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1.
Br J Haematol ; 204(5): 1894-1898, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38279625

RESUMO

Frequency, distribution and prognostic meaning of ALK-partner genes other than NPM1 in ALK-positive anaplastic large-cell lymphoma (ALCL) are unknown. Forty-nine of 316 ALCL diagnosed in the NHL-BFM study group showed no nuclear ALK expression suggestive of a variant ALK-partner; 41 were analysed by genomic capture high-throughput sequencing or specific RT-PCRs. NPM1::ALK was detected in 13 cases. Among the 28 patients with a non-NPM1::ALK-fusion partner, ATIC (n = 8; 29%) and TPM3 (n = 9; 32%) were the most common. Five of eight patients with ATIC::ALK-positive ALCL relapsed, none of nine with TPM3::ALK. Variant ALK-partners are rare and potentially associated with different prognoses.


Assuntos
Quinase do Linfoma Anaplásico , Linfoma Anaplásico de Células Grandes , Nucleofosmina , Humanos , Linfoma Anaplásico de Células Grandes/genética , Linfoma Anaplásico de Células Grandes/patologia , Criança , Masculino , Feminino , Quinase do Linfoma Anaplásico/genética , Quinase do Linfoma Anaplásico/análise , Adolescente , Pré-Escolar , Proteínas de Fusão Oncogênica/genética , Prognóstico , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Lactente , Tropomiosina
2.
J Clin Apher ; 39(3): e22128, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38829041

RESUMO

BACKGROUND: Due to development of chronic lung allograft dysfunction (CLAD), prognosis for patients undergoing lung transplantation (LTx) is still worse compared to other solid organ transplant recipients. Treatment options for slowing down CLAD progression are scarce with extracorporeal photopheresis (ECP) as an established rescue therapy. The aim of the study was to identify characteristics of responders and non-responders to ECP treatment, assess their survival, lung function development and by that define the subset of patients who should receive early ECP treatment. METHODS: We performed a retrospective study of all LTx patients receiving ECP treatment at the University Hospital Zurich between January 2010 and March 2020. Patients were followed-up for a maximum period of 5 years. Mortality and lung function development were assessed by CLAD stage and by CLAD subtype before initiation of ECP treatment. RESULTS: Overall, 105 patients received at least one ECP following LTx. A total of 57 patients (61.3%) died within the study period with a median survival of 15 months. Mortality was 57% for patients who started ECP at CLAD1, 39% for CLAD2, 93% for CLAD3, and 90% for CLAD4 (p < 0.001). Survival and lung function development was best in young patients at early CLAD stages 1 and 2. Response to ECP treatment was worst in patients with CLAD-RAS/mixed subtype (14.3%) and patients with ECP initiation in CLAD stages 3 (7.1%) and 4 (11.1%). Survival was significantly better in a subset of patients with recurrent acute allograft dysfunction and earlier start of ECP treatment (105 vs 15 months). CONCLUSION: In this retrospective analysis of a large group of CLAD patients treated with ECP after LTx, early initiation of ECP was associated with better long-term survival. Besides a subset of patients suffering of recurrent allograft dysfunction, especially a subset of patients defined as responders showed an improved response rate and survival, suggesting that ECP should be initiated in early CLAD stages and young patients. ECP might therefore prevent long-term disease progression even in patients with CLAD refractory to other treatment options and thus prevent or delay re-transplantation.


Assuntos
Transplante de Pulmão , Fotoferese , Humanos , Fotoferese/métodos , Estudos Retrospectivos , Masculino , Feminino , Pessoa de Meia-Idade , Adulto , Aloenxertos , Doença Crônica , Recidiva , Disfunção Primária do Enxerto/terapia , Disfunção Primária do Enxerto/mortalidade
3.
Opt Express ; 31(14): 22997-23007, 2023 Jul 03.
Artigo em Inglês | MEDLINE | ID: mdl-37475395

RESUMO

Micro-light emitting diodes (µ-LEDs) suffer from a drastic drop in internal quantum efficiency that emerges with the miniaturization of pixels down to the single micrometer size regime. In addition, the light extraction efficiency (LEE) and far field characteristics change significantly as the pixel size approaches the wavelength of the emitted light. In this work, we systematically investigate the fundamental optical properties of nitride-based µ-LEDs with the focus on pixel sizes from 1 µm to 5 µm and various pixel sidewall angles from 0∘ to 60∘ using finite-difference time-domain simulations. We find that the LEE strictly increases with decreasing pixel size, resulting in a LEE improvement of up to 45% for a 1 µm pixel compared to a 20 µm pixel. The ideal pixel sidewall angle varies between 35∘ and 40∘, leading to a factor of 1.4 enhancement with respect to vertical pixel sidewalls. For pixel sizes in the order of 2 µm and smaller, a substantial transition of far field properties can be observed. Here, the far field shape depends severely on the pixel sidewall angle and affects the LEE within a solid angle of ±15∘. Moreover, we investigate the impact of emission wavelength and observe major differences in optical characteristics for blue, green and red emitting pixels, which is relevant for real-world applications. Finally, we discuss the implications of the assumptions we made and their significance for the design of µ-LEDs.

4.
Blood ; 135(14): 1124-1132, 2020 04 02.
Artigo em Inglês | MEDLINE | ID: mdl-31961927

RESUMO

Children with refractory or relapsed Burkitt lymphoma (BL) or Burkitt leukemia (B-AL) have a poor chance to survive. We describe characteristics, outcome, reinduction, and transplantation approaches and evaluate risk factors among children with progression of a BL/B-AL included in Non-Hodgkin's Lymphoma-Berlin-Frankfurt-Münster studies between 1986 and 2016. Treatment recommendation was reinduction including rituximab from the early 2000s followed by blood stem cell transplantation. The 3-year survival of the 157 children was 18.5 ± 3%. Survival significantly improved from 11 ± 3% before to 27 ± 5% after 2000 (P < .001), allowing for risk factor analyses among the latter 75 patients. Survival of 14 patients with relapse after initial therapy for low-risk disease (R1/R2) was 50 ± 13% compared with 21 ± 5% for 61 patients progressing after R3/R4 therapy (P < .02). A total of 25 of 28 patients with progression during first-line therapy, 31 of 32 with progression during reinduction, 15 of 16 not reaching a complete remission (CR) before transplantation, 9 of 10 treated with rituximab front-line, and all 13 patients not receiving rituximab during reinduction died. Forty-six patients received stem cell transplantation (20 autologous, 26 allogeneic). Survival after a regimen combining rituximab with continuous-infusion chemotherapy followed by allogeneic transplantation was 67 ± 12% compared with 18 ± 5% for all other regimen and transplantations (P = .003). Patients with relapsed BL/B-AL have a poor chance to survive after current effective front-line therapies. Progression during initial or reinduction chemotherapy and initial high-risk disease are risk factors in relapse. Time-condensed continuous-infusion reinduction followed by stem cell transplantation forms the basis for testing new drugs.


Assuntos
Antineoplásicos Imunológicos/uso terapêutico , Linfoma de Burkitt/terapia , Transplante de Células-Tronco Hematopoéticas , Recidiva Local de Neoplasia/terapia , Rituximab/uso terapêutico , Adolescente , Linfoma de Burkitt/epidemiologia , Criança , Progressão da Doença , Feminino , Humanos , Masculino , Recidiva Local de Neoplasia/epidemiologia , Análise de Sobrevida , Transplante Homólogo , Resultado do Tratamento
5.
Haematologica ; 105(8): 2141-2149, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-31649129

RESUMO

Detection of minimal disseminated disease is a validated prognostic factor in ALK-positive anaplastic large cell lymphoma. We previously reported that quantification of minimal disease by quantitative real-time polymerase chain reaction (RQ-PCR) in bone marrow applying a cut-off of 10 copies NPM-ALK/104 copies of ABL1 identifies very high-risk patients. In the present study, we aimed to confirm the prognostic value of quantitative minimal disseminated disease evaluation and to validate digital polymerase chain reaction (dPCR) as an alternative method. Among 91 patients whose bone marrow was analyzed by RQ-PCR, more than 10 normalized copy-numbers correlated with stage III/IV disease, mediastinal and visceral organ involvement and low anti-ALK antibody titers. The cumulative incidence of relapses of 18 patients with more than 10 normalized copy-numbers of NPM-ALK was 61±12% compared to 21±5% for the remaining 73 patients (P=0.0002). Results in blood correlated with those in bone marrow (r=0.74) in 70 patients for whom both materials could be tested. Transcripts were quantified by RQ-PCR and dPCR in 75 bone marrow and 57 blood samples. Copy number estimates using dPCR and RQ-PCR correlated in 132 samples (r=0.85). Applying a cut-off of 30 copies NPM-ALK/104 copies ABL1 for quantification by dPCR, almost identical groups of patients were separated as those separated by RQ-PCR. In summary, the prognostic impact of quantification of minimal disseminated disease in bone marrow could be confirmed for patients with anaplastic large cell lymphoma. Blood can substitute for bone marrow. Quantification of minimal disease by dPCR provides a promising tool to facilitate harmonization of minimal disease measurement between laboratories and for clinical studies.


Assuntos
Linfoma Anaplásico de Células Grandes , Quinase do Linfoma Anaplásico , Criança , Humanos , Linfoma Anaplásico de Células Grandes/diagnóstico , Linfoma Anaplásico de Células Grandes/genética , Recidiva Local de Neoplasia , Reação em Cadeia da Polimerase , Prognóstico , Proteínas Tirosina Quinases , Receptores Proteína Tirosina Quinases/genética
6.
Clin Immunol ; 195: 77-81, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30077013

RESUMO

Patients with Nucleophosmin (NPM)-Anaplastic lymphoma kinase (ALK)-positive anaplastic large cell lymphoma (ALCL) mount ALK autoantibodies. The titer of these autoantibodies inversely correlates with the risk of relapse. The epitopes recognized by these autoantibodies in NPM-ALK might be associated with different ALK-antibody levels. We used overlapping peptide microarray technology to analyze epitope-binding to NPM-ALK by plasma or serum from 129 ALK-positive ALCL patients and 21 controls. Antibodies present in sera from ALCL patients bound to epitopes mainly in the C-terminal region of the ALK portion of NPM-ALK (amino acid positions 469-496, 561-588, 617-644). Patients with higher ALK antibody titers detected the epitope 561-588 more frequently as well as three further epitopes at the N-terminus of the kinase domain compared to patients with intermediate and low titers. These results identify new potential target epitopes for immunotherapy in ALK-positive ALCL. The methodology can be adapted for more reproducible analyses of tumor antigen detection.


Assuntos
Antígenos de Neoplasias/metabolismo , Epitopos de Linfócito B/metabolismo , Imunoterapia/métodos , Linfoma Anaplásico de Células Grandes/imunologia , Peptídeos/metabolismo , Proteínas Tirosina Quinases/metabolismo , Antígenos de Neoplasias/genética , Autoanticorpos/sangue , Criança , Mapeamento de Epitopos , Epitopos de Linfócito B/genética , Humanos , Peptídeos/genética , Proteínas Tirosina Quinases/genética , Recidiva , Risco
8.
Haematologica ; 103(3): 477-485, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29242300

RESUMO

Patients with anaplastic lymphoma kinase-positive anaplastic large cell lymphoma often present with B-symptoms or hemophagocytosis and generate an anti-tumor immune response. Specific serum cytokine levels or profiles may reflect the tumor burden, non-specific immune stimulation by the tumor or differences in the strength of the patients' anti-lymphoma immunity. We systematically correlated pretreatment concentrations of 25 cytokines with clinical and biological characteristics in a well-characterized cohort of 119 uniformly treated pediatric patients with anaplastic large cell lymphoma. Fifteen patients with anaplastic large cell lymphoma in remission and 11 patients with low-stage B-cell lymphoma served as controls. Concentrations of interleukin-9, interleukin-10, interleukin-17a, hepatocyte growth factor, soluble interleukin-2 receptor, and soluble CD30 were significantly higher in initial sera of patients than in the sera of subjects from both control groups, indicating an anaplastic large cell lymphoma-type cytokine signature. The levels of interleukin-6, interferon-γ, interferon γ-induced protein, and soluble interleukin-2 receptor correlated with the stage, initial general condition, minimal disseminated disease, anaplastic lymphoma kinase-antibody titers, and the risk of relapse among patients with anaplastic lymphoma kinase-positive anaplastic large cell lymphoma. Only interleukin-6 showed an independent prognostic value in multivariate analyses. Pretreatment cytokine profiles in patients with anaplastic large cell lymphoma reflect a tumor signature as well as tumor burden and also differences in the strength of the patients' immune response.


Assuntos
Citocinas/sangue , Linfoma Anaplásico de Células Grandes/sangue , Adolescente , Quinase do Linfoma Anaplásico/análise , Criança , Pré-Escolar , Feminino , Humanos , Imunidade , Lactente , Masculino , Prognóstico , Carga Tumoral
11.
Best Pract Res Clin Haematol ; 36(1): 101444, 2023 03.
Artigo em Inglês | MEDLINE | ID: mdl-36907641

RESUMO

Anaplastic lymphoma kinase (ALK)-positive anaplastic large cell lymphoma (ALCL) is a CD30-positive T cell lymphoma characterized by signalling from constitutively activated ALK fusion proteins. Most children and adolescents present in advanced stages, often with extranodal disease and B symptoms. The current front-line therapy standard of six cycles polychemotherapy reaches an event-free survival of 70%. The strongest independent prognostic factors are minimal disseminated disease and early minimal residual disease. At relapse, ALK-inhibitors, Brentuximab Vedotin, Vinblastine, or second line chemotherapy are effective re-inductions. Survival at relapse exceeds 60-70% with consolidation according to the time of relapse (Vinblastine monotherapy or allogeneic hematopoietic stem cell transplantation) so that the overall survival reaches 95%. It needs to be shown whether check-point inhibitors or long-term ALK-inhibition may substitute for transplantation. The future necessitates international cooperative trials testing whether a shift of paradigm to a chemotherapy-free regimen can cure ALK-positive ALCL.


Assuntos
Linfoma Anaplásico de Células Grandes , Criança , Humanos , Adolescente , Linfoma Anaplásico de Células Grandes/diagnóstico , Linfoma Anaplásico de Células Grandes/tratamento farmacológico , Linfoma Anaplásico de Células Grandes/patologia , Receptores Proteína Tirosina Quinases/metabolismo , Receptores Proteína Tirosina Quinases/uso terapêutico , Quinase do Linfoma Anaplásico/uso terapêutico , Vimblastina/uso terapêutico , Recidiva Local de Neoplasia
12.
Cancers (Basel) ; 14(7)2022 Mar 27.
Artigo em Inglês | MEDLINE | ID: mdl-35406475

RESUMO

Minimal disseminated and residual disease (MDD/MRD) analyzed by qualitative PCR for NPM-ALK fusion transcripts are validated prognostic factors in pediatric ALK-positive anaplastic large cell lymphoma (ALCL). Although potentially promising, MDD quantification by quantitative real-time PCR in international trials is technically challenging. Quantification of early MRD might further improve risk stratification. We aimed to assess droplet digital PCR for quantification of minimal disease in an inter-laboratory setting in a large cohort of 208 uniformly treated ALCL patients. Inter-laboratory quality control showed high concordance. Using a previously described cut-off of 30 copies NPM-ALK/104 copies ABL1 (NCN) in bone marrow and peripheral blood, MDD quantification allowed identification of very high-risk patients (5-year PFS% 34 ± 5 for patients with ≥30 NCN compared to 74 ± 6 and 76 ± 5 for patients with negative or <30 NCN, respectively, p < 0.0001). While MRD positivity was confirmed as a prognostic marker for the detection of very high-risk patients in this large study, quantification of MRD fusion transcripts did not improve stratification. PFS% was 80 ± 5 and 73 ± 6 for MDD- and MRD-negative patients, respectively, versus 35 ± 10 and 16 ± 8 for MRD-positive patients with <30 and ≥30 NCN, p < 0.0001. Our results suggest that MDD quantification by dPCR enables improved patient stratification in international clinical studies and patient selection for early clinical trials already at diagnosis.

13.
Nat Commun ; 12(1): 5577, 2021 09 22.
Artigo em Inglês | MEDLINE | ID: mdl-34552066

RESUMO

Anaplastic large cell lymphoma (ALCL), an aggressive CD30-positive T-cell lymphoma, comprises systemic anaplastic lymphoma kinase (ALK)-positive, and ALK-negative, primary cutaneous and breast implant-associated ALCL. Prognosis of some ALCL subgroups is still unsatisfactory, and already in second line effective treatment options are lacking. To identify genes defining ALCL cell state and dependencies, we here characterize super-enhancer regions by genome-wide H3K27ac ChIP-seq. In addition to known ALCL key regulators, the AP-1-member BATF3 and IL-2 receptor (IL2R)-components are among the top hits. Specific and high-level IL2R expression in ALCL correlates with BATF3 expression. Confirming a regulatory link, IL-2R-expression decreases following BATF3 knockout, and BATF3 is recruited to IL2R regulatory regions. Functionally, IL-2, IL-15 and Neo-2/15, a hyper-stable IL-2/IL-15 mimic, accelerate ALCL growth and activate STAT1, STAT5 and ERK1/2. In line, strong IL-2Rα-expression in ALCL patients is linked to more aggressive clinical presentation. Finally, an IL-2Rα-targeting antibody-drug conjugate efficiently kills ALCL cells in vitro and in vivo. Our results highlight the importance of the BATF3/IL-2R-module for ALCL biology and identify IL-2Rα-targeting as a promising treatment strategy for ALCL.


Assuntos
Fatores de Transcrição de Zíper de Leucina Básica/genética , Linfoma Anaplásico de Células Grandes/genética , Receptores de Interleucina-2/genética , Proteínas Repressoras/genética , Animais , Fatores de Transcrição de Zíper de Leucina Básica/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica , Humanos , Imunoconjugados/farmacologia , Interleucina-15/farmacologia , Interleucina-2/farmacologia , Subunidade alfa de Receptor de Interleucina-2/genética , Subunidade alfa de Receptor de Interleucina-2/imunologia , Subunidade alfa de Receptor de Interleucina-2/metabolismo , Antígeno Ki-1/genética , Antígeno Ki-1/metabolismo , Linfoma Anaplásico de Células Grandes/tratamento farmacológico , Linfoma Anaplásico de Células Grandes/metabolismo , Linfoma Anaplásico de Células Grandes/patologia , Camundongos , Receptores de Interleucina-2/imunologia , Receptores de Interleucina-2/metabolismo , Sequências Reguladoras de Ácido Nucleico , Proteínas Repressoras/metabolismo , Transdução de Sinais/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
14.
J Clin Oncol ; 38(34): 3999-4009, 2020 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-32730187

RESUMO

PURPOSE: To analyze the efficacy of a risk-stratified treatment of children with relapsed anaplastic large cell lymphoma (ALCL). The ALCL-Relapse trial (ClinicalTrials.gov identifier: NCT00317408) stratified patients according to the time of relapse and CD3 expression to prospectively test reinduction approaches combined with consolidation by allogeneic or autologous hematopoietic stem cell transplantation (SCT) and vinblastine monotherapy. PATIENTS AND METHODS: Patients with progression during frontline therapy (very high risk) or a CD3-positive relapse (high risk) were scheduled for allogeneic SCT after reinduction chemotherapy. Patients with a CD3-negative relapse within 1 year after initial diagnosis or prior exposure to vinblastine (intermediate risk) received autologous SCT after carmustine-etoposide-cytarabine-melphalan. This arm was terminated prematurely, and subsequent patients received vinblastine monotherapy instead. Patients with a CD3-negative relapse > 1 year after initial diagnosis (low risk) received vinblastine monotherapy. RESULTS: One hundred sixteen patients met the inclusion criteria; 105 evaluable patients with CNS-negative disease had a 5-year event-free survival (EFS) of 53% ± 5% and a 5-year overall survival (OS) of 78% ± 4%. Before termination of autologous SCT, EFS rates of patients in the very-high- (n = 17), high- (n = 26), intermediate- (n = 32), and low- (n = 21) risk groups were 41% ± 12%, 62% ± 10%, 44% ± 9%, and 81% ± 9%; the respective OS rates were 59% ± 12%, 73% ± 9%, 78% ± 7%, and 90% ± 6%. Analyzing only the patients in the intermediate-risk group consolidated per protocol by autologous SCT, EFS and OS of 23 patients were 30% ± 10% and 78% ± 9%, respectively. All 5 patients with intermediate risk receiving vinblastine monotherapy after the amendment experienced relapse again. CONCLUSION: Shorter time to relapse was the strongest predictor of subsequent relapse. Allogeneic SCT offers a chance for cure in patients with high-risk ALCL relapse. For early relapsed ALCL autologous SCT was not effective. Vinblastine monotherapy achieved cure in patients with late relapse; however, it was not effective for early relapses.


Assuntos
Transplante de Células-Tronco Hematopoéticas/métodos , Linfoma Anaplásico de Células Grandes/terapia , Vimblastina/uso terapêutico , Adolescente , Adulto , Criança , Pré-Escolar , Progressão da Doença , Feminino , Humanos , Lactente , Linfoma Anaplásico de Células Grandes/tratamento farmacológico , Masculino , Estudos Prospectivos , Fatores de Risco , Prevenção Secundária , Vimblastina/provisão & distribuição , Adulto Jovem
15.
Cancers (Basel) ; 10(4)2018 Apr 10.
Artigo em Inglês | MEDLINE | ID: mdl-29642597

RESUMO

Patients with anaplastic lymphoma kinase (ALK)-positive anaplastic large cell lymphoma (ALCL) mount a humoral and cellular immune response against ALK. More than 90% of children and adolescents with ALK-positive ALCL have detectable anti-ALK antibodies in serum or plasma, and the antibody titer inversely correlates with the risk of relapse. ALK-specific CD8 and CD4 T cell responses have been described in patients with ALK-positive ALCL. Vaccination with ALK DNA led to protection against lymphoma growth in a murine model. Collectively, these data suggest that the ALK-specific immune response is involved in the control of the disease. The characteristics of the humoral and cellular immune response against ALK as well as tumor immune escape mechanisms have been increasingly investigated. However, tumor and host factors contributing to the individual immune response against ALK are still largely unknown. Depending on the individual strength of the immune response and its determinants, individualized immunological approaches might be appropriate for the consolidation of ALCL patients. Strategies such as ALK vaccination could be effective for those with a pre-existing anti-tumor immunity, while an allogeneic blood stem cell transplantation or check-point inhibition could be effective for others.

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