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1.
Cancer ; 128(5): 1004-1014, 2022 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-34726773

RESUMO

BACKGROUND: The clinical benefit of cusatuzumab, a CD70-directed monoclonal antibody with enhanced effector functions, was investigated in patients with relapsed/refractory (R/R) cutaneous T-cell lymphoma (CTCL). METHODS: In this cohort expansion of the ARGX-110-1201 study, 27 patients with R/R CTCL received cusatuzumab at 1 (n = 11) or 5 mg/kg (n = 16) once every 3 weeks to investigate its safety, dose, and exploratory efficacy. The pharmacokinetics, immunogenicity, CD70 expression, and CD70/CD27 biology were also assessed. RESULTS: The most common adverse events included infusion-related reactions, pyrexia, and asthenia. Eighteen serious adverse events (grade 1-3) were reported in 11 patients; 1 of these (vasculitis) was considered drug-related. For 8 of the 11 patients receiving 1 mg/kg, anti-drug antibodies (ADAs) affected the minimal concentration, and this resulted in undetectable cusatuzumab concentrations at the end of treatment and, in some cases, a loss of response. This effect was greatly reduced in the patients receiving 5 mg/kg. The overall response rate was 23%; this included 1 complete response and 5 partial responses (PRs) in 26 of the 27 evaluable patients. In addition, 9 patients achieved stable disease. The mean duration on cusatuzumab was 5.2 months, and the median duration was 2.5 months. Patients with Sézary syndrome (SS) achieved a 60% PR rate with a dosage of 5 mg/kg and a 33% PR rate with a dosage of 1 mg/kg; this resulted in an overall response rate of 50% for patients with SS at both doses. CONCLUSIONS: Cusatuzumab was well tolerated, and antitumor activity was observed at both 1 and 5 mg/kg in highly pretreated patients with R/R CTCL. The observed dose-dependent effect on exposure supports the use of 5 mg/kg for future development.


Assuntos
Anticorpos Monoclonais , Antineoplásicos , Linfoma Cutâneo de Células T , Neoplasias Cutâneas , Anticorpos Monoclonais/efeitos adversos , Antineoplásicos/uso terapêutico , Ligante CD27 , Humanos , Linfoma Cutâneo de Células T/tratamento farmacológico , Recidiva Local de Neoplasia/patologia , Neoplasias Cutâneas/tratamento farmacológico , Resultado do Tratamento
2.
Am J Hematol ; 95(2): 178-187, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31821591

RESUMO

Primary immune thrombocytopenia (ITP) is an acquired autoimmune bleeding disorder, characterized by a low platelet count (<100 × 109 /L) in the absence of other causes associated with thrombocytopenia. In most patients, IgG autoantibodies directed against platelet receptors can be detected. They accelerate platelet clearance and destruction, inhibit platelet production, and impair platelet function, resulting in increased risk of bleeding and impaired quality of life. Efgartigimod is a human IgG1 antibody Fc-fragment, a natural ligand of the neonatal Fc receptor (FcRn), engineered for increased affinity to FcRn, while preserving its characteristic pH-dependent binding. Efgartigimod blocks FcRn, preventing IgG recycling, and causing targeted IgG degradation. In this Phase 2 study, 38 patients were randomized 1:1:1 to receive four weekly intravenous infusions of either placebo (N = 12) or efgartigimod at a dose of 5 mg/kg (N = 13) or 10 mg/kg (N = 13). This short treatment cycle of efgartigimod in patients with ITP, predominantly refractory to previous lines of therapy, was shown to be well tolerated, and demonstrated a favorable safety profile consistent with Phase 1 data. Efgartigimod induced a rapid reduction of total IgG levels (up to 63.7% mean change from baseline), which was associated with clinically relevant increases in platelet counts (46% patients on efgartigimod vs 25% on placebo achieved a platelet count of ≥50 × 109 /L on at least two occasions, and 38% vs 0% achieved ≥50 × 109 /L for at least 10 cumulative days), and a reduced proportion of patients with bleeding. Taken together, these data warrant further evaluation of FcRn antagonism as a novel therapeutic approach in ITP.


Assuntos
Fragmentos Fc das Imunoglobulinas/uso terapêutico , Imunoglobulina G/uso terapêutico , Púrpura Trombocitopênica Idiopática , Receptores Fc/antagonistas & inibidores , Adulto , Idoso , Método Duplo-Cego , Feminino , Seguimentos , Antígenos de Histocompatibilidade Classe I/sangue , Humanos , Masculino , Pessoa de Meia-Idade , Contagem de Plaquetas , Púrpura Trombocitopênica Idiopática/sangue , Púrpura Trombocitopênica Idiopática/tratamento farmacológico , Receptores Fc/sangue
3.
Haematologica ; 101(3): 363-70, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26659916

RESUMO

Renal impairment is associated with poor prognosis in myeloma. This analysis of the pivotal phase 3 FIRST trial examined the impact of renally adapted dosing of lenalidomide and dexamethasone on outcomes of patients with different degrees of renal impairment. Transplant-ineligible patients not requiring dialysis were randomized 1:1:1 to receive continuous lenalidomide and dexamethasone until disease progression (n=535) or for 18 cycles (72 weeks; n=541), or melphalan, prednisone, and thalidomide for 12 cycles (72 weeks; n=547). Follow-up is ongoing. Patients were grouped by baseline creatinine clearance into no (≥ 80 mL/min [n=389]), mild (≥ 50 to < 80 mL/min [n=715]), moderate (≥ 30 to < 50 mL/min [n=372]), and severe impairment (< 30 mL/min [n=147]) subgroups. Continuous lenalidomide and dexamethasone therapy reduced the risk of progression or death in no, mild, and moderate renal impairment subgroups vs. melphalan, prednisone, and thalidomide therapy (HR = 0.67, 0.70, and 0.65, respectively). Overall survival benefits were observed with continuous lenalidomide and dexamethasone treatment vs. melphalan, prednisone, and thalidomide treatment in no or mild renal impairment subgroups. Renal function improved from baseline in 52.6% of lenalidomide and dexamethasone-treated patients. The safety profile of continuous lenalidomide and dexamethasone was consistent across renal subgroups, except for grade 3/4 anemia and rash, which increased with increasing severity of renal impairment. Continuous lenalidomide and dexamethasone treatment, with renally adapted lenalidomide dosing, was effective for most transplant-ineligible patients with myeloma and renal impairment. Trial registration: ClinicalTrials.gov (NCT00689936); EudraCT (2007-004823-39). Funding: Intergroupe Francophone du Myélome and the Celgene Corporation.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Dexametasona/uso terapêutico , Mieloma Múltiplo/tratamento farmacológico , Insuficiência Renal/tratamento farmacológico , Talidomida/análogos & derivados , Adulto , Idoso , Idoso de 80 Anos ou mais , Creatinina/sangue , Progressão da Doença , Esquema de Medicação , Feminino , Humanos , Lenalidomida , Masculino , Melfalan/uso terapêutico , Pessoa de Meia-Idade , Mieloma Múltiplo/complicações , Mieloma Múltiplo/diagnóstico , Mieloma Múltiplo/mortalidade , Prednisona/uso terapêutico , Prognóstico , Estudos Prospectivos , Insuficiência Renal/complicações , Insuficiência Renal/diagnóstico , Insuficiência Renal/mortalidade , Índice de Gravidade de Doença , Análise de Sobrevida , Talidomida/uso terapêutico , Resultado do Tratamento
4.
EJHaem ; 5(5): 940-950, 2024 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-39415900

RESUMO

MP0250 is a designed ankyrin repeat protein that specifically inhibits both vascular endothelial growth factor A (VEGF-A) and hepatocyte growth factor (HGF), aiming at potentiating cancer therapy by disrupting the tumour microenvironment. Encouraging results from a phase 1 trial of MP0250 in patients with solid tumours prompted further investigation in multiple myeloma (MM) as both MP0250 targets are reported to be drivers of MM pathogenesis. In this open-label, single-arm phase 1b/2 study (NCT03136653) in patients with proteasome inhibitor- and/or immunomodulatory drug-relapsed or refractory MM, MP0250 was administered every 3 weeks with standard bortezomib/dexamethasone regimen. Thirty-three patients received at least one dose of MP0250. The most frequent treatment-related adverse events were arterial hypertension (58.1%), thrombocytopenia (32.3%), proteinuria (29.0%) and peripheral oedema (19.4%). Of the 28 patients evaluable for response (median age: 60 [range 44-75]), nine achieved at least partial response, corresponding to an overall response rate of 32.1% (95% confidence interval [CI]: 17.9%, 50.7%), with a median duration of response of 8 months (95% CI 5-NR). An additional three patients achieved minimal response and nine stable diseases as the best overall response. Overall median progression-free survival was 4.2 months (95% CI 1.9-7.1). These findings are in line with the results of recent trials testing new agents on comparable patient cohorts and provide initial evidence of clinical benefit for patients with refractory/relapsed MM treated with MP0250 in combination with bortezomib/dexamethasone. Further clinical evaluation in the emerging MM treatment landscape would be required to confirm the clinical potential of MP0250.

5.
Cancer Immunol Res ; 12(7): 921-943, 2024 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-38683145

RESUMO

The prognosis of patients with acute myeloid leukemia (AML) is limited, especially for elderly or unfit patients not eligible for hematopoietic stem cell (HSC) transplantation. The disease is driven by leukemic stem cells (LSCs), which are characterized by clonal heterogeneity and resistance to conventional therapy. These cells are therefore believed to be a major cause of progression and relapse. We designed MP0533, a multispecific CD3-engaging designed ankyrin repeat protein (DARPin) that can simultaneously bind to three antigens on AML cells (CD33, CD123, and CD70), aiming to enable avidity-driven T cell-mediated killing of AML cells coexpressing at least two of the antigens. In vitro, MP0533 induced selective T cell-mediated killing of AML cell lines, as well as patient-derived AML blasts and LSCs, expressing two or more target antigens, while sparing healthy HSCs, blood, and endothelial cells. The higher selectivity also resulted in markedly lower levels of cytokine release in normal human blood compared to single antigen-targeting T-cell engagers. In xenograft AML mice models, MP0533 induced tumor-localized T-cell activation and cytokine release, leading to complete eradication of the tumors while having no systemic adverse effects. These studies show that the multispecific-targeting strategy used with MP0533 holds promise for improved selectivity toward LSCs and efficacy against clonal heterogeneity, potentially bringing a new therapeutic option to this group of patients with a high unmet need. MP0533 is currently being evaluated in a dose-escalation phase 1 study in patients with relapsed or refractory AML (NCT05673057).


Assuntos
Leucemia Mieloide Aguda , Células-Tronco Neoplásicas , Linfócitos T , Humanos , Leucemia Mieloide Aguda/imunologia , Leucemia Mieloide Aguda/terapia , Leucemia Mieloide Aguda/patologia , Animais , Camundongos , Células-Tronco Neoplásicas/imunologia , Células-Tronco Neoplásicas/metabolismo , Linfócitos T/imunologia , Linfócitos T/metabolismo , Subunidade alfa de Receptor de Interleucina-3/imunologia , Subunidade alfa de Receptor de Interleucina-3/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto , Lectina 3 Semelhante a Ig de Ligação ao Ácido Siálico/metabolismo , Lectina 3 Semelhante a Ig de Ligação ao Ácido Siálico/imunologia , Complexo CD3/imunologia , Linhagem Celular Tumoral , Citotoxicidade Imunológica
6.
J Clin Oncol ; 39(2): 145-154, 2021 01 10.
Artigo em Inglês | MEDLINE | ID: mdl-33301375

RESUMO

PURPOSE: A first-in-human study was performed with MP0250, a DARPin drug candidate. MP0250 specifically inhibits both vascular endothelial growth factor (VEGF) and hepatocyte growth factor (HGF) with the aim of disrupting the tumor microenvironment. PATIENTS AND METHODS: A multicenter, open-label, repeated-dose, phase I study was conducted to assess the safety, tolerability, and pharmacokinetics of MP0250 in 45 patients with advanced solid tumors. In the dose-escalation part, 24 patients received MP0250 as a 3-hour infusion once every 2 weeks at five different dose levels (0.5-12 mg/kg). Once the maximum tolerated dose (MTD) was established, 21 patients were treated with a 1-hour infusion (n = 13, 8 mg/kg, once every 2 weeks and n = 8, 12 mg/kg, once every 3 weeks) of MP0250 in the dose confirmation cohorts. RESULTS: In the dose-escalation cohort, patients treated with 12 mg/kg MP0250 once every 2 weeks experienced dose-limiting toxicities. Therefore, MTD was 8 mg/kg once every 2 weeks or 12 mg/kg once every 3 weeks. The most common adverse events (AEs) were hypertension (69%), proteinuria (51%), and diarrhea and nausea (both 36%); hypoalbuminemia was reported in 24% of patients. Most AEs were consistent with inhibition of the VEGF and HGF pathways. Exposure was dose-proportional and sustained throughout the dosing period for all patients (up to 15 months). The half-life was about 2 weeks. Signs of single-agent antitumor activity were observed: 1 unconfirmed partial response with a time to progression of 23 weeks and 24 patients with stable disease, with the longest duration of 72 weeks and a median duration of 18 weeks. CONCLUSION: MP0250 is a first-in-class DARPin drug candidate with suitable tolerability and appropriate pharmacokinetic properties for further development in combination with other anticancer therapies.


Assuntos
Fator de Crescimento de Hepatócito/antagonistas & inibidores , Neoplasias/tratamento farmacológico , Proteínas Recombinantes de Fusão/administração & dosagem , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores , Adulto , Idoso , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacocinética , Estudos de Coortes , Relação Dose-Resposta a Droga , Feminino , Fator de Crescimento de Hepatócito/metabolismo , Humanos , Infusões Intravenosas , Masculino , Pessoa de Meia-Idade , Terapia de Alvo Molecular , Neoplasias/metabolismo , Neoplasias/patologia , Proteínas Recombinantes de Fusão/efeitos adversos , Proteínas Recombinantes de Fusão/farmacocinética , Microambiente Tumoral , Fator A de Crescimento do Endotélio Vascular/metabolismo , Adulto Jovem
7.
Biomedicines ; 9(6)2021 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-34200749

RESUMO

Dysregulation of MET signaling has been implicated in tumorigenesis and metastasis. ARGX-111 combines complete blockade of this pathway with enhanced tumor cell killing and was investigated in 24 patients with MET-positive advanced cancers in a phase 1b study at four dose levels (0.3-10 mg/kg). ARGX-111 was well tolerated up to 3 mg/kg (MTD). Anti-tumor activity was observed in nearly half of the patients (46%) with a mean duration of treatment of 12 weeks. NHance® mutations in the Fc of ARGX-111 increased affinity for the neonatal Fc receptor (FcRn) at acidic pH, stimulating transcytosis across FcRn-expressing cells and radiolabeled ARGX-111 accumulated in lymphoid tissues, bone and liver, organs expressing FcRn at high levels in a biodistribution study using human FcRn transgenic mice. In line with this, we observed, in a patient with MET-amplified (>10 copies) gastric cancer, diminished metabolic activity in multiple metastatic lesions in lymphoid and bone tissues by 18F-FDG-PET/CT after two infusions with 0.3 mg/kg ARGX-111. When escalated to 1 mg/kg, a partial response was reached. Furthermore, decreased numbers of CTC (75%) possibly by the enhanced tumor cell killing witnessed the modes of action of the drug, warranting further clinical investigation of ARGX-111.

8.
Nat Med ; 26(9): 1459-1467, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32601337

RESUMO

Acute myeloid leukemia (AML) is driven by leukemia stem cells (LSCs) that resist conventional chemotherapy and are the major cause of relapse1,2. Hypomethylating agents (HMAs) are the standard of care in the treatment of older or unfit patients with AML, but responses are modest and not durable3-5. Here we demonstrate that LSCs upregulate the tumor necrosis factor family ligand CD70 in response to HMA treatment resulting in increased CD70/CD27 signaling. Blocking CD70/CD27 signaling and targeting CD70-expressing LSCs with cusatuzumab, a human αCD70 monoclonal antibody with enhanced antibody-dependent cellular cytotoxicity activity, eliminated LSCs in vitro and in xenotransplantation experiments. Based on these preclinical results, we performed a phase 1/2 trial in previously untreated older patients with AML with a single dose of cusatuzumab monotherapy followed by a combination therapy with the HMA azacitidine ( NCT03030612 ). We report results from the phase 1 dose escalation part of the clinical trial. Hematological responses in the 12 patients enrolled included 8 complete remission, 2 complete remission with incomplete blood count recovery and 2 partial remission with 4 patients achieving minimal residual disease negativity by flow cytometry at <10-3. Median time to response was 3.3 months. Median progression-free survival was not reached yet at the time of the data cutoff. No dose-limiting toxicities were reported and the maximum tolerated dose of cusatuzumab was not reached. Importantly, cusatuzumab treatment substantially reduced LSCs and triggered gene signatures related to myeloid differentiation and apoptosis.


Assuntos
Antineoplásicos/uso terapêutico , Ligante CD27/antagonistas & inibidores , Leucemia Mieloide Aguda/tratamento farmacológico , Células-Tronco Neoplásicas/efeitos dos fármacos , Anticorpos Monoclonais/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Apoptose/efeitos dos fármacos , Azacitidina/uso terapêutico , Metilação de DNA/efeitos dos fármacos , Metilação de DNA/genética , Humanos , Leucemia Mieloide Aguda/patologia , Resultado do Tratamento , Membro 7 da Superfamília de Receptores de Fatores de Necrose Tumoral/metabolismo
9.
Scand J Infect Dis ; 41(10): 777-81, 2009.
Artigo em Inglês | MEDLINE | ID: mdl-19593691

RESUMO

With expanding travel activities, visceral leishmaniasis increasingly occurs in non-endemic areas and affects immunocompetent individuals with no other risk factor than holidays at the Mediterranean coast. We report 3 instructive Swiss cases of visceral leishmaniasis presenting with fever of unknown origin and pancytopenia and review current diagnostic and therapeutic concepts.


Assuntos
Leishmania donovani/isolamento & purificação , Leishmaniose Visceral/diagnóstico , Viagem , Adulto , Gluconato de Antimônio e Sódio/uso terapêutico , Antiprotozoários/uso terapêutico , Diagnóstico Diferencial , Feminino , Febre/parasitologia , Infecções por HIV/parasitologia , Humanos , Leishmaniose Visceral/sangue , Leishmaniose Visceral/tratamento farmacológico , Leishmaniose Visceral/parasitologia , Masculino , Região do Mediterrâneo
10.
Neurology ; 92(23): e2661-e2673, 2019 06 04.
Artigo em Inglês | MEDLINE | ID: mdl-31118245

RESUMO

OBJECTIVE: To investigate safety and explore efficacy of efgartigimod (ARGX-113), an anti-neonatal Fc receptor immunoglobulin G1 Fc fragment, in patients with generalized myasthenia gravis (gMG) with a history of anti-acetylcholine receptor (AChR) autoantibodies, who were on stable standard-of-care myasthenia gravis (MG) treatment. METHODS: A phase 2, exploratory, randomized, double-blind, placebo-controlled, 15-center study is described. Eligible patients were randomly assigned (1:1) to receive 4 doses over a 3-week period of either 10 mg/kg IV efgartigimod or matched placebo combined with their standard-of-care therapy. Primary endpoints were safety and tolerability. Secondary endpoints included efficacy (change from baseline to week 11 of Myasthenia Gravis Activities of Daily Living, Quantitative Myasthenia Gravis, and Myasthenia Gravis Composite disease severity scores, and of the revised 15-item Myasthenia Gravis Quality of Life scale), pharmacokinetics, pharmacodynamics, and immunogenicity. RESULTS: Of the 35 screened patients, 24 were enrolled and randomized: 12 received efgartigimod and 12 placebo. Efgartigimod was well-tolerated in all patients, with no serious or severe adverse events reported, no relevant changes in vital signs or ECG findings observed, and no difference in adverse events between efgartigimod and placebo treatment. All patients treated with efgartigimod showed a rapid decrease in total immunoglobulin G (IgG) and anti-AChR autoantibody levels, and assessment using all 4 efficacy scales consistently demonstrated that 75% showed a rapid and long-lasting disease improvement. CONCLUSIONS: Efgartigimod was safe and well-tolerated. The correlation between reduction of levels of pathogenic IgG autoantibodies and disease improvement suggests that reducing pathogenic autoantibodies with efgartigimod may offer an innovative approach to treat MG. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that efgartigimod is safe and well-tolerated in patients with gMG.


Assuntos
Fatores Imunológicos/uso terapêutico , Miastenia Gravis/tratamento farmacológico , Receptores Fc/antagonistas & inibidores , Atividades Cotidianas , Corticosteroides/uso terapêutico , Adulto , Idoso , Autoanticorpos/imunologia , Inibidores da Colinesterase/uso terapêutico , Método Duplo-Cego , Feminino , Antígenos de Histocompatibilidade Classe I , Humanos , Fragmentos Fc das Imunoglobulinas/uso terapêutico , Imunossupressores/uso terapêutico , Masculino , Pessoa de Meia-Idade , Miastenia Gravis/imunologia , Receptores Colinérgicos/imunologia , Resultado do Tratamento , Adulto Jovem
11.
J Leukoc Biol ; 81(6): 1599-608, 2007 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-17347302

RESUMO

The death-associated protein kinase 2 (DAPK2) belongs to a family of Ca(2+)/calmodulin-regulated serine/threonine kinases involved in apoptosis. During investigation of candidate genes operative in granulopoiesis, we identified DAPK2 as highly expressed. Subsequent investigations demonstrated particularly high DAPK2 expression in normal granulocytes compared with monocytes/macrophages and CD34(+) progenitor cells. Moreover, significantly increased DAPK2 mRNA levels were seen when cord blood CD34(+) cells were induced to differentiate toward neutrophils in tissue culture. In addition, all-trans retinoic acid (ATRA)-induced neutrophil differentiation of two leukemic cell lines, NB4 and U937, revealed significantly higher DAPK2 mRNA expression paralleled by protein induction. In contrast, during differentiation of CD34(+) and U937 cells toward monocytes/macrophages, DAPK2 mRNA levels remained low. In primary leukemia, low expression of DAPK2 was seen in acute myeloid leukemia samples, whereas chronic myeloid leukemia samples in chronic phase showed intermediate expression levels. Lentiviral vector-mediated expression of DAPK2 in NB4 cells enhanced, whereas small interfering RNA-mediated DAPK2 knockdown reduced ATRA-induced granulocytic differentiation, as evidenced by morphology and neutrophil stage-specific maturation genes, such as CD11b, G-CSF receptor, C/EBPepsilon, and lactoferrin. In summary, our findings implicate a role for DAPK2 in granulocyte maturation.


Assuntos
Proteínas Quinases Dependentes de Cálcio-Calmodulina/biossíntese , Leucemia Mieloide/patologia , Células Mieloides/citologia , Mielopoese/fisiologia , Neutrófilos/citologia , Doença Aguda , Antígenos CD34/metabolismo , Antígenos de Diferenciação/metabolismo , Proteínas Reguladoras de Apoptose , Diferenciação Celular , Linhagem Celular Tumoral , Doença Crônica , Proteínas Quinases Associadas com Morte Celular , Perfilação da Expressão Gênica , Granulócitos/citologia , Granulócitos/fisiologia , Células-Tronco Hematopoéticas/citologia , Células-Tronco Hematopoéticas/fisiologia , Humanos , Leucemia Mieloide/metabolismo , Células Mieloides/fisiologia , Neutrófilos/fisiologia , RNA Interferente Pequeno/biossíntese , Tretinoína/farmacologia , Regulação para Cima
12.
Med Klin (Munich) ; 103(4): 245-8, 2008 Apr 15.
Artigo em Alemão | MEDLINE | ID: mdl-18484209

RESUMO

BACKGROUND: Malignant lymphoma of the prostate is rare. In the literature, about 165 cases with either a primary lymphoma of the prostate or secondary infiltration of the prostate by a lymphoma are described. CASE REPORT: The case of a 59-year-old patient with an irregular tumor in the prostatic region, but normal prostate-specific antigen (PSA), a fracture in the vertebral column and a bilateral enlargement of the suprarenal glands is presented. Repetitive prostate biopsy revealed the diagnosis of a diffuse large B cell lymphoma. Further staging examinations gave hints to an epidural infiltration. A polychemotherapy including intrathecal drug applications was initiated. Staging after four therapeutic cycles already showed good partial remission of all lymphoma manifestations. After two further therapeutic cycles, a CT scan showed a small rest of prostatic bulk, but PET-CT did not detect vital lymphatic tissue (complete remission). CONCLUSION: In cases of irregular prostatic enlargements, carcinoma has to be considered as the most frequent diagnosis. Nevertheless, also a solitary lymphoma or infiltration of the prostate by a systemic lymphoma has to be taken into account, especially if the PSA value is in the normal range.


Assuntos
Linfoma Difuso de Grandes Células B , Neoplasias da Próstata , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biópsia , Ciclofosfamida/uso terapêutico , Doxorrubicina/uso terapêutico , Humanos , Linfoma Difuso de Grandes Células B/sangue , Linfoma Difuso de Grandes Células B/diagnóstico , Linfoma Difuso de Grandes Células B/diagnóstico por imagem , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Linfoma Difuso de Grandes Células B/patologia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Tomografia por Emissão de Pósitrons , Prednisona/uso terapêutico , Próstata/patologia , Antígeno Prostático Específico/sangue , Neoplasias da Próstata/sangue , Neoplasias da Próstata/diagnóstico , Neoplasias da Próstata/diagnóstico por imagem , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/patologia , Indução de Remissão , Tomografia Computadorizada por Raios X , Vincristina/uso terapêutico
13.
J Clin Invest ; 128(10): 4372-4386, 2018 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-30040076

RESUMO

BACKGROUND: Intravenous Ig (IVIg), plasma exchange, and immunoadsorption are frequently used in the management of severe autoimmune diseases mediated by pathogenic IgG autoantibodies. These approaches modulating IgG levels can, however, be associated with some severe adverse reactions and a substantial burden to patients. Targeting the neonatal Fc receptor (FcRn) presents an innovative and potentially more effective, safer, and more convenient alternative for clearing pathogenic IgGs. METHODS: A randomized, double-blind, placebo-controlled first-in-human study was conducted in 62 healthy volunteers to explore single and multiple ascending intravenous doses of the FcRn antagonist efgartigimod. The study objectives were to assess safety, tolerability, pharmacokinetics, pharmacodynamics, and immunogenicity. The findings of this study were compared with the pharmacodynamics profile elicited by efgartigimod in cynomolgus monkeys. RESULTS: Efgartigimod treatment resulted in a rapid and specific clearance of serum IgG levels in both cynomolgus monkeys and healthy volunteers. In humans, single administration of efgartigimod reduced IgG levels up to 50%, while multiple dosing further lowered IgGs on average by 75% of baseline levels. Approximately 8 weeks following the last administration, IgG levels returned to baseline. Efgartigimod did not alter the homeostasis of albumin or Igs other than IgG, and no serious adverse events related to efgartigimod infusion were observed. CONCLUSION: Antagonizing FcRn using efgartigimod is safe and results in a specific, profound, and sustained reduction of serum IgG levels. These results warrant further evaluation of this therapeutic approach in IgG-driven autoimmune diseases. TRIAL REGISTRATION: Clinicaltrials.gov NCT03457649. FUNDING: argenx BVBA.


Assuntos
Doenças Autoimunes , Fragmentos Fc das Imunoglobulinas/administração & dosagem , Imunoglobulina G/sangue , Receptores Fc/antagonistas & inibidores , Adulto , Animais , Autoanticorpos/sangue , Doenças Autoimunes/sangue , Doenças Autoimunes/tratamento farmacológico , Células CHO , Cricetulus , Método Duplo-Cego , Feminino , Antígenos de Histocompatibilidade Classe I , Humanos , Fragmentos Fc das Imunoglobulinas/efeitos adversos , Macaca fascicularis , Masculino
15.
Clin Cancer Res ; 23(21): 6411-6420, 2017 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-28765328

RESUMO

Purpose: The purpose of this study was to evaluate safety, pharmacokinetics, pharmacodynamics, and preliminary antitumor efficacy of ARGX-110, a glyco-engineered monoclonal antibody, targeting CD70, in patients with CD70 expressing advanced malignancies.Experimental Design: Dose escalation with a sequential 3+3 design was performed in five steps at the 0.1, 1, 2, 5, and 10 mg/kg dose levels (N = 26). ARGX-110 was administered intravenously every 3 weeks until progression or intolerable toxicity. Dose-limiting toxicity was evaluated in the 21 days following the first ARGX-110 administration (Cycle 1). Samples for pharmacokinetics and pharmacodynamics were collected.Results: Dose-limiting toxicity was not observed and the maximum tolerated dose was not reached. ARGX-110 was generally well tolerated, with no dose-related increase in treatment-emergent adverse events (TEAE). The most common TEAE were fatigue and drug related infusion-related reactions (IRR). Of the 20 SAEs reported, five events, all IRRs, were considered related to ARGX-110. ARGX-110 demonstrates dose proportionality over the dose range 1 to 10 mg/kg, but not at 0.1 mg/kg and a terminal half-life of 10 to 13 days. The best overall response was stable disease (14/26) in all 26 evaluable patients with various malignancies and the mean duration of treatment was 15 weeks. No dose-response related antitumor activity was observed, but biomarker readouts provided signs of biological activity, particularly in patients with hematologic malignancies.Conclusions: This dose-escalation phase I trial provides evidence of good tolerability of ARGX-110, pharmacokinetics, and preliminary antitumor activity at all dose levels in generally heavily pretreated patients with advanced CD70-positive malignancies. Clin Cancer Res; 23(21); 6411-20. ©2017 AACR.


Assuntos
Anticorpos Anti-Idiotípicos/administração & dosagem , Anticorpos Monoclonais/administração & dosagem , Ligante CD27/imunologia , Neoplasias/tratamento farmacológico , Adulto , Idoso , Anticorpos Anti-Idiotípicos/efeitos adversos , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais/farmacocinética , Ligante CD27/antagonistas & inibidores , Relação Dose-Resposta a Droga , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/classificação , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/patologia , Feminino , Humanos , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Neoplasias/imunologia , Neoplasias/patologia
16.
J Clin Oncol ; 34(30): 3609-3617, 2016 10 20.
Artigo em Inglês | MEDLINE | ID: mdl-27325857

RESUMO

Purpose This analysis of the FIRST trial in patients with newly diagnosed multiple myeloma (MM) ineligible for stem-cell transplantation examined updated outcomes and impact of patient age. Patients and Methods Patients with untreated symptomatic MM were randomly assigned at a one-to-one-to-one ratio to lenalidomide plus low-dose dexamethasone until disease progression (Rd continuous), Rd for 72 weeks (18 cycles; Rd18), or melphalan, prednisone, and thalidomide (MPT; 72 weeks), stratified by age (≤ 75 v > 75 years), disease stage (International Staging System stage I/II v III), and country. The primary end point was progression-free survival. Rd continuous and MPT were primary comparators. Results Between August 21, 2008, and March 7, 2011, 1,623 patients were enrolled (Rd continuous, n = 535; Rd18, n = 541; MPT, n = 547), including 567 (35%) age older than 75 years. Higher rates of advanced-stage disease and renal impairment were observed in patients older than 75 versus 75 years of age or younger. Rd continuous reduced the risk of progression or death compared with MPT by 31% (hazard ratio [HR], 0.69; 95% CI, 0.59 to 0.80; P < .001) overall, 36% (HR, 0.64; 95% CI, 0.53 to 0.77; P < .001) in patients age 75 years or younger, and 20% (HR, 0.80; 95% CI, 0.62 to 1.03; P = .084) in those age older than 75 years. Median overall survival was longer with Rd continuous than with MPT, including a 14-month difference in patients age older than 75 years. Progression-free survival with Rd18 was similar to that with MPT, and overall survival with Rd18 was marginally inferior to that with Rd continuous. Rates of grade 3 to 4 treatment-emergent adverse events were similar for Rd continuous-treated patients age 75 years or older and those age older than 75 years; however, older patients had more frequent lenalidomide dose reductions. Conclusion Results support Rd continuous treatment as a new standard of care for stem-cell transplantation-ineligible patients with newly diagnosed MM of all ages.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Mieloma Múltiplo/tratamento farmacológico , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Dexametasona/administração & dosagem , Progressão da Doença , Intervalo Livre de Doença , Feminino , Humanos , Lenalidomida , Masculino , Melfalan/administração & dosagem , Pessoa de Meia-Idade , Mieloma Múltiplo/patologia , Estadiamento de Neoplasias , Prednisona/administração & dosagem , Taxa de Sobrevida , Talidomida/administração & dosagem , Talidomida/efeitos adversos , Talidomida/análogos & derivados
17.
Rev Med Suisse ; 1(20): 1328-30, 1333-4, 2005 May 18.
Artigo em Francês | MEDLINE | ID: mdl-15991624

RESUMO

Advances in cancer biology have led to the development of screening tests that allow an early diagnosis. Cancer screening is not just the matter of a single individual patient, it is a matter of public health. Screening is commonly viewed as of no harm, when in fact harms are associated with the majority of cancer screening tests. A test should only be used when the potential of benefit clearly outweighs the risks for harm. The data in the literature are not always clear cut and in a lot of cases guidelines are somewhat controversial. What is known and what is unknown about screening tests is quite different from what is believed by the public. The aim of this work is to summarize the different methods and guidelines in cancer screening to help choosing the right test at the right time for the right person.


Assuntos
Programas de Rastreamento , Neoplasias/diagnóstico , Guias de Prática Clínica como Assunto , Tomada de Decisões , Humanos , Seleção de Pacientes , Saúde Pública
18.
Am J Surg Pathol ; 26(4): 498-504, 2002 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-11914629

RESUMO

The histopathologic features of acute radiation-induced colitis in humans have been described in occasional, >20-year-old studies, but they have not been analyzed in detail. We characterize such findings in 34 patients with rectal cancer who underwent surgery a few days after preoperative irradiation with 25 Gy given over 5-7 days, and we compare the results to the histopathologic features detected in 18 patients treated by a conventional preoperative irradiation protocol consisting of 45 Gy during 5 weeks followed by surgery after a time interval of at least 3 weeks. Short-term preoperative irradiation therapy generally induced severe mucosal inflammation characterized by increased cellularity of the lamina propria, prominent eosinophilic infiltrates, crypt disarray, surface and crypt epithelial damage, nuclear abnormalities, and presence of apoptotic bodies in the crypt epithelium. These histopathologic features were absent or detected only occasionally in the patient group treated according to the long-term preoperative irradiation protocol. Despite acute severe inflammation, none of the patients treated by short-term irradiation developed perioperative complications. These observations indicate that acute radiation colitis may remain clinically silent and resolve spontaneously within a few weeks after irradiation. Given the widening acceptance of short-term preoperative irradiation protocols for rectal cancer, pathologists should be aware of the rather characteristic histologic findings of acute radiation colitis and avoid unnecessary concern of clinicians. The differential diagnosis includes infectious colitis, collagenous and ischemic colitis, nonsteroidal anti-inflammatory drug-associated colitis, and chronic idiopathic inflammatory bowel disease.


Assuntos
Colite/patologia , Lesões por Radiação/patologia , Neoplasias Retais/radioterapia , Doença Aguda , Adulto , Idoso , Idoso de 80 Anos ou mais , Colite/etiologia , Seguimentos , Humanos , Inflamação/patologia , Pessoa de Meia-Idade , Lesões por Radiação/etiologia , Neoplasias Retais/cirurgia
19.
Leuk Lymphoma ; 45(6): 1205-7, 2004 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-15360002

RESUMO

B-cell chronic lymphocytic leukemia is a heterogenous disease with disturbed apoptosis in which the precise molecular defects leading to this pathogenesis are still unclear. The p73 gene (a p53 homologue) encodes 2 proteins with opposing functions. TAp73 induces cell cycle arrest and apoptosis, whilst the oncogenic deltaNp73 inhibits both TAp73 and p53 induced apoptosis. Microsatellite analysis was performed to investigate the p73 gene locus in B-CLL. Moreover, we investigated the expression of the TAp73 and deltaNp73 variant by measuring the mRNA transcripts in 51 B-CLL patients by real-time RT-PCR. And in addition, protein expression was analyzed by Western blotting technique in 20 B-CLL patients. There was no evidence of clonal loss of heterozygosity at 1p36, the p73 gene locus in B-CLL patients. The real time RT-PCR analysis showed that the expression of both p73 gene variants was much higher in leukemic cells compared to controls. In 17/20 (85%) patients deltaNp73 and TAp73 protein were present. The observed increase of expression of the antiapoptotic deltaNp73 variant in neoplastic cells may lead to a functional p53 inactivation. This mechanism might be relevant in malignancies with an intact p53 gene but disturbed apoptosis mechanisms such as in B-CLL.


Assuntos
Biomarcadores Tumorais/genética , Proteínas de Ligação a DNA/genética , Leucemia Linfocítica Crônica de Células B/genética , Proteínas Nucleares/genética , Western Blotting , Genes Supressores de Tumor , Humanos , Leucemia Linfocítica Crônica de Células B/metabolismo , Perda de Heterozigosidade , Repetições de Microssatélites , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Proteína Tumoral p73 , Proteínas Supressoras de Tumor , Regulação para Cima
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