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1.
Nature ; 592(7854): 463-468, 2021 04.
Artículo en Inglés | MEDLINE | ID: mdl-33762734

RESUMEN

Mutated isocitrate dehydrogenase 1 (IDH1) defines a molecularly distinct subtype of diffuse glioma1-3. The most common IDH1 mutation in gliomas affects codon 132 and encodes IDH1(R132H), which harbours a shared clonal neoepitope that is presented on major histocompatibility complex (MHC) class II4,5. An IDH1(R132H)-specific peptide vaccine (IDH1-vac) induces specific therapeutic T helper cell responses that are effective against IDH1(R132H)+ tumours in syngeneic MHC-humanized mice4,6-8. Here we describe a multicentre, single-arm, open-label, first-in-humans phase I trial that we carried out in 33 patients with newly diagnosed World Health Organization grade 3 and 4 IDH1(R132H)+ astrocytomas (Neurooncology Working Group of the German Cancer Society trial 16 (NOA16), ClinicalTrials.gov identifier NCT02454634). The trial met its primary safety endpoint, with vaccine-related adverse events restricted to grade 1. Vaccine-induced immune responses were observed in 93.3% of patients across multiple MHC alleles. Three-year progression-free and death-free rates were 0.63 and 0.84, respectively. Patients with immune responses showed a two-year progression-free rate of 0.82. Two patients without an immune response showed tumour progression within two years of first diagnosis. A mutation-specificity score that incorporates the duration and level of vaccine-induced IDH1(R132H)-specific T cell responses was associated with intratumoral presentation of the IDH1(R132H) neoantigen in pre-treatment tumour tissue. There was a high frequency of pseudoprogression, which indicates intratumoral inflammatory reactions. Pseudoprogression was associated with increased vaccine-induced peripheral T cell responses. Combined single-cell RNA and T cell receptor sequencing showed that tumour-infiltrating CD40LG+ and CXCL13+ T helper cell clusters in a patient with pseudoprogression were dominated by a single IDH1(R132H)-reactive T cell receptor.


Asunto(s)
Vacunas contra el Cáncer/inmunología , Vacunas contra el Cáncer/uso terapéutico , Glioma/diagnóstico , Glioma/terapia , Isocitrato Deshidrogenasa/genética , Isocitrato Deshidrogenasa/inmunología , Mutación , Adulto , Células Cultivadas , Progresión de la Enfermedad , Femenino , Glioma/genética , Glioma/inmunología , Humanos , Masculino , Proteínas Mutantes/genética , Proteínas Mutantes/inmunología , Fenotipo , Receptores de Antígenos de Linfocitos T/inmunología , Tasa de Supervivencia , Linfocitos T/inmunología
2.
Lancet Oncol ; 24(1): 45-53, 2023 01.
Artículo en Inglés | MEDLINE | ID: mdl-36493793

RESUMEN

BACKGROUND: The European EPI-CT study aims to quantify cancer risks from CT examinations of children and young adults. Here, we assess the risk of brain cancer. METHODS: We pooled data from nine European countries for this cohort study. Eligible participants had at least one CT examination before age 22 years documented between 1977 and 2014, had no previous diagnosis of cancer or benign brain tumour, and were alive and cancer-free at least 5 years after the first CT. Participants were identified through the Radiology Information System in 276 hospitals. Participants were linked with national or regional registries of cancer and vital status, and eligible cases were patients with brain cancers according to WHO International Classification of Diseases for Oncology. Gliomas were analysed separately to all brain cancers. Organ doses were reconstructed using historical machine settings and a large sample of CT images. Excess relative risks (ERRs) of brain cancer per 100 mGy of cumulative brain dose were calculated with linear dose-response modelling. The outcome was the first reported diagnosis of brain cancer after an exclusion period of 5 years after the first electronically recorded CT examination. FINDINGS: We identified 948 174 individuals, of whom 658 752 (69%) were eligible for our study. 368 721 (56%) of 658 752 participants were male and 290 031 (44%) were female. During a median follow-up of 5·6 years (IQR 2·4-10·1), 165 brain cancers occurred, including 121 (73%) gliomas. Mean cumulative brain dose, lagged by 5 years, was 47·4 mGy (SD 60·9) among all individuals and 76·0 mGy (100·1) among people with brain cancer. A significant linear dose-response relationship was observed for all brain cancers (ERR per 100 mGy 1·27 [95% CI 0·51-2·69]) and for gliomas separately (ERR per 100 mGy 1·11 [0·36-2·59]). Results were robust when the start of follow-up was delayed beyond 5 years and when participants with possibly previously unreported cancers were excluded. INTERPRETATION: The observed significant dose-response relationship between CT-related radiation exposure and brain cancer in this large, multicentre study with individual dose evaluation emphasises careful justification of paediatric CTs and use of doses as low as reasonably possible. FUNDING: EU FP7; Belgian Cancer Registry; La Ligue contre le Cancer, L'Institut National du Cancer, France; Ministry of Health, Labour and Welfare of Japan; German Federal Ministry of Education and Research; Worldwide Cancer Research; Dutch Cancer Society; Research Council of Norway; Consejo de Seguridad Nuclear, Generalitat de Catalunya, Spain; US National Cancer Institute; UK National Institute for Health Research; Public Health England.


Asunto(s)
Neoplasias Encefálicas , Glioma , Neoplasias Inducidas por Radiación , Exposición a la Radiación , Niño , Humanos , Masculino , Femenino , Adulto Joven , Adulto , Estudios de Cohortes , Dosis de Radiación , Neoplasias Inducidas por Radiación/epidemiología , Neoplasias Inducidas por Radiación/etiología , Neoplasias Inducidas por Radiación/patología , Neoplasias Encefálicas/diagnóstico por imagen , Neoplasias Encefálicas/epidemiología , Neoplasias Encefálicas/etiología , Glioma/diagnóstico por imagen , Glioma/epidemiología , Glioma/etiología , Exposición a la Radiación/efectos adversos , Tomografía Computarizada por Rayos X/efectos adversos , Tomografía Computarizada por Rayos X/métodos
3.
Pediatr Blood Cancer ; 67(4): e28130, 2020 04.
Artículo en Inglés | MEDLINE | ID: mdl-31867835

RESUMEN

BACKGROUND: Limited data on the prevalence and medical care of sickle cell disease (SCD) in Germany are available. Here, we make use of a patient registry to characterize the burden of disease and the treatment modalities for patients with SCD in Germany. PROCEDURE: A nationwide German registry for patients with SCD documents basic data on diagnosis and patient history retrospectively at the time of registration. A prospective annual documentation provides more details on complications and treatment of SCD. For the current analyses, data of 439 patients were available. RESULTS: Most patients had homozygous SCD (HbSS 75.1%, HbS/ß-thalassemia 13.2%, and HbSC 11.3%). The median age at diagnosis was 1.9 years (interquartile range, 0.6-4.4 years), most patients were diagnosed when characteristic symptoms occurred. Sepsis and stroke had affected 3.2% and 4.2% of patients, respectively. During the first year of observation, 48.3% of patients were admitted to a hospital and 10.1% required intensive care. Prophylactic penicillin was prescribed to 95.6% of patients with homozygous SCD or HbS/ß thalassemia below the age of six and hydroxycarbamide to 90.4% of patients above the age of two years. At least one annual transcranial Doppler ultrasound was documented for 74.8% of patients between 2 and 18 years. CONCLUSION: With an estimated number of at least 2000, the prevalence of SCD in Germany remains low. Prospectively, we expect that the quality of care for children with SCD will be further improved by an earlier diagnosis after the anticipated introduction of a newborn screening program for SCD.


Asunto(s)
Anemia de Células Falciformes/epidemiología , Adulto , Niño , Alemania/epidemiología , Humanos , Prevalencia , Sistema de Registros
4.
Gesundheitswesen ; 82(S 02): S158-S164, 2020 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-31597185

RESUMEN

HINTERGRUND: In Sekundärdaten existieren oftmals unstrukturierte Freitexte. In dieser Arbeit wird ein Text-Mining-System validiert, um unstrukturierte medizinische Daten für Forschungszwecke zu extrahieren. METHODEN: Aus einer radiologischen Klinik wurden aus 7102 CT-Befunden 1000 zufällig ausgewählt. Diese wurden von 2 Medizinern manuell in definierte Befundgruppen eingeteilt. Zur automatisierten Verschlagwortung und Klassifizierung wurde die Textanalyse-Software Averbis Extraction Platform (AEP) eingesetzt. Besonderheiten des Systems sind u. a. eine morphologische Analyse zur Zerlegung zusammengesetzter Wörter sowie die Erkennung von Nominalphrasen, Abkürzungen und negierten Aussagen. Anhand der extrahierten standardisierten Schlüsselwörter werden Befundberichte mithilfe maschineller Lernverfahren den vorgegebenen Befundgruppen zugeordnet. Zur Bewertung von Reliabilität und Validität des automatisierten Verfahrens werden die automatisierten und 2 unabhängige manuelle Klassifizierungen in mehreren Durchläufen auf Übereinstimmungen hin verglichen. ERGEBNISSE: Die manuelle Klassifizierung war zu zeitaufwendig. Bei der automatisierten Verschlagwortung stellte sich in unseren Daten die Klassifizierung nach ICD-10 als ungeeignet heraus. Ebenfalls zeigte sich, dass die Stichwortsuche keine verlässlichen Ergebnisse liefert. Computerunterstütztes Textmining in Kombination mit maschinellem Lernen führte zu verlässlichen Klassifizierungen. Die Inter-Rater-Reliabilität der beiden manuellen Klassifizierungen, sowie der maschinellen und der manuellen Klassifizierung war sehr hoch. Beide manuelle Klassifizierungen stimmten in 93% aller Befunde überein. Der Kappa-Koeffizient beträgt 0,89 [95% Konfidenzintervall (KI) 0,87-0,92]. Die automatische Klassifizierung stimmte in 86% aller Befunde mit der unabhängigen, zweiten manuellen Klassifizierung überein (Kappa-Koeffizient 0,79 [95% KI 0,75-0,81]). DISKUSSION: Die Klassifizierung der Software AEP war sehr gut. In unserer Studie folgte sie allerdings einem systematischen Muster. Die meisten falschen Zuordnungen finden sich in Befunden, die auf ein erhöhtes Krebsrisiko hinweisen. Die Freitextstruktur der Befunde lässt Bedenken hinsichtlich der Machbarkeit einer rein automatisierten Analyse aufkommen. Die Kombination aus menschlichem Intellekt und einer intelligenten, lernfähigen Software erscheint als zukunftsweisend, um unstrukturierte aber wichtige Textinformationen der Forschung zugänglich machen zu können.


Asunto(s)
Registros Médicos , Semántica , Minería de Datos , Alemania
7.
Clin Transl Sci ; 16(12): 2483-2493, 2023 12.
Artículo en Inglés | MEDLINE | ID: mdl-37920921

RESUMEN

Expression of CYP3A5 protein is a basal and acquired resistance mechanism of pancreatic ductal adenocarcinoma cells conferring protection against the CYP3A and CYP2C8 substrate paclitaxel through metabolic degradation. Inhibition of CYP3A isozymes restores the cells sensitivity to paclitaxel. The combination of gemcitabine and nab-paclitaxel is an established regimen for the treatment of metastasized or locally advanced inoperable pancreatic cancer. Cobicistat is a CYP3A inhibitor developed for the pharmacoenhancement of protease inhibitors. The addition of cobicistat to gemcitabine and nab-paclitaxel may increase the antitumor effect. We will conduct a phase I dose escalation trial with a classical 3 + 3 design to investigate the safety, tolerability, and pharmacokinetics (PKs) of gemcitabine, nab-paclitaxel, and cobicistat. Although the doses of gemcitabine (1000 mg/m2 ) and cobicistat (150 mg) are fixed, three dose levels of nab-paclitaxel (75, 100, and 125 mg/m2 ) will be explored to account for a potential PK drug interaction. After the dose escalation phase, we will set the recommended dose for expansion (RDE) and treat up to nine patients in an expansion part of the trial. The trial is registered under the following identifiers EudraCT-Nr. 2019-001439-29, drks.de: DRKS00029409, and ct.gov: NCT05494866. Overcoming resistance to paclitaxel by CYP3A5 inhibition may lead to an increased efficacy of the gemcitabine and nab-paclitaxel regimen. Safety, efficacy, PK, and RDE data need to be acquired before investigating this combination in a large-scale clinical study.


Asunto(s)
Carcinoma Ductal Pancreático , Citostáticos , Neoplasias Pancreáticas , Humanos , Gemcitabina , Citocromo P-450 CYP3A , Inhibidores del Citocromo P-450 CYP3A , Citostáticos/uso terapéutico , Desoxicitidina/efectos adversos , Cobicistat , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Paclitaxel/efectos adversos , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias Pancreáticas/patología , Carcinoma Ductal Pancreático/tratamiento farmacológico , Carcinoma Ductal Pancreático/patología , Ensayos Clínicos Fase I como Asunto
8.
Trials ; 24(1): 591, 2023 Sep 15.
Artículo en Inglés | MEDLINE | ID: mdl-37715270

RESUMEN

BACKGROUND: About 50% of older patients with acute myeloid leukemia (AML) fail to attain complete remission (CR) following cytarabine plus anthracycline-based induction therapy. Salvage chemotherapy regimens are based on high-dose cytarabine (HiDAC), which is frequently combined with mitoxantrone (HAM regimen). However, CR rates remain low, with less than one-third of the patients achieving a CR. FLT3-ITD has consistently been identified as an unfavorable molecular marker in both relapsed and refractory (r/r)-AML. One-quarter of patients who received midostaurin are refractory to induction therapy and relapse rate at 2 years exceeds 40%. The oral second-generation bis-aryl urea tyrosine kinase inhibitor quizartinib is a very selective FLT3 inhibitor, has a high capacity for sustained FLT3 inhibition, and has an acceptable toxicity profile. METHODS: In this multicenter, upfront randomized phase II trial, all patients receive quizartinib combined with HAM (cytarabine 3g/m2 bidaily day one to day three, mitoxantrone 10mg/m2 days two and three) during salvage therapy. Efficacy is assessed by comparison to historical controls based on the matched threshold crossing approach with achievement of CR, complete remission with incomplete hematologic recovery (CRi), or complete remission with partial recovery of peripheral blood counts (CRh) as primary endpoint. During consolidation therapy (chemotherapy and allogeneic hematopoietic cell transplantation), patients receive either prophylactic quizartinib therapy or measurable residual disease (MRD)-triggered preemptive continuation therapy with quizartinib according to up-front randomization. The matched threshold crossing approach is a novel study-design to enhance the classic single-arm trial design by including matched historical controls from previous clinical studies. It overcomes common disadvantages of single-armed and small randomized studies, since the expected outcome of the observed study population can be adjusted based on the matched controls with a comparable distribution of known prognostic and predictive factors. Furthermore, balanced treatment groups lead to stable statistical models. However, one of the limitations of our study is the inability to adjust for unobserved or unknown confounders. Addressing the primary endpoint, CR/CRi/CRh after salvage therapy, the maximal sample size of 80 patients is assessed generating a desirable power of the used adaptive design, assuming a logistic regression is performed at a one-sided significance level α=0.05, the aspired power is 0.8, and the number of matching partners per intervention patient is at least 1. After enrolling 20 patients, the trial sample size will be recalculated in an interim analysis based on a conditional power argument. CONCLUSION: Currently, there is no commonly accepted standard for salvage chemotherapy treatment. The objective of the salvage therapy is to reduce leukemic burden, achieve the best possible remission, and perform a hemopoietic stem-cell transplantation. Thus, in patients with FLT3-ITD mutation, the comparison of quizartinib with intensive salvage therapy versus chemotherapy alone appears as a logical consequence in terms of efficacy and safety. ETHICS AND DISSEMINATION: Ethical approval and approvals from the local and federal competent authorities were granted. Trial results will be reported via peer-reviewed journals and presented at conferences and scientific meetings. TRIAL REGISTRATION: ClinicalTrials.gov NCT03989713; EudraCT Number: 2018-002675-17.


Asunto(s)
Leucemia Mieloide Aguda , Mitoxantrona , Humanos , Mitoxantrona/efectos adversos , Leucemia Mieloide Aguda/tratamiento farmacológico , Compuestos de Fenilurea/efectos adversos , Enfermedad Crónica , Citarabina/efectos adversos , Tirosina Quinasa 3 Similar a fms/genética
9.
Nat Med ; 29(12): 3111-3119, 2023 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-37946058

RESUMEN

Over one million European children undergo computed tomography (CT) scans annually. Although moderate- to high-dose ionizing radiation exposure is an established risk factor for hematological malignancies, risks at CT examination dose levels remain uncertain. Here we followed up a multinational cohort (EPI-CT) of 948,174 individuals who underwent CT examinations before age 22 years in nine European countries. Radiation doses to the active bone marrow were estimated on the basis of body part scanned, patient characteristics, time period and inferred CT technical parameters. We found an association between cumulative dose and risk of all hematological malignancies, with an excess relative risk of 1.96 (95% confidence interval 1.10 to 3.12) per 100 mGy (790 cases). Similar estimates were obtained for lymphoid and myeloid malignancies. Results suggest that for every 10,000 children examined today (mean dose 8 mGy), 1-2 persons are expected to develop a hematological malignancy attributable to radiation exposure in the subsequent 12 years. Our results strengthen the body of evidence of increased cancer risk at low radiation doses and highlight the need for continued justification of pediatric CT examinations and optimization of doses.


Asunto(s)
Neoplasias Hematológicas , Neoplasias Inducidas por Radiación , Exposición a la Radiación , Humanos , Niño , Adolescente , Adulto Joven , Adulto , Dosis de Radiación , Neoplasias Inducidas por Radiación/epidemiología , Neoplasias Inducidas por Radiación/etiología , Neoplasias Inducidas por Radiación/patología , Neoplasias Hematológicas/epidemiología , Neoplasias Hematológicas/etiología , Exposición a la Radiación/efectos adversos , Tomografía Computarizada por Rayos X/efectos adversos
10.
Radiat Res ; 196(1): 74-99, 2021 07 01.
Artículo en Inglés | MEDLINE | ID: mdl-33914893

RESUMEN

Within the European Epidemiological Study to Quantify Risks for Paediatric Computerized Tomography (EPI-CT study), a cohort was assembled comprising nearly one million children, adolescents and young adults who received over 1.4 million computed tomography (CT) examinations before 22 years of age in nine European countries from the late 1970s to 2014. Here we describe the methods used for, and the results of, organ dose estimations from CT scanning for the EPI-CT cohort members. Data on CT machine settings were obtained from national surveys, questionnaire data, and the Digital Imaging and Communications in Medicine (DICOM) headers of 437,249 individual CT scans. Exposure characteristics were reconstructed for patients within specific age groups who received scans of the same body region, based on categories of machines with common technology used over the time period in each of the 276 participating hospitals. A carefully designed method for assessing uncertainty combined with the National Cancer Institute Dosimetry System for CT (NCICT, a CT organ dose calculator), was employed to estimate absorbed dose to individual organs for each CT scan received. The two-dimensional Monte Carlo sampling method, which maintains a separation of shared and unshared error, allowed us to characterize uncertainty both on individual doses as well as for the entire cohort dose distribution. Provided here are summaries of estimated doses from CT imaging per scan and per examination, as well as the overall distribution of estimated doses in the cohort. Doses are provided for five selected tissues (active bone marrow, brain, eye lens, thyroid and female breasts), by body region (i.e., head, chest, abdomen/pelvis), patient age, and time period (1977-1990, 1991-2000, 2001-2014). Relatively high doses were received by the brain from head CTs in the early 1990s, with individual mean doses (mean of 200 simulated values) of up to 66 mGy per scan. Optimization strategies implemented since the late 1990s have resulted in an overall decrease in doses over time, especially at young ages. In chest CTs, active bone marrow doses dropped from over 15 mGy prior to 1991 to approximately 5 mGy per scan after 2001. Our findings illustrate patterns of age-specific doses and their temporal changes, and provide suitable dose estimates for radiation-induced risk estimation in epidemiological studies.


Asunto(s)
Dosis de Radiación , Tomografía Computarizada por Rayos X , Adolescente , Niño , Preescolar , Estudios de Cohortes , Europa (Continente)/epidemiología , Femenino , Humanos , Lactante , Recién Nacido , Masculino , Fantasmas de Imagen
11.
Trials ; 22(1): 765, 2021 Nov 03.
Artículo en Inglés | MEDLINE | ID: mdl-34732236

RESUMEN

BACKGROUND: Overall survival remains poor in older patients with acute myeloid leukemia (AML) with less than 10% being alive after 5 years. In recent studies, a significant improvement in event-free, relapse-free and overall survival was shown by adding gemtuzumab ozogamicin (GO), a humanized antibody-drug conjugate directed against CD33, to intensive induction therapy once or in a sequential dosing schedule. Glasdegib, the small-molecule inhibitor of smoothened (SMO), also showed improved overall survival in patients not eligible for intensive chemotherapy when combined with low-dose cytarabine compared to low-dose cytarabine alone. These findings warrant further investigations in the phase III GnG trial. METHODS/DESIGN: This is a randomized phase III trial with measurable residual disease (MRD) after induction therapy and event-free survival (EFS) as primary endpoints. The two research questions are addressed in a 2 by 2 factorial design. Patients age 60 years and older are upfront randomized 1:1 in one of the two induction arms: GO administered to intensive induction therapy on days 1,4, and 7 versus GO administered once on day 1 (GO-147 versus GO-1), and double-blinded 1:1 in one of the subsequent treatment arms glasdegib vs. placebo as adjunct to consolidation therapy and as single-agent maintenance therapy for six months. Chemotherapy backbone for induction therapy consists of standard 7 + 3 schedule with cytarabine 200 mg/m2 continuously days 1 to 7, daunorubicin 60 mg/m2 days 1, 2, and 3 and high-dose cytarabine (1 g/m2, bi-daily, days 1, 2, and 3) for consolidation therapy. Addressing two primary endpoints, MRD-negativity after induction therapy and event-free survival (EFS), 252 evaluable patients are needed to reject each of the two null hypotheses at a two-sided significance level of 2.5% with a power of at least 85%. ETHICS AND DISSEMINATION: Ethical approval and approvals from the local and federal competent authorities were granted. Trial results will be reported via peer-reviewed journals and presented at conferences and scientific meetings. TRIAL STATUS: Protocol version: 1st version 20.10.2020, no amendments yet. Study initiation on February 16, 2021. First patient was recruited on April 1st. TRIAL REGISTRATION: ClinicalTrials.gov NCT04093505 ; EudraCT 2019-003913-32. Registered on October 30, 2018.


Asunto(s)
Quimioterapia de Inducción , Leucemia Mieloide Aguda , Anciano , Aminoglicósidos/efectos adversos , Anticuerpos Monoclonales Humanizados/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Bencimidazoles , Gemtuzumab , Humanos , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/tratamiento farmacológico , Persona de Mediana Edad , Compuestos de Fenilurea
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