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1.
Int J Cancer ; 145(7): 1798-1808, 2019 10 01.
Artículo en Inglés | MEDLINE | ID: mdl-30680712

RESUMEN

PF-06647263, a novel antibody-drug conjugate consisting of an anti-EFNA4 antibody linked to a calicheamicin payload, has shown potent antitumor activity in human xenograft tumor models, including triple-negative breast cancer (TNBC). In the dose-escalation part 1 of this multicenter, open-label, phase I study (NCT02078752), successive cohorts of patients (n, 48) with advanced solid tumors and no available standard therapy received PF-06647263 every 3 weeks (Q3W) or every week (QW), following a modified toxicity probability interval (mTPI) method (initial dosing: 0.015 mg/kg Q3W). Primary objective in part 1 was to estimate the maximum tolerated dose (MTD) and select the recommended phase 2 dose (RP2D). In part 2 (dose-expansion cohort), 12 patients with pretreated, metastatic TNBC received PF-06647263 at the RP2D to further evaluate tumor response and overall safety. PF-06647263 QW administration (n, 23) was better tolerated than the Q3W regimen (n, 25) with only 1 DLT reported (thrombocytopenia). The most common AEs with the QW regimen (fatigue, nausea, vomiting, mucosal inflammation, thrombocytopenia, and diarrhea) were mostly mild to moderate in severity. The MTD was not estimated. PF-06647263 exposures increased in a dose-related manner across the doses evaluated. The RP2D was determined to be 0.015 mg/kg QW. Six (10%) patients achieved a confirmed partial response and 22 (36.7%) patients had stable disease. No correlations were observed between tumor responses and EFNA4 expression levels. Study findings showed manageable safety and favorable PK for PF-06647263 administered QW at the RP2D, with preliminary evidence of limited antitumor activity in patients with TNBC and ovarian cancer.


Asunto(s)
Aminoglicósidos/administración & dosificación , Anticuerpos Monoclonales de Origen Murino/administración & dosificación , Metástasis de la Neoplasia/tratamiento farmacológico , Neoplasias/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Aminoglicósidos/efectos adversos , Animales , Anticuerpos Monoclonales de Origen Murino/efectos adversos , Esquema de Medicación , Efrina-A4/metabolismo , Femenino , Humanos , Masculino , Dosis Máxima Tolerada , Ratones , Persona de Mediana Edad , Neoplasias/metabolismo , Resultado del Tratamiento , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Neoplasias de la Mama Triple Negativas/metabolismo
2.
Curr Oncol Rep ; 16(11): 409, 2014 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-25286906

RESUMEN

High-dose interferon is the current standard of care for the adjuvant treatment of high-risk cutaneous melanoma. Despite numerous clinical trials using interferon in a variety of doses and schedules, none have demonstrated a meaningful clinical improvement relative to standard high-dose interferon. Recently however, a phase III trial using biochemotherapy demonstrated a superior relapse-free survival benefit over standard interferon. In addition, several agents approved for use in metastatic melanoma are being investigated in the adjuvant setting.


Asunto(s)
Anticuerpos Monoclonales/uso terapéutico , Antineoplásicos/uso terapéutico , Factores Inmunológicos/uso terapéutico , Interferón-alfa/uso terapéutico , Neoplasias Cutáneas/tratamiento farmacológico , Quimioterapia Adyuvante , Ensayos Clínicos como Asunto , Supervivencia sin Enfermedad , Humanos
3.
J Clin Oncol ; 41(9): 1714-1724, 2023 03 20.
Artículo en Inglés | MEDLINE | ID: mdl-36669146

RESUMEN

PURPOSE: This study evaluated the safety, pharmacokinetics, pharmacodynamics, and preliminary efficacy of milademetan, a small-molecule murine double minute-2 (MDM2) inhibitor, in patients with advanced cancers. PATIENTS AND METHODS: In this first-in-human phase I study, patients with advanced solid tumors or lymphomas received milademetan orally once daily as extended/continuous (days 1-21 or 1-28 every 28 days) or intermittent (days 1-7, or days 1-3 and 15-17 every 28 days) schedules. The primary objective was to determine the recommended phase II dose and schedule. Secondary objectives included tumor response according to standard evaluation criteria. Predefined analyses by tumor type were performed. Safety and efficacy analyses included all patients who received milademetan. RESULTS: Between July 2013 and August 2018, 107 patients were enrolled and received milademetan. The most common grade 3/4 drug-related adverse events were thrombocytopenia (29.0%), neutropenia (15.0%), and anemia (13.1%). Respective rates at the recommended dose and schedule (260 mg once daily on days 1-3 and 15-17 every 28 days, ie, 3/14 days) were 15.0%, 5.0%, and 0%. Across all cohorts (N = 107), the disease control rate was 45.8% (95% CI, 36.1 to 55.7) and median progression-free survival was 4.0 months (95% CI, 3.4 to 5.7). In the subgroup with dedifferentiated liposarcomas, the disease control rate and median progression-free survival were 58.5% (95% CI, 44.1 to 71.9) and 7.2 months overall (n = 53), and 62.0% (95% CI, 35.4 to 84.8) and 7.4 months with the recommended intermittent schedule (n = 16), respectively. CONCLUSION: An intermittent dosing schedule of 3/14 days of milademetan mitigates dose-limiting hematologic abnormalities while maintaining efficacy. Notable single-agent activity with milademetan in dedifferentiated liposarcomas has prompted a randomized phase III trial (MANTRA).


Asunto(s)
Antineoplásicos , Liposarcoma , Linfoma , Neoplasias , Humanos , Animales , Ratones , Neoplasias/tratamiento farmacológico , Antineoplásicos/efectos adversos , Linfoma/tratamiento farmacológico , Piridinas/uso terapéutico , Liposarcoma/tratamiento farmacológico , Dosis Máxima Tolerada , Proteínas Proto-Oncogénicas c-mdm2/uso terapéutico
4.
J Hematol Oncol ; 14(1): 127, 2021 08 18.
Artículo en Inglés | MEDLINE | ID: mdl-34407844

RESUMEN

BACKGROUND: The PI3K/AKT/mTOR (PAM) pathway is a key regulator of tumor therapy resistance. We investigated M2698, an oral p70S6K/AKT dual inhibitor, in patients with advanced cancer who failed standard therapies. METHODS: M2698 was administered as monotherapy (escalation, 15-380 mg daily; food effect cohort, 240-320 mg daily) and combined with trastuzumab or tamoxifen. RESULTS: Overall, 101 patients were treated (M2698, n = 62; M2698/trastuzumab, n = 13; M2698/tamoxifen, n = 26). Patients were predominantly aged < 65 years, were female, had performance status 1 and were heavily pretreated. There was a dose- and concentration-dependent inhibition of pS6 levels in peripheral blood mononuclear cells and tumor tissue. M2698 was well tolerated; the most common treatment-emergent adverse events were gastrointestinal, abnormal dreams and fatigue (serious, attributed to M2698: monotherapy, 8.1%; M2698/trastuzumab, 7.7%; M2698/tamoxifen, 11.5% of patients). The recommended phase 2 doses of M2698 were 240 mg QD (monotherapy), 160 mg QD (M2698/trastuzumab) and 160 mg QD/240 mg intermittent regimen (M2698/tamoxifen). In the monotherapy cohort, 27.4% of patients had stable disease at 12 weeks; no objective response was noted. The median progression-free survival (PFS) durations in patients with PAM pathway alterations with and without confounding markers (KRAS, EGFR, AKT2) were 1.4 months and 2.8 months, respectively. Two patients with breast cancer (M2698/trastuzumab, n = 1; M2698/tamoxifen, n = 1) had partial response; their PFS durations were 31 months and 2.7 months, respectively. CONCLUSIONS: M2698 was well tolerated. Combined with trastuzumab or tamoxifen, M2698 demonstrated antitumor activity in patients with advanced breast cancer resistant to multiple standard therapies, suggesting that it could overcome treatment resistance. Trial registration ClinicalTrials.gov, NCT01971515. Registered October 23, 2013.


Asunto(s)
Antineoplásicos/uso terapéutico , Neoplasias/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/uso terapéutico , Proteínas Proto-Oncogénicas c-akt/antagonistas & inhibidores , Proteínas Quinasas S6 Ribosómicas 70-kDa/antagonistas & inhibidores , Anciano , Anciano de 80 o más Años , Antineoplásicos/efectos adversos , Antineoplásicos/sangre , Femenino , Humanos , Masculino , Persona de Mediana Edad , Inhibidores de Proteínas Quinasas/efectos adversos , Inhibidores de Proteínas Quinasas/sangre , Resultado del Tratamiento
5.
Cancer Immunol Immunother ; 59(3): 409-17, 2010 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-19730859

RESUMEN

In situ expression of a foreign antigen and an immune-modulating cytokine by intratumoral DNA electroporation was tested as a cancer therapy regimen. Transgene expression in the tumors was sustained for 2-3 weeks after intratumoral electroporation with mammalian expression plasmid containing firefly luciferase cDNA. Electroporation with cDNA encoding tetanus toxin fragment C (TetC) induced tetanus toxin-binding antibody, demonstrating immune recognition of the transgene product. Intratumoral electroporation with TetC and IL-12 cDNA after mice were treated with CD25 mAb to remove regulatory T cells induced IFN-gamma producing T-cell response to tumor-associated antigen, heavy inflammatory infiltration, regression of established tumors and immune memory to protect mice from repeated tumor challenge. Intratumoral expression of immune-modulating molecules may be most suitable in the neoadjuvant setting to enhance the therapeutic efficacy and provide long-term protection.


Asunto(s)
Vacunas contra el Cáncer/inmunología , Vacunas contra el Cáncer/uso terapéutico , Neoplasias/inmunología , Neoplasias/terapia , Vacunas de ADN/inmunología , Vacunas de ADN/uso terapéutico , Animales , Electroporación , Expresión Génica , Memoria Inmunológica , Interleucina-12/genética , Activación de Linfocitos , Ratones , Ratones Endogámicos BALB C , Fragmentos de Péptidos/genética , Linfocitos T Reguladores/inmunología , Toxina Tetánica/genética , Transfección , Transgenes
6.
Breast Cancer Res Treat ; 120(1): 35-45, 2010 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-19308726

RESUMEN

TaqMan Gene Expression assays were used to profile the mRNA expression of estrogen receptor (ERalpha and ERbeta) and estrogen metabolism enzymes including cytosolic sulfotransferases (SULT1E1, SULT1A1, SULT2A1, and SULT2B1), steroid sulfatase (STS), aromatase (CYP19), 17beta-hydroxysteroid dehydrogenases (17betaHSD1 and 2), CYP1B1, and catechol-O-methyltransferase (COMT) in an MCF10A-derived lineage cell culture model for basal-like human breast cancer progression and in ERalpha-positive luminal MCF7 breast cancer cells. Low levels of ERalpha and ERbeta mRNA were present in MCF10A-derived cell lines. SULT1E1 mRNA was more abundant in confluent relative to subconfluent MCF10A cells, a non-tumorigenic proliferative breast disease cell line. SULT1E1 was also expressed in preneoplastic MCF10AT1 and MCF10AT1K.cl2 cells, but was markedly repressed in neoplastic MCF10A-derived cell lines as well as in MCF7 cells. Steroid-metabolizing enzymes SULT1A1 and SULT2B1 were only expressed in MCF7 cells. STS and COMT were widely detected across cell lines. Pro-estrogenic 17betaHSD1 mRNA was most abundant in neoplastic MCF10CA1a and MCF10DCIS.com cells, while 17betaHSD2 mRNA was more prominent in parental MCF10A cells. CYP1B1 mRNA was most abundant in MCF7 cells. Treatment with the histone deacetylase inhibitor trichostatin A (TSA) induced SULT1E1 and CYP19 mRNA but suppressed CYP1B1, STS, COMT, 17betaHSD1, and 17betaHSD2 mRNA in MCF10A lineage cell lines. In MCF7 cells, TSA treatment suppressed ERalpha, CYP1B1, STS, COMT, SULT1A1, and SULT2B1 but induced ERbeta, CYP19 and SULT2A1 mRNA expression. The results indicate that relative to the MCF7 breast cancer cell line, key determinants of breast estrogen metabolism are differentially regulated in the MCF10A-derived lineage model for breast cancer progression.


Asunto(s)
Neoplasias de la Mama/genética , Neoplasias de la Mama/metabolismo , Receptor alfa de Estrógeno/genética , Receptor beta de Estrógeno/genética , Estrógenos/metabolismo , 17-Hidroxiesteroide Deshidrogenasas/biosíntesis , 17-Hidroxiesteroide Deshidrogenasas/metabolismo , Aromatasa/biosíntesis , Aromatasa/metabolismo , Hidrocarburo de Aril Hidroxilasas/biosíntesis , Hidrocarburo de Aril Hidroxilasas/metabolismo , Western Blotting , Catecol O-Metiltransferasa/biosíntesis , Catecol O-Metiltransferasa/metabolismo , Línea Celular Tumoral , Citocromo P-450 CYP1B1 , Progresión de la Enfermedad , Inhibidores Enzimáticos/farmacología , Receptor alfa de Estrógeno/metabolismo , Receptor beta de Estrógeno/metabolismo , Femenino , Expresión Génica , Humanos , ARN Mensajero/análisis , Esteril-Sulfatasa/biosíntesis , Esteril-Sulfatasa/metabolismo , Sulfotransferasas/biosíntesis , Sulfotransferasas/metabolismo , Transfección
7.
Cancer Discov ; 10(1): 40-53, 2020 01.
Artículo en Inglés | MEDLINE | ID: mdl-31732494

RESUMEN

Adenosine mediates immunosuppression within the tumor microenvironment through triggering adenosine 2A receptors (A2AR) on immune cells. To determine whether this pathway could be targeted as an immunotherapy, we performed a phase I clinical trial with a small-molecule A2AR antagonist. We find that this molecule can safely block adenosine signaling in vivo. In a cohort of 68 patients with renal cell cancer (RCC), we also observe clinical responses alone and in combination with an anti-PD-L1 antibody, including subjects who had progressed on PD-1/PD-L1 inhibitors. Durable clinical benefit is associated with increased recruitment of CD8+ T cells into the tumor. Treatment can also broaden the circulating T-cell repertoire. Clinical responses are associated with an adenosine-regulated gene-expression signature in pretreatment tumor biopsies. A2AR signaling, therefore, represents a targetable immune checkpoint distinct from PD-1/PD-L1 that restricts antitumor immunity. SIGNIFICANCE: This first-in-human study of an A2AR antagonist for cancer treatment establishes the safety and feasibility of targeting this pathway by demonstrating antitumor activity with single-agent and anti-PD-L1 combination therapy in patients with refractory RCC. Responding patients possess an adenosine-regulated gene-expression signature in pretreatment tumor biopsies.See related commentary by Sitkovsky, p. 16.This article is highlighted in the In This Issue feature, p. 1.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma de Células Renales/tratamiento farmacológico , Resistencia a Antineoplásicos/efectos de los fármacos , Neoplasias Renales/tratamiento farmacológico , Recurrencia Local de Neoplasia/tratamiento farmacológico , Receptor de Adenosina A2A/química , Terapia Recuperativa , Adulto , Anciano , Anticuerpos Monoclonales Humanizados/administración & dosificación , Carcinoma de Células Renales/patología , Femenino , Estudios de Seguimiento , Furanos/administración & dosificación , Humanos , Neoplasias Renales/patología , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia/patología , Pronóstico , Piridinas/administración & dosificación , Pirimidinas/administración & dosificación , Receptor de Adenosina A2A/metabolismo , Tasa de Supervivencia
8.
Cancer Immunol Immunother ; 58(5): 759-67, 2009 May.
Artículo en Inglés | MEDLINE | ID: mdl-18836716

RESUMEN

Direct comparison and ranking of vaccine formulations in pre-clinical studies will expedite the identification of cancer vaccines for clinical trials. Two human ErbB-2 (Her-2) vaccines, naked DNA and whole cell vaccine, were tested side-by-side in wild type and Her-2 transgenic mice. Both vaccines can induce humoral and cellular immunity to the entire repertoire of Her-2 epitopes. Mice were electro-vaccinated i.m. with a mixture of pGM-CSF and pE2TM, the latter encodes Her-2 extracellular and transmembrane domains. Alternatively, mice were injected i.p. with human ovarian cancer SKOV3 cells that have amplified Her-2. In wild type mice, comparable levels of Her-2 antibodies (Ab) were induced by these two vaccines. However, T cell immunity and protection against Her-2(+) tumors were superior in DNA vaccinated mice. In BALB Her-2 transgenic (Tg) mice, which were tolerant to Her-2, DNA and cell vaccines were administered after regulatory T cells (Treg) were removed by anti-CD25 mAb. Again, comparable levels of Her-2 Ab were induced, but DNA vaccines rendered greater anti-tumor activity. In B6xDR3 Her-2 Tg mice that expressed the autoimmune prone HLA-DR3 allele, higher levels of Her-2 Ab were induced by SKOV3 cell than by Her-2 DNA. But anti-tumor activity was still more profound in DNA vaccinated mice. Therefore, Her-2 DNA vaccine induced greater anti-tumor immunity than cell vaccine, whether mice were tolerant to Her-2 or susceptible to autoimmunity. Through such side-by-side comparisons in appropriate pre-clinical test systems, the more effective vaccine formulations will emerge as candidates for clinical trials.


Asunto(s)
Vacunas contra el Cáncer/inmunología , Antígenos HLA-DR/inmunología , Inmunoterapia Activa/métodos , Neoplasias Experimentales/terapia , Receptor ErbB-2/inmunología , Vacunas de ADN/inmunología , Animales , Presentación de Antígeno , Vacunas contra el Cáncer/uso terapéutico , Línea Celular Tumoral/inmunología , Línea Celular Tumoral/trasplante , Femenino , Genes erbB-2 , Glicoproteínas/genética , Glicoproteínas/inmunología , Antígenos HLA-DR/genética , Cadenas alfa de HLA-DR , Cadenas HLA-DRB1 , Humanos , Inmunidad Celular , Interferón gamma/metabolismo , Depleción Linfocítica , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Transgénicos , Neoplasias Experimentales/inmunología , Neoplasias Experimentales/prevención & control , Neoplasias Ováricas/patología , Ratas , Receptor ErbB-2/genética , Linfocitos T Citotóxicos/inmunología , Linfocitos T Citotóxicos/metabolismo , Vacunas de ADN/uso terapéutico , Ensayos Antitumor por Modelo de Xenoinjerto
9.
Ann Pharmacother ; 43(4): 761-6, 2009 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-19336648

RESUMEN

OBJECTIVE: To report the occurrence of fatal acute liver failure following addition of levothyroxine to a regimen of sunitinib and acetaminophen. CASE SUMMARY: A 57-year-old woman who started sunitinib treatment for relapsed metastatic gastrointestinal stromal tumor after imatinib failure had disease stabilization and normal liver function through 8 cycles of sunitinib 50 mg/day for 4 weeks, followed by 2 weeks off treatment. Her continuing medications included acetaminophen approximately 4.5 g/wk, as well as standard medications for asthma. In cycle 8, she received oral levothyroxine 50-150 microg/day for approximately 30 days to control hypothyroidism before beginning cycle 9 of sunitinib. On day 4 of cycle 9, she was hospitalized with progressively rising circulating liver enzyme levels. She died 4 days postadmission despite discontinuation of sunitinib and initiation of intensive supportive treatment. At autopsy, her liver showed severe centrilobular necrosis with moderate-to-severe steatosis and minimal parenchymal invasion by the neoplasm. Viral stains were negative. DISCUSSION: Hepatic failure has been reported rarely in patients receiving sunitinib. Autopsy results excluded neoplastic disease progression and viral infection in the etiology of the event, and the patient may have died of the combined interaction of sunitinib, acetaminophen, and levothyroxine. Although sunitinib was not more than a possible hepatotoxin (Roussel Uclaf Causality Assessment Method) and may even have been hepatoprotective over a 48-week period against chronic intake of acetaminophen (probable hepatotoxin) by producing regional hypothyroidism within the liver, it is hypothesized that correction of the putative hepatic hypothyroidism with oral levothyroxine (possible hepatotoxin) and reinitiation of sunitinib treatment may have triggered hepatic necrosis. CONCLUSIONS: Acetaminophen should be used with particular caution in patients receiving sunitinib. In sunitinib-treated patients who also require levothyroxine therapy, increased caution in restarting subsequent sunitinib treatment and discontinuation of acetaminophen, if possible, is advisable. Further evaluation of this potential interaction is warranted.


Asunto(s)
Acetaminofén/efectos adversos , Indoles/efectos adversos , Fallo Hepático/inducido químicamente , Pirroles/efectos adversos , Tiroxina/efectos adversos , Acetaminofén/administración & dosificación , Quimioterapia Combinada/efectos adversos , Resultado Fatal , Femenino , Humanos , Indoles/administración & dosificación , Fallo Hepático/diagnóstico , Persona de Mediana Edad , Pirroles/administración & dosificación , Sunitinib , Tiroxina/administración & dosificación
10.
Lung Cancer (Auckl) ; 5: 35-42, 2014.
Artículo en Inglés | MEDLINE | ID: mdl-28210140

RESUMEN

Non-small-cell lung cancer (NSCLC) is a heterogeneous disease and a challenging malignancy to treat, as many patients have advanced disease at the time of diagnosis. Recent advances have led to the identification of molecularly defined subtypes of NSCLC, namely for patients with adenocarcinoma histology. The most recently identified molecular target is the anaplastic lymphoma kinase (ALK) gene rearrangement, and patient responses to the ALK inhibitor crizotinib have led to its approval in this selected patient population. Like other tyrosine kinase inhibitors, resistance to crizotinib ultimately develops by various mechanisms requiring alternative therapeutic options. This review article discusses the management of patients with the ALK gene rearrangement, mechanisms of crizotinib resistance, and future potential therapeutic options.

11.
Am J Health Syst Pharm ; 68(1): 43-6, 2011 Jan 01.
Artículo en Inglés | MEDLINE | ID: mdl-21164064

RESUMEN

PURPOSE: A possible case of levofloxacin-induced thrombocytopenia is reported. SUMMARY: A 73-year-old Caucasian woman with stage IV squamous cell cancer of the oral cavity arrived at the hospital with a 6-day history of epistaxis; petechiae over her arms, legs, and abdomen; and bruises over her forearms. Her comorbidities included hypertension, type 2 diabetes mellitus, and coronary artery disease. Two weeks before arrival at the hospital, the patient had been admitted to the hospital with community-acquired pneumonia (CAP) and given a 10-day course of levofloxacin 500 mg daily, which she completed 4 days before this admission. Her platelet count was 7,000 cells/mm(3) on admission. Her home medications included aspirin 325 mg daily, ranitidine 150 mg twice daily, alprazolam 0.25 mg daily, and methadone 10 mg twice daily. She last received cetuximab six weeks before this hospital admission. No other new medications were recently introduced. She had no known drug allergies and no recent heparin exposure. The patient was given a platelet transfusion and treated empirically with prednisone for possible immune thrombocytopenic purpura, though drug-induced thrombocytopenia (DIT) was also suspected. She was restarted on her home medications except for aspirin. She was discharged with a 7-day course of oral corticosteroids. At discharge, her platelet count was 38,000 cells/mm(3). Corticosteroids were discontinued when DIT was established to be the most likely diagnosis. CONCLUSION: A 73-year-old woman with stage IV squamous cell cancer of the oral cavity developed a possible case of levofloxacin-induced thrombocytopenia after receiving the drug for 10 days for treatment of CAP.


Asunto(s)
Antibacterianos/efectos adversos , Levofloxacino , Ofloxacino/efectos adversos , Trombocitopenia/inducido químicamente , Anciano , Antibacterianos/uso terapéutico , Carcinoma de Células Escamosas/complicaciones , Femenino , Humanos , Neoplasias de la Boca/complicaciones , Ofloxacino/uso terapéutico , Recuento de Plaquetas , Neumonía Bacteriana/complicaciones , Neumonía Bacteriana/tratamiento farmacológico
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