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1.
Neuropathol Appl Neurobiol ; 49(2): e12899, 2023 04.
Artículo en Inglés | MEDLINE | ID: mdl-36879456

RESUMEN

AIMS: How and why lymphoma cells home to the central nervous system and vitreoretinal compartment in primary diffuse large B-cell lymphoma of the central nervous system remain unknown. Our aim was to create an in vivo model to study lymphoma cell tropism to the central nervous system. METHODS: We established a patient-derived central nervous system lymphoma xenograft mouse model and characterised xenografts derived from four primary and four secondary central nervous system lymphoma patients using immunohistochemistry, flow cytometry and nucleic acid sequencing technology. In reimplantation experiments, we analysed dissemination patterns of orthotopic and heterotopic xenografts and performed RNA sequencing of different involved organs to detect differences at the transcriptome level. RESULTS: We found that xenografted primary central nervous system lymphoma cells home to the central nervous system and eye after intrasplenic transplantation, mimicking central nervous system and primary vitreoretinal lymphoma pathology, respectively. Transcriptomic analysis revealed distinct signatures for lymphoma cells in the brain in comparison to the spleen as well as a small overlap of commonly regulated genes in both primary and secondary central nervous system lymphoma. CONCLUSION: This in vivo tumour model preserves key features of primary and secondary central nervous system lymphoma and can be used to explore critical pathways for the central nervous system and retinal tropism with the goal to find new targets for novel therapeutic approaches.


Asunto(s)
Neoplasias del Sistema Nervioso Central , Linfoma de Células B Grandes Difuso , Neoplasias de la Retina , Humanos , Animales , Ratones , Xenoinjertos , Neoplasias de la Retina/diagnóstico , Neoplasias de la Retina/tratamiento farmacológico , Neoplasias de la Retina/patología , Cuerpo Vítreo/metabolismo , Cuerpo Vítreo/patología , Neoplasias del Sistema Nervioso Central/patología , Sistema Nervioso Central/patología , Linfoma de Células B Grandes Difuso/tratamiento farmacológico , Linfoma de Células B Grandes Difuso/genética , Linfoma de Células B Grandes Difuso/patología , Retina/metabolismo
2.
Cancer Immunol Immunother ; 71(12): 2913-2928, 2022 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-35476127

RESUMEN

Wilms' tumor 1 (WT1) protein is highly immunogenic and overexpressed in acute myeloid leukemia (AML), consequently ranked as a promising target for novel immunotherapeutic strategies. Here we report our experience of a phase I/II clinical trial (NCT01051063) of a vaccination strategy based on WT1 recombinant protein (WT1-A10) together with vaccine adjuvant AS01B in five elderly AML patients (median age 69 years, range 63-75) receiving a total of 62 vaccinations (median 18, range 3-20) after standard chemotherapy. Clinical benefit was observed in three patients: one patient achieved measurable residual disease clearance during WT1 vaccination therapy, another patient maintained long-term molecular remission over 59 months after the first vaccination cycle. Interestingly, in one case, we observed a complete clonal switch at AML relapse with loss of WT1 expression, proposing suppression of the original AML clone by WT1-based vaccination therapy. Detected humoral and cellular CD4+ T cell immune responses point to efficient immune stimulation post-vaccination, complementing hints for induced conventional T cell infiltration into the bone marrow and a shift from senescent/exhausted to a more activated T cell profile. Overall, the vaccinations with WT1 recombinant protein had an acceptable safety profile and were thus well tolerated.To conclude, our data provide evidence of potential clinical efficacy of WT1 protein-based vaccination therapy in AML patients, warranting further investigations.


Asunto(s)
Vacunas contra el Cáncer , Leucemia Mieloide Aguda , Anciano , Humanos , Persona de Mediana Edad , Leucemia Mieloide Aguda/terapia , Proteínas Recombinantes/uso terapéutico , Vacunación , Proteínas WT1/uso terapéutico
3.
Blood ; 122(1): 93-9, 2013 Jul 04.
Artículo en Inglés | MEDLINE | ID: mdl-23670178

RESUMEN

The World Health Organization (WHO) classification of myeloproliferative neoplasms (MPNs) comprises several entities including essential thrombocythemia (ET); primary myelofibrosis (PMF); and MPN, unclassifiable (MPN,U). Differential diagnosis between ET and early, prefibrotic PMF can be challenging but is critical because clinical course and outcome vary considerably between these entities. We have previously shown that the transcription factor nuclear factor erythroid 2 (NF-E2) is aberrantly expressed in MPN patients. Here we demonstrate that NF-E2 is mislocalized in PMF cells and that aberrant NF-E2 localization discriminates statistically highly significantly between ET and PMF. A threshold of 20% nuclear NF-E2 staining was cross-validated by ".682+ bootstrapping." Moreover, this cutoff correctly classifies diagnostic bone marrow biopsies of MPN,U patients specified upon follow-up as ET or PMF with 92% accuracy. Because interobserver concordance between independent pathologists was high (Spearman's rank correlation coefficient, 0.727), we propose that quantitative NF-E2 immunohistochemistry represents a diagnostic tool that can reliably support a differential diagnosis between ET and PMF.


Asunto(s)
Células Eritroides/metabolismo , Subunidad p45 del Factor de Transcripción NF-E2/metabolismo , Mielofibrosis Primaria/diagnóstico , Mielofibrosis Primaria/patología , Trombocitemia Esencial/diagnóstico , Trombocitemia Esencial/patología , Antígenos CD/metabolismo , Biopsia , Estudios de Cohortes , Diagnóstico Diferencial , Células Eritroides/patología , Humanos , Inmunohistoquímica/estadística & datos numéricos , Variaciones Dependientes del Observador , Pronóstico , Receptores de Transferrina/metabolismo , Bancos de Tejidos
4.
Histochem Cell Biol ; 141(4): 431-40, 2014 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-24292846

RESUMEN

The inhibitors of DNA binding (ID) inhibit basic helix-loop-helix transcription factors and thereby guide cellular differentiation and proliferation. To elucidate the involvement of IDs in hematopoiesis and acute leukemias (AL), we analyzed ID2 and ID3 expression in hematopoiesis and leukemic blasts in bone marrow biopsies (BMB). BMB of healthy stem cell donors (n = 19) and BMB of patients with acute myeloid leukemia (AML) with myelodysplasia-related changes (AML-MD; n = 19), de novo AML (n = 20), B-acute lymphoblastic leukemia (B-ALL) (n = 23), T-ALL (n = 19), were immunohistochemically stained for ID2 and ID3 expression. The expression patterns were evaluated and quantified for each hematopoietic lineage and each leukemia subtype. In normal BMB, immature granulopoiesis showed weak ID2 and strong ID3 expression, which was lost during maturation (p < 0.001). Erythropoiesis remained negative for ID2/3 (p < 0.001). ID2/3 expression differed between immature granulopoiesis and leukemic blasts (p < 0.001). Moreover, differential ID2/3 expression was seen between AL subgroups: AML, especially AML-MD, had more ID2- (p < 0.001) and ID3-positive (p < 0.001) blasts than ALL. We show a comprehensive in situ picture of ID2/3 expression in hematopoiesis and AL. Morphologically, ID2/3 proteins seem to be involved in the granulopoietic maturation. Importantly, the distinct ID2/3 expression patterns in AL indicate a specific deregulation of ID2/3 in the various types of AL and may support subtyping of AL.


Asunto(s)
Granulocitos/citología , Granulocitos/metabolismo , Proteína 2 Inhibidora de la Diferenciación/biosíntesis , Proteínas Inhibidoras de la Diferenciación/análisis , Proteínas Inhibidoras de la Diferenciación/biosíntesis , Leucemia Mieloide Aguda/clasificación , Leucemia Mieloide Aguda/metabolismo , Proteínas de Neoplasias/análisis , Proteínas de Neoplasias/biosíntesis , Biopsia , Células de la Médula Ósea/química , Células de la Médula Ósea/citología , Células de la Médula Ósea/metabolismo , Femenino , Granulocitos/química , Humanos , Proteína 2 Inhibidora de la Diferenciación/análisis , Leucemia Mieloide Aguda/diagnóstico , Masculino , Persona de Mediana Edad , Estudios Retrospectivos
5.
NPJ Precis Oncol ; 8(1): 180, 2024 Aug 14.
Artículo en Inglés | MEDLINE | ID: mdl-39143272

RESUMEN

Despite major advances in molecular profiling and classification of primary brain tumors, personalized treatment remains limited for most patients. Here, we explored the feasibility of individual molecular profiling and the efficacy of biomarker-guided therapy for adult patients with primary brain cancers in the real-world setting within the molecular tumor board Freiburg, Germany. We analyzed genetic profiles, personalized treatment recommendations, and clinical outcomes of 102 patients with 21 brain tumor types. Alterations in the cell cycle, BRAF, and mTOR pathways most frequently led to personalized treatment recommendations. Molecularly informed therapies were recommended in 71% and implemented in 32% of patients with completed molecular diagnostics. The disease control rate following targeted treatment was 50% and the overall response rate was 30%, with a progression-free survival 2/1 ratio of at least 1.3 in 31% of patients. This study highlights the efficacy of molecularly guided treatment and the need for biomarker-stratified trials in brain cancers.

6.
Neuro Oncol ; 23(12): 2076-2084, 2021 12 01.
Artículo en Inglés | MEDLINE | ID: mdl-33984138

RESUMEN

BACKGROUND: In patients with presumed primary CNS lymphoma (PCNSL), a systemic manifestation is found only in a small minority. Although bone marrow biopsy (BMB) is recommended for staging, its diagnostic value is unclear. METHODS: A retrospective analysis of 392 patients with presumed PCNSL from 3 university hospitals and 33 patients with secondary CNS lymphoma (SCNSL) and initial CNS involvement from a multicenter Germany-wide prospective registry was performed. RESULTS: A BMB was performed and documented in 320/392 patients with presumed PCNSL; 23 had pathologic results. One harbored the same lymphoma in the brain and bone marrow (BM), 22 showed findings in BM discordant to the histology of brain lymphoma; n = 12 harbored a low-grade lymphoma in the BM, the other showed B-cell proliferation but no proof of lymphoma (n = 5), monoclonal B cells (n = 3), or abnormalities not B-cell-associated (n = 2). In the group of SCNSL with initial CNS manifestation, 32/33 patients underwent BMB; 7 were documented with bone marrow involvement (BMI); 1 had concordant results in the brain and BM with no other systemic manifestation. Six had additional systemic lymphoma manifestations apart from the brain and BM. CONCLUSIONS: In only 2 out of 352 (0.6%) patients with CNS lymphoma (320 presumed PCNSL and 32 SCNSL), BMB had an impact on diagnosis and treatment. While collected in a selected cohort, these findings challenge the value of BMB as part of routine staging in presumed PCNSL.


Asunto(s)
Linfoma no Hodgkin , Linfoma , Biopsia , Médula Ósea/patología , Fluorodesoxiglucosa F18 , Humanos , Linfoma no Hodgkin/patología , Estadificación de Neoplasias , Estudios Retrospectivos
7.
Cancers (Basel) ; 13(5)2021 Mar 08.
Artículo en Inglés | MEDLINE | ID: mdl-33800365

RESUMEN

Molecular precision oncology faces two major challenges: first, to identify relevant and actionable molecular variants in a rapidly changing field and second, to provide access to a broad patient population. Here, we report a four-year experience of the Molecular Tumor Board (MTB) of the Comprehensive Cancer Center Freiburg (Germany) including workflows and process optimizations. This retrospective single-center study includes data on 488 patients enrolled in the MTB from February 2015 through December 2018. Recommendations include individual molecular diagnostics, molecular stratified therapies, assessment of treatment adherence and patient outcomes including overall survival. The majority of MTB patients presented with stage IV oncologic malignancies (90.6%) and underwent an average of 2.1 previous lines of therapy. Individual diagnostic recommendations were given to 487 patients (99.8%). A treatment recommendation was given in 264 of all cases (54.1%) which included a molecularly matched treatment in 212 patients (43.4%). The 264 treatment recommendations were implemented in 76 patients (28.8%). Stable disease was observed in 19 patients (25.0%), 17 had partial response (22.4%) and five showed a complete remission (6.6%). An objective response was achieved in 28.9% of cases with implemented recommendations and for 4.5% of the total population (22 of 488 patients). By optimizing the MTB workflow, case-discussions per session increased significantly while treatment adherence and outcome remained stable over time. Our data demonstrate the feasibility and effectiveness of molecular-guided personalized therapy for cancer patients in a clinical routine setting showing a low but robust and durable disease control rate over time.

8.
Leuk Res ; 39(4): 462-70, 2015 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-25697066

RESUMEN

Polo-like kinase 1 (PLK1) is an important regulator of the cell cycle and is overexpressed in various solid and hematological malignancies. Small molecule inhibitors targeting PLK1, such as BI2536 or BI6727 (Volasertib) are a promising therapeutic approach in such malignancies. Here, we show a loss of specifically localized PLK1 in AML blasts in vivo, accompanied by mitotic arrest with transition into apoptosis, in bone marrow biopsies of AML patients after treatment with BI2536. We verify these results in live cell imaging experiments with the AML cell line HL-60, and demonstrate that non-neoplastic, immortalized lymphoblastoid cells are also sensitive to PLK1 inhibition. It is demonstrated that normal granulopoietic precursors have similar PLK1 expression levels as leukemic blasts. These results are in line with the adverse effects of PLK1 inhibition and underline the great potential of PLK1 inhibitors in the treatment of AML.


Asunto(s)
Apoptosis/efectos de los fármacos , Médula Ósea/efectos de los fármacos , Proteínas de Ciclo Celular/antagonistas & inhibidores , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/patología , Mitosis/efectos de los fármacos , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Proteínas Proto-Oncogénicas/antagonistas & inhibidores , Pteridinas/farmacología , Anciano , Anciano de 80 o más Años , Antimitóticos/farmacología , Crisis Blástica/tratamiento farmacológico , Crisis Blástica/enzimología , Crisis Blástica/patología , Western Blotting , Médula Ósea/enzimología , Médula Ósea/patología , Proteínas de Ciclo Celular/metabolismo , Proliferación Celular/efectos de los fármacos , Femenino , Humanos , Técnicas para Inmunoenzimas , Leucemia Mieloide Aguda/enzimología , Masculino , Proteínas Serina-Treonina Quinasas/metabolismo , Proteínas Proto-Oncogénicas/metabolismo , ARN Mensajero/genética , Reacción en Cadena en Tiempo Real de la Polimerasa , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Células Tumorales Cultivadas , Quinasa Tipo Polo 1
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