.
Article in English | MEDLINE | ID: mdl-36959495

ABSTRACT

The incidence and biochemical consequences of rare tumor subtypes are often hard to study. Fibrolamellar liver cancer (FLC) is a rare malignancy affecting adolescents and young adults. To better characterize the incidence and biochemical consequences of this disease, we combined a comprehensive analysis of the electronic medical record and national payer data and found that FLC incidence is likely five to eight times higher than previous estimates. By employing unsupervised learning on clinical laboratory data from patients with hyperammonemia, we find that FLC-associated hyperammonemia mirrors metabolic dysregulation in urea cycle disorders. Our findings demonstrate that advanced computational analysis of rich clinical datasets can provide key clinical and biochemical insights into rare cancers.

6.
JCO Precis Oncol ; 7: e2300272, 2023 09.
Article in English | MEDLINE | ID: mdl-37769223

ABSTRACT

PURPOSE: Next-generation sequencing (NGS) of tumor-derived, circulating cell-free DNA (cfDNA) may aid in diagnosis, prognostication, and treatment of patients with hepatocellular carcinoma (HCC). The operating characteristics of cfDNA mutational profiling must be determined before routine clinical implementation. METHODS: This was a single-center, retrospective study with the primary objective of defining genomic alterations in circulating cfDNA along with plasma-tissue genotype agreement between NGS of matched tumor samples in patients with advanced HCC. cfDNA was analyzed using a clinically validated 129-gene NGS assay; matched tissue-based NGS was analyzed with a US Food and Drug Administration-authorized NGS tumor assay. RESULTS: Fifty-three plasma samples from 51 patients with histologically confirmed HCC underwent NGS-based cfDNA analysis. Genomic alterations were detected in 92.2% of patients, with the most commonly mutated genes including TERT promoter (57%), TP53 (47%), CTNNB1 (37%), ARID1A (18%), and TSC2 (14%). In total, 37 (73%) patients underwent paired tumor NGS, and concordance was high for mutations observed in patient-matched plasma samples: TERT (83%), TP53 (94%), CTNNB1 (92%), ARID1A (100%), and TSC2 (71%). In 10 (27%) of 37 tumor-plasma samples, alterations were detected by cfDNA analysis that were not detected in the patient-matched tumors. Potentially actionable mutations were identified in 37% of all cases including oncogenic/likely oncogenic alterations in TSC1/2 (18%), BRCA1/2 (8%), and PIK3CA (8%). Higher average variant allele fraction was associated with elevated alpha-fetoprotein, increased tumor volume, and no previous systemic therapy, but did not correlate with overall survival in treatment-naïve patients. CONCLUSION: Tumor mutation profiling of cfDNA in HCC represents an alternative to tissue-based genomic profiling, given the high degree of tumor-plasma NGS concordance; however, genotyping of both blood and tumor may be required to detect all clinically actionable genomic alterations.


Subject(s)
Carcinoma, Hepatocellular , Cell-Free Nucleic Acids , Circulating Tumor DNA , Liver Neoplasms , United States , Humans , Carcinoma, Hepatocellular/genetics , Carcinoma, Hepatocellular/pathology , BRCA1 Protein , Retrospective Studies , Liver Neoplasms/genetics , Liver Neoplasms/pathology , Circulating Tumor DNA/genetics , BRCA2 Protein , Cell-Free Nucleic Acids/genetics
7.
Target Oncol ; 17(5): 517-527, 2022 09.
Article in English | MEDLINE | ID: mdl-36114955

ABSTRACT

BACKGROUND: First-line standard-of-care therapy for advanced cholangiocarcinoma is gemcitabine plus cisplatin; there is no established second-line systemic therapy. Fibroblast growth factor receptor (FGFR)-2 fusions/rearrangements can be oncogenic drivers, occurring almost exclusively in intrahepatic cholangiocarcinoma, but little is known about whether FGFR2 status affects the response to systemic chemotherapy. OBJECTIVE: We aimed to evaluate the effects of FGFR2 status on survival outcomes in patients receiving systemic therapy for intrahepatic cholangiocarcinoma. METHODS: In this retrospective analysis, patients treated with systemic therapy at Memorial Sloan Kettering Cancer Center for intrahepatic cholangiocarcinoma were categorized into three cohorts: FGFR2 fusions; other FGFR2 alterations; no FGFR2 alterations. Endpoints were overall survival and progression-free survival per therapy line. RESULTS: In total, 132 patients with intrahepatic cholangiocarcinoma were included (FGFR2 fusions, n = 15; other FGFR2 alterations, n = 2 [data not reported]; no FGFR2 alterations, n = 115). First-line therapy was platinum based in 93% of patients; 80% received platinum/pyrimidine-based second-line therapy. For patients with FGFR2 fusions and no FGFR2 alterations, respectively, median overall survival from diagnosis was 31.3 months (95% confidence interval [CI] 5.8-not estimable months) [n = 9] and 21.7 months (95% CI 16.1-26.6) [n = 109]; median progression-free survival in first-line therapy was 6.2 months (95% CI 2.0-16.8) [n = 15] and 7.2 months (95% CI 5.0-8.3) [n = 107], and median progression-free survival in second-line therapy was 5.6 months (95% CI 2.8-10.3) [n = 8] and 3.7 months (95% CI 2.6-5.6) [n = 81]. CONCLUSIONS: Patients with intrahepatic cholangiocarcinoma and FGFR2 fusions may have a better prognosis than those without FGFR2 alterations in terms of overall survival, and progression-free survival on second-line, but not first-line systemic therapy. Progression-free survival improvement on second-line chemotherapy may imply an important impact of prior chemotherapy as first line.


Intrahepatic cholangiocarcinoma (iCCA) can be caused by changes in many different genes. One type of change in iCCA is a fibroblast growth factor receptor 2 gene (FGFR2) fusion. In fusions, the FGFR2 gene has fused to another gene. Our study examined people with iCCA to compare the overall survival following diagnosis for people with FGFR2 changes and people without. We also measured progression-free survival, which is the time from their first chemotherapy dose until their cancer got worse. All participants had iCCA and their first or second treatment was chemotherapy. Fifteen participants had FGFR2 fusions and 115 had no FGFR2 changes. We found that participants with FGFR2 fusions lived longer (median 31 months) than those without these fusions (median 22 months). During their first treatment, median progression-free survival was similar for participants with and without FGFR2 fusions. After the second chemotherapy, median progression-free survival was about 2 months longer for participants with FGFR2 fusions than those without. Results will vary from person to person and will depend on other factors. However, people with iCCA with FGFR2 fusions may stay slightly longer on their second treatment without their cancer getting worse. With chemotherapy, they may also live somewhat longer than those without FGFR2 fusions.


Subject(s)
Bile Duct Neoplasms , Cholangiocarcinoma , Bile Duct Neoplasms/drug therapy , Bile Duct Neoplasms/pathology , Bile Ducts, Intrahepatic/pathology , Cholangiocarcinoma/drug therapy , Cholangiocarcinoma/genetics , Cisplatin/therapeutic use , Humans , Progression-Free Survival , Pyrimidines/therapeutic use , Receptor, Fibroblast Growth Factor, Type 2/genetics , Retrospective Studies
8.
Cancer Med ; 11(3): 602-617, 2022 02.
Article in English | MEDLINE | ID: mdl-34951132

ABSTRACT

BACKGROUND: Hepatocellular carcinoma (HCC) patient-derived xenograft (PDX) models hold potential to advance knowledge in HCC biology to help improve systemic therapies. Beside hepatitis B virus-associated tumors, HCC is poorly established in PDX. METHODS: PDX formation from fresh HCC biopsies were obtained and implanted intrahepatically or in subrenal capsule (SRC). Mouse liver injury was induced in immunodeficient Fah-/-  mice through cycling off nitisinone after HCC biopsy implantation, versus continuous nitisinone as non-liver injury controls. Mice with macroscopically detectable PDX showed rising human alpha1-antitrypsin (hAAT) serum levels, and conversely, no PDX was observed in mice with undetectable hAAT. RESULTS: Using rising hAAT as a marker for PDX formation, 20 PDX were established out of 45 HCC biopsy specimens (44%) reflecting the four major HCC etiologies most commonly identified at Memorial SloanKettering similar to many other institutions in the United States. PDX was established only in severely immunodeficient mice lacking lymphocytes and NK cells. Implantation under the renal capsule improved PDX formation two-fold compared to intrahepatic implantation. Two out of 18 biopsies required murine liver injury to establish PDX, one associated with hepatitis C virus and one with alcoholic liver disease. PDX tumors were histologically comparable to biopsy specimens and 75% of PDX lines could be passaged. CONCLUSIONS: Using cycling off nitisinone-induced liver injury, HCC biopsies implanted under the renal capsule of severely immunodeficient mice formed PDX with 57% efficiency as determined by rising hAAT levels. These findings facilitate a more efficient make-up of PDX for research into subset-specific HCC.


Subject(s)
Carcinoma, Hepatocellular , Liver Neoplasms , Animals , Biopsy , Carcinoma, Hepatocellular/pathology , Disease Models, Animal , Heterografts , Humans , Liver Neoplasms/pathology , Mice , United States , Xenograft Model Antitumor Assays
9.
Cancer Med ; 10(9): 3059-3067, 2021 05.
Article in English | MEDLINE | ID: mdl-33811482

ABSTRACT

BACKGROUND: Preclinical data suggest that vascular endothelial growth factor (VEGF) and transforming growth factor (TGF)-ß signaling interact to stimulate angiogenesis and suppress antitumor immune responses. Thus, combined inhibition of both pathways may offer greater antitumor activity compared with VEGF-targeted antiangiogenic monotherapy against hepatocellular carcinoma (HCC). METHODS: This is a multicenter, open-label, phase 1b study of galunisertib, an inhibitor of TGF-ß receptor 1, and ramucirumab, an anti-VEGF receptor 2 antibody, in patients with advanced HCC aiming to define the maximum tolerated dose (MTD). Secondary objectives included safety, pharmacokinetics (PK), antitumor efficacy, and plasma alpha-fetoprotein and TGF-ß kinetics. Dose escalation employed a 3 + 3 design. Patients received galunisertib at 80 mg (cohort 1) or 150 mg (cohort 2) orally twice a day on days 1-14 of a 28-day cycle combined with ramucirumab 8 mg/kg intravenously every 2 weeks. RESULTS: Eight patients were enrolled: three in cohort 1 and five in cohort 2 (two patients were unevaluable due to rapid disease progression and replaced). No dose-limiting toxicities were observed. Treatment-related adverse events (AEs) of any grade in ≥2 patients included nausea (25%) and vomiting (25%). There was one Grade 3 treatment-related AE, a cerebrovascular accident possibly related to ramucirumab. Galunisertib exposure was dose-proportional and not affected by ramucirumab. The RECIST version 1.1 objective response rate and disease control rate were 0% and 12.5%, respectively. CONCLUSION: Combination therapy was safe and tolerable and displayed favorable PK. The MTD was established at galunisertib at 150 mg orally twice a day and ramucirumab 8 mg/kg intravenously every 2 weeks. The results do not support the preclinical hypothesis that blocking TGFß signaling enhances efficacy of VEGF-targeted therapy; thus further clinical development was halted for the combination of galunisertib and ramucirumab.


Subject(s)
Antibodies, Monoclonal, Humanized/administration & dosage , Antineoplastic Agents/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Carcinoma, Hepatocellular/drug therapy , Liver Neoplasms/drug therapy , Pyrazoles/administration & dosage , Quinolines/administration & dosage , Aged , Aged, 80 and over , Antibodies, Monoclonal, Humanized/adverse effects , Antibodies, Monoclonal, Humanized/pharmacokinetics , Antineoplastic Agents/adverse effects , Antineoplastic Agents/pharmacokinetics , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Carcinoma, Hepatocellular/metabolism , Carcinoma, Hepatocellular/pathology , Female , Humans , Liver Neoplasms/metabolism , Liver Neoplasms/pathology , Male , Maximum Tolerated Dose , Middle Aged , Nausea/chemically induced , Prospective Studies , Pyrazoles/adverse effects , Pyrazoles/pharmacokinetics , Quinolines/adverse effects , Quinolines/pharmacokinetics , Receptor, Transforming Growth Factor-beta Type I/antagonists & inhibitors , Response Evaluation Criteria in Solid Tumors , Vascular Endothelial Growth Factor A/metabolism , Vascular Endothelial Growth Factor Receptor-2/antagonists & inhibitors , Vomiting/chemically induced , alpha-Fetoproteins/analysis , Ramucirumab
10.
Elife ; 2: e00747, 2013 Jun 25.
Article in English | MEDLINE | ID: mdl-23805382

ABSTRACT

In solid tumors, targeted treatments can lead to dramatic regressions, but responses are often short-lived because resistant cancer cells arise. The major strategy proposed for overcoming resistance is combination therapy. We present a mathematical model describing the evolutionary dynamics of lesions in response to treatment. We first studied 20 melanoma patients receiving vemurafenib. We then applied our model to an independent set of pancreatic, colorectal, and melanoma cancer patients with metastatic disease. We find that dual therapy results in long-term disease control for most patients, if there are no single mutations that cause cross-resistance to both drugs; in patients with large disease burden, triple therapy is needed. We also find that simultaneous therapy with two drugs is much more effective than sequential therapy. Our results provide realistic expectations for the efficacy of new drug combinations and inform the design of trials for new cancer therapeutics. DOI:http://dx.doi.org/10.7554/eLife.00747.001.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Evolution, Molecular , Neoplasms/drug therapy , Humans , Mutation , Neoplasms/genetics
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