RESUMEN
Anaplastic large cell lymphoma (ALCL) and inflammatory myofibroblastic tumor (IMT) are rare cancers observed predominantly in children and young adults. ALCL accounts for 10-15% of all pediatric non-Hodgkin lymphomas and is commonly diagnosed at an advanced stage of disease. In children, 84-91% of cases of ALCL harbor an anaplastic lymphoma kinase (ALK) gene translocation. IMT is a rare mesenchymal neoplasm that also tends to occur in children and adolescents. Approximately 50-70% of IMT cases involve rearrangements in the ALK gene. A combination of chemotherapeutic drugs is typically used for children with ALK-positive ALCL, and the only known curative therapy for ALK-positive IMT is complete surgical resection. Crizotinib, a first-generation ALK inhibitor, was approved in the USA in 2021 for pediatric patients and young adults with relapsed or refractory ALK-positive ALCL; however, its safety and efficacy have not been established in older adults. In 2022, crizotinib was approved for adult and pediatric patients with unresectable, recurrent, or refractory ALK-positive IMT. This podcast provides an overview of ALK-positive ALCL and IMT. We discuss the current treatment landscape, the role of ALK tyrosine kinase inhibitors, and areas of future research.
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Pediatric non-Hodgkin lymphoma (NHL) includes over 30 histologies (many with subtypes), with approximately 800 cases per year in the United States. Improvements in survival in NHL over the past 5 decades align with the overall success of the cooperative trial model with dramatic improvements in outcomes. As an example, survival for advanced Burkitt lymphoma is now >95%. Major remaining challenges include survival for relapsed and refractory disease and long-term morbidity in NHL survivors. Langerhans cell histiocytosis (LCH) was added to the NHL Committee portfolio in recognition of LCH as a neoplastic disorder and the tremendous unmet need for improved outcomes. The goal of the Children' Oncology Group NHL Committee is to identify optimal cures for every child and young adult with NHL (and LCH). Further advances will require creative solutions, including engineering study groups to combine rare populations, biology-based eligibility, alternative endpoints, facilitating international collaborations, and coordinated correlative biology.
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Histiocitosis de Células de Langerhans , Linfoma no Hodgkin , Linfoma , Adulto Joven , Niño , Humanos , Linfoma no Hodgkin/terapia , Linfoma no Hodgkin/patología , Morbilidad , Oncología MédicaRESUMEN
Anaplastic large cell lymphoma (ALCL) is the most common type of mature T-cell non-Hodgkin lymphoma in children/adolescents. ALCL is characterized by expression of CD30 in the neoplastic lymphoid cells with frequent expression of anaplastic lymphoma kinase (ALK), especially within the pediatric population. Despite multiple efforts to optimize the use of conventional chemotherapy, outcomes in children, adolescents, and adults with ALCL remain suboptimal. Thus, there is a need to improve survival for those with high-risk disease and decrease therapy exposures and toxicities for those with low-risk disease. Targeted therapies, such as the anti-CD30 antibody-drug conjugate, brentuximab vedotin, are new important therapeutic options. Phase I and II studies in adults with relapsed/refractory CD30+ lymphomas, including ALCL, demonstrated the safety and efficacy of brentuximab vedotin, leading to FDA approval for relapsed/refractory ALCL in adults and successful incorporation into frontline therapies. Clinical trials in the pediatric population demonstrated similar results in those with relapsed/refractory ALCL. Incorporation of brentuximab vedotin into upfront therapy for children and adolescents with ALCL showed that this novel combination therapy has clinical advantages in comparison to conventional agents alone. Brentuximab vedotin is well-tolerated in both the pediatric and adult populations, even when used in combination with conventional agents. Brentuximab vedotin is an ideal agent to treat ALCL with excellent targeted activity and limited toxicity. Future studies are needed to identify how brentuximab vedotin should be utilized when combined with immunotherapy or other targeted agents (e.g., ALK inhibitors) in both the upfront and relapsed/refractory setting.
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Antineoplásicos , Inmunoconjugados , Linfoma Anaplásico de Células Grandes , Adulto , Adolescente , Humanos , Niño , Brentuximab Vedotina/uso terapéutico , Linfoma Anaplásico de Células Grandes/tratamiento farmacológico , Linfoma Anaplásico de Células Grandes/metabolismo , Linfoma Anaplásico de Células Grandes/patología , Recurrencia Local de Neoplasia/tratamiento farmacológico , Antineoplásicos/uso terapéutico , Inmunoconjugados/uso terapéutico , Inmunoconjugados/farmacologíaRESUMEN
Preventing the biogenesis of disease-relevant proteins is an attractive therapeutic strategy, but attempts to target essential protein biogenesis factors have been hampered by excessive toxicity. Here we describe KZR-8445, a cyclic depsipeptide that targets the Sec61 translocon and selectively disrupts secretory and membrane protein biogenesis in a signal peptide-dependent manner. KZR-8445 potently inhibits the secretion of pro-inflammatory cytokines in primary immune cells and is highly efficacious in a mouse model of rheumatoid arthritis. A cryogenic electron microscopy structure reveals that KZR-8445 occupies the fully opened Se61 lateral gate and blocks access to the lumenal plug domain. KZR-8445 binding stabilizes the lateral gate helices in a manner that traps select signal peptides in the Sec61 channel and prevents their movement into the lipid bilayer. Our results establish a framework for the structure-guided discovery of novel therapeutics that selectively modulate Sec61-mediated protein biogenesis.
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Proteínas de la Membrana , Señales de Clasificación de Proteína , Animales , Ratones , Transporte de Proteínas , Proteínas de la Membrana/metabolismo , Canales de Translocación SEC/química , Canales de Translocación SEC/genética , Canales de Translocación SEC/metabolismo , Biosíntesis de ProteínasRESUMEN
The prognosis is dismal (2-year overall survival less than 25%) for childhood, adolescent, and young adult (CAYA) with relapsed and/or refractory (R/R) non-Hodgkin lymphoma (NHL). Novel targeted therapies are desperately needed for this poor-risk population. CD19, CD20, CD22, CD79a, CD38, CD30, LMP1 and LMP2 are attractive targets for immunotherapy in CAYA patients with R/R NHL. Novel anti-CD20 monoclonal antibodies, anti-CD38 monoclonal antibody, antibody drug conjugates and T and natural killer (NK)-cell bispecific and trispecific engagers are being investigated in the R/R setting and are changing the landscape of NHL therapy. A variety of cellular immunotherapies such as viral activated cytotoxic T-lymphocyte, chimeric antigen receptor (CAR) T-cells, NK and CAR NK-cells have been investigated and provide alternative options for CAYA patients with R/R NHL. Here, we provide an update and clinical practice guidance of utilizing these cellular and humoral immunotherapies in CAYA patients with R/R NHL.
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Antineoplásicos , Inmunoconjugados , Linfoma no Hodgkin , Adulto Joven , Humanos , Niño , Adolescente , Linfoma no Hodgkin/tratamiento farmacológico , Inmunoterapia , Antineoplásicos/uso terapéutico , Inmunoconjugados/uso terapéutico , Células Asesinas Naturales/patología , Inmunoterapia Adoptiva , Antígenos CD19RESUMEN
Zetomipzomib (KZR-616) is a selective inhibitor of the immunoproteasome currently undergoing clinical investigation in autoimmune disorders. Here, we characterized KZR-616 in vitro and in vivo using multiplexed cytokine analysis, lymphocyte activation and differentiation, and differential gene expression analysis. KZR-616 blocked production of >30 pro-inflammatory cytokines in human peripheral blood mononuclear cells (PBMCs), polarization of T helper (Th) cells, and formation of plasmablasts. In the NZB/W F1 mouse model of lupus nephritis (LN), KZR-616 treatment resulted in complete resolution of proteinuria that was maintained at least 8 weeks after the cessation of dosing and was mediated in part by alterations in T and B cell activation, including reduced numbers of short and long-lived plasma cells. Gene expression analysis of human PBMCs and tissues from diseased mice revealed a consistent and broad response focused on inhibition of T, B, and plasma cell function and the Type I interferon pathway and promotion of hematopoietic cell lineages and tissue remodeling. In healthy volunteers, KZR-616 administration resulted in selective inhibition of the immunoproteasome and blockade of cytokine production following ex vivo stimulation. These data support the ongoing development of KZR-616 in autoimmune disorders such as systemic lupus erythematosus (SLE)/LN.
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Leucocitos Mononucleares , Nefritis Lúpica , Humanos , Animales , Ratones , Leucocitos Mononucleares/metabolismo , Citocinas/metabolismo , InmunidadRESUMEN
PURPOSE: Arm crizotinib (CZ) of the Children's Oncology Group trial ANHL12P1 (ClinicalTrials.gov identifier: NCT01979536) examined the efficacy and toxicity of adding CZ to standard chemotherapy for children with newly diagnosed, nonlocalized ALK+ CD30+ anaplastic large-cell lymphoma (ALCL). PATIENTS AND METHODS: Between 2013 and 2019, 66 enrolled children received CZ with chemotherapy. Patients received a 5-day prophase followed by six chemotherapy cycles at 21-day intervals with CZ administered twice daily during each 21-day cycle. The study was temporarily closed for two periods (total 12 months) to evaluate toxicity, during which CZ was discontinued. Measurements of NPM-ALK fusion transcripts in peripheral blood were performed at diagnosis for minimal disseminated disease (MDD). RESULTS: The 2-year event-free survival (EFS) is 76.8% (95% CI, 68.5 to 88.1) and the 2-year overall survival is 95.2% (95% CI, 85.7 to 98.4). Fifteen patients relapsed and one patient died; median time to relapse was 7.4 months from diagnosis, with relapses occurring after chemotherapy was complete. The 66 patients completed 384 cycles of chemotherapy. Thirteen of the 66 patients experienced a grade 2+ thromboembolic adverse event (19.7%; 95% CI, 11.1 to 31.3). In the 25 patients who received mandated prophylactic anticoagulation, there were two thromboembolic events (8.0%; 95% CI, 0.01 to 26). Patients with negative MDD had a superior outcome, with an EFS of 85.6% (95% CI, 68.6 to 93.8); positive MDD was associated with a lower EFS of 58.1% (95% CI, 33.4 to 76.4). CONCLUSION: Arm CZ of ANHL12P1 demonstrated that the addition of CZ to standard treatment prevented relapses during therapy for children with ALCL, MDD predicted EFS, and the addition of CZ resulted in unexpected thromboembolic events. Overall survival and EFS rates are consistent with the highest reported outcomes for children with ALCL.
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Linfoma Anaplásico de Células Grandes , Humanos , Niño , Crizotinib/uso terapéutico , Linfoma Anaplásico de Células Grandes/diagnóstico , Proteínas Tirosina Quinasas Receptoras/uso terapéutico , Recurrencia Local de Neoplasia/tratamiento farmacológico , Quinasa de Linfoma AnaplásicoRESUMEN
The first (2017) and sixth (2021) multistakeholder Paediatric Strategy Forums focused on anaplastic lymphoma kinase (ALK) inhibition in paediatric malignancies. ALK is an important oncogene and target in several paediatric tumours (anaplastic large cell lymphoma [ALCL], inflammatory myofibroblastic tumour [IMT], neuroblastoma and hemispheric gliomas in infants and young children) with unmet therapeutic needs. ALK tyrosine kinase inhibitors have been demonstrated to be active both in ALK fusion-kinase positive ALCL and IMT. ALK alterations differ, with fusions occurring in ALCL, IMT and gliomas, and activating mutations and amplification in neuroblastoma. While there are many ALK inhibitors in development, the number of children diagnosed with ALK driven malignancies is very small. The objectives of this ALK Forum were to (i) Describe current knowledge of ALK biology in childhood cancers; (ii) Provide an overview of the development of ALK inhibitors for children; (iii) Identify the unmet needs taking into account planned or current ongoing trials; (iv) Conclude how second/third-generation inhibitors could be evaluated and prioritised; (v) Identify lessons learnt from the experience with ALK inhibitors to accelerate the paediatric development of other anti-cancer targeted agents in the new regulatory environments. There has been progress over the last four years, with more trials of ALK inhibitors opened in paediatrics and more regulatory submissions. In January 2021, the US Food and Drug Administration approved crizotinib for the treatment of paediatric and young adult patients with relapsed or refractory ALCL and there are paediatric investigation plans (PIPs) for brigatinib and for crizotinib in ALCL and IMT. In ALCL, the current goal is to investigate the inclusion of ALK inhibitors in front-line therapy with the aim of decreasing toxicity with higher/similar efficacy compared to present first-line therapies. For IMT, the focus is to develop a joint prospective trial with one product in children, adolescents and adults, taking advantage of the common biology across the age spectrum. As approximately 50% of IMTs are ALK-positive, molecular analysis is required to identify patients to be treated with an ALK inhibitor. For neuroblastoma, crizotinib has not shown robust anti-tumour activity. A focused and sequential development of ALK inhibitors with very good central nervous system (CNS) penetration in CNS tumours with ALK fusions should be undertaken. The Forum reinforced the strong need for global academic collaboration, very early involvement of regulators with studies seeking possible registration and early academia-multicompany engagement. Innovations in study design and conduct and the use of 'real-world data' supporting development in these rare sub-groups of patients for whom randomised clinical trials are not feasible are important initiatives. A focused and sequenced development strategy, where one product is evaluated first with other products being assessed sequentially, is applicable for ALK inhibitors and other medicinal products in children.
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Quinasa de Linfoma Anaplásico/antagonistas & inhibidores , Desarrollo de Medicamentos/organización & administración , Colaboración Intersectorial , Neoplasias/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/uso terapéutico , Quinasa de Linfoma Anaplásico/genética , Niño , Ensayos Clínicos como Asunto , Industria Farmacéutica/organización & administración , Unión Europea/organización & administración , Humanos , Cooperación Internacional , Oncología Médica/organización & administración , Neoplasias/genética , Pediatría/organización & administración , Inhibidores de Proteínas Quinasas/farmacología , Estados Unidos , United States Food and Drug Administration/organización & administraciónRESUMEN
Approximately 30% of pediatric patients with anaplastic large cell lymphoma (ALCL) relapse. Although brentuximab vedotin has demonstrated excellent activity in ALCL, it has not been used for newly diagnosed patients. Children's Oncology Group (COG) trial ANHL12P1 determined the toxicity and efficacy of brentuximab vedotin with chemotherapy in children with newly diagnosed nonlocalized anaplastic large cell lymphoma kinase (ALK)+/CD30+ ALCL. From 2013 to 2017, 68 children with ALK+ ALCL were enrolled and received brentuximab vedotin. All patients received 5-day prophase, followed by 6 cycles of chemotherapy. Brentuximab vedotin was given on day 1 of each of the 6 cycles. Of the 67 patients eligible for toxicity evaluation, 66 completed all 6 cycles of chemotherapy, resulting in 399 evaluable cycles. There were no toxic deaths, no case of progressive multifocal leukoencephalopathy syndrome, and no case of grade 3 or 4 neuropathy. The 2-year event-free survival (EFS) was 79.1% (95% confidence interval [CI], 67.2-87.1). The 2-year overall survival (OS) was 97.0% (95% CI, 88.1-99.2). Fourteen patients relapsed. Eleven of 14 (79%) relapses occurred within 10 months of diagnosis; only 1 patient (1.5%) relapsed during therapy. Quantitative reverse transcription polymerase chain reaction for NPM-ALK at baseline (minimal disseminated disease) demonstrated prognostic value for EFS (P = .0004). Overall, the addition of brentuximab vedotin to standard chemotherapy does not add significant toxicity or alter the desired interval between cycles. The addition of brentuximab vedotin prevented relapses during therapy, and the OS and EFS estimates compare favorably with results obtained using conventional chemotherapy. This trial was registered at www.clinicaltrials.gov as #NCT01979536.
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Quinasa de Linfoma Anaplásico , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Brentuximab Vedotina/administración & dosificación , Linfoma Anaplásico de Células Grandes , Proteínas de Neoplasias , Adolescente , Adulto , Quinasa de Linfoma Anaplásico/genética , Quinasa de Linfoma Anaplásico/metabolismo , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Brentuximab Vedotina/efectos adversos , Niño , Preescolar , Supervivencia sin Enfermedad , Femenino , Humanos , Linfoma Anaplásico de Células Grandes/tratamiento farmacológico , Linfoma Anaplásico de Células Grandes/enzimología , Linfoma Anaplásico de Células Grandes/genética , Linfoma Anaplásico de Células Grandes/mortalidad , Masculino , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Tasa de SupervivenciaRESUMEN
Anaplastic large cell lymphoma (ALCL) is a T cell Non-Hodgkin Lymphoma that mainly presents in paediatric and young adult patients. The majority of cases express a chimeric fusion protein resulting in hyperactivation of anaplastic lymphoma kinase (ALK) as the consequence of a chromosomal translocation. Rarer cases lack expression of ALK fusion proteins and are categorised as ALCL, ALK-. An adapted regimen of an historic chemotherapy backbone is still used to this day, yielding overall survival (OS) of over 90% but with event-free survival (EFS) at an unacceptable 70%, improving little over the past 30 years. It is clear that continued adaption of current therapies will probably not improve these statistics and, for progress to be made, integration of biology with the design and implementation of future clinical trials is required. Indeed, advances in our understanding of the biology of ALCL are outstripping our ability to clinically translate them; laboratory-based research has highlighted a plethora of potential therapeutic targets but, with high survival rates combined with a scarcity of funding and patients to implement paediatric trials of novel agents, progress is slow. However, advances must be made to reduce the side-effects of intensive chemotherapy regimens whilst maintaining, if not improving, OS and EFS.
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Quinasa de Linfoma Anaplásico/genética , Quinasa de Linfoma Anaplásico/metabolismo , Linfoma Anaplásico de Células Grandes/etiología , Linfoma Anaplásico de Células Grandes/metabolismo , Investigación Biomédica Traslacional , Quinasa de Linfoma Anaplásico/antagonistas & inhibidores , Biomarcadores de Tumor , Niño , Terapia Combinada , Manejo de la Enfermedad , Humanos , Linfoma Anaplásico de Células Grandes/diagnóstico , Linfoma Anaplásico de Células Grandes/terapia , Terapia Molecular Dirigida , Pronóstico , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéutico , Resultado del TratamientoRESUMEN
Monosomy 7 may be a poor prognostic indicator in pediatric myelodysplastic syndrome. There are case reports of children with monosomy 7 who undergo spontaneous remission 2 to 24 months after diagnosis. We report a case of a child with bone marrow failure and monosomy 7 who underwent spontaneous remission 75 months after diagnosis. The patient had no exposure to chemotherapeutic or immunosuppressive agents. The patient did not receive chemotherapy or other treatment during the 75 months. Despite remaining positive for monosomy 7, he never developed myelodysplasia or acute myeloid leukemia. Spontaneous remission of monosomy 7 may occur years after diagnosis in some patients.
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Trastornos de Fallo de la Médula Ósea/genética , Deleción Cromosómica , Remisión Espontánea , Niño , Cromosomas Humanos Par 7 , Humanos , Síndromes Mielodisplásicos , PronósticoRESUMEN
Selective immunoproteasome inhibition is a promising approach for treating autoimmune disorders, but optimal proteolytic active site subunit inhibition profiles remain unknown. We reveal here our design of peptide epoxyketone-based selective low molecular mass polypeptide-7 (LMP7) and multicatalytic endopeptidase complex subunit-1 (MECL-1) subunit inhibitors. Utilizing these and our previously disclosed low molecular mass polypeptide-2 (LMP2) inhibitor, we demonstrate a requirement of dual LMP7/LMP2 or LMP7/MECL-1 subunit inhibition profiles for potent cytokine expression inhibition and in vivo efficacy in an inflammatory disease model. These and additional findings toward optimized solubility led the design and selection of KZR-616 disclosed here and presently in clinical trials for treatment of rheumatic disease.
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Antiinflamatorios no Esteroideos/farmacología , Artritis Reumatoide/tratamiento farmacológico , Morfolinas/farmacología , Inhibidores de Proteasoma/farmacología , Administración Intravenosa , Animales , Antiinflamatorios no Esteroideos/química , Antiinflamatorios no Esteroideos/farmacocinética , Artritis Experimental/tratamiento farmacológico , Línea Celular Tumoral , Cisteína Endopeptidasas/metabolismo , Citocinas/metabolismo , Diseño de Fármacos , Femenino , Humanos , Ratones Endogámicos BALB C , Morfolinas/química , Morfolinas/farmacocinética , Oligopéptidos/farmacología , Complejo de la Endopetidasa Proteasomal/inmunología , Complejo de la Endopetidasa Proteasomal/metabolismo , Inhibidores de Proteasoma/química , Inhibidores de Proteasoma/farmacocinética , Relación Estructura-ActividadRESUMEN
Building upon the success of bortezomib (VELCADE) and carfilzomib (KYPROLIS), the design of a next generation of inhibitors targeting specific subunits within the immunoproteasome is of interest for the treatment of autoimmune disease. There are three catalytic subunits within the immunoproteasome (low molecular mass polypeptide-7, -2, and multicatalytic endopeptidase complex subunit-1; LMP7, LMP2, and MECL-1), and a campaign was undertaken to design a potent and selective LMP2 inhibitor with sufficient properties to allow for sustained inhibition in vivo. Screening a focused library of epoxyketones revealed a series of potent dipeptides that were optimized to provide the highly selective inhibitor KZR-504 (12).
RESUMEN
Carfilzomib (CFZ) is a second-generation proteasome inhibitor that is Food and Drug Administration and European Commission approved for the treatment of relapsed or refractory multiple myeloma. CFZ is an epoxomicin derivative with an epoxyketone electrophilic warhead that irreversibly adducts the catalytic threonine residue of the ß5 subunit of the proteasome. Although CFZ produces a highly potent, sustained inactivation of the proteasome, the electrophilic nature of the drug could potentially produce off-target protein adduction. To address this possibility, we synthesized an alkynyl analog of CFZ and investigated protein adduction by this analog in HepG2 cells. Using click chemistry coupled with streptavidin based IP and shotgun tandem mass spectrometry (MS/MS), we identified two off-target proteins, cytochrome P450 27A1 (CYP27A1) and glutathione S-transferase omega 1 (GSTO1), as targets of the alkynyl CFZ probe. We confirmed the adduction of CYP27A1 and GSTO1 by streptavidin capture and immunoblotting methodology and then site-specifically mapped the adducts with targeted MS/MS methods. Although CFZ adduction of CYP27A1 and GSTO1 in vitro decreased the activities of these enzymes, the small fraction of these proteins modified by CFZ in intact cells should limit the impact of these off-target modifications. The data support the high selectivity of CFZ for covalent modification of its therapeutic targets, despite the presence of a reactive electrophile. The approach we describe offers a generalizable method to evaluate the safety profile of covalent protein-modifying therapeutics.
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Colestanotriol 26-Monooxigenasa/metabolismo , Glutatión Transferasa/metabolismo , Oligopéptidos/química , Inhibidores de Proteasoma/síntesis química , Línea Celular Tumoral , Química Clic , Células Hep G2 , Humanos , Estructura Molecular , Inhibidores de Proteasoma/química , Inhibidores de Proteasoma/farmacología , Espectrometría de Masas en TándemRESUMEN
Posttransplant lymphoproliferative disorder (PTLD) is a diversely manifesting group of lymphoid or plasmacytic proliferations found in solid organ and bone marrow transplant recipients. PTLD occurs as a result of immunosuppression and is often driven by the Epstein Barr virus. Although most commonly of B-cell origin, similar to B-cell lymphomas, PTLD can rarely present as a plasmacytic process, resembling multiple myeloma. Although more common in adults, 8 cases of plasmacytoma-like PTLD have been reported in pediatric renal and combined small bowel-liver transplant recipients. Here, we present a rare report of a plasmacytoma-like PTLD case in a pediatric heart transplant recipient.
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Trasplante de Corazón/efectos adversos , Huésped Inmunocomprometido , Trastornos Linfoproliferativos/inmunología , Plasmacitoma/inmunología , Válvula Aórtica/anomalías , Enfermedad de la Válvula Aórtica Bicúspide , Cardiomiopatía Dilatada/etiología , Cardiomiopatía Dilatada/cirugía , Preescolar , Femenino , Rechazo de Injerto/prevención & control , Cardiopatías Congénitas/complicaciones , Enfermedades de las Válvulas Cardíacas/complicaciones , Enfermedades de las Válvulas Cardíacas/congénito , Humanos , Inmunosupresores/uso terapéuticoRESUMEN
BACKGROUND: Optimal therapy for children and adolescents with advanced stage anaplastic large cell lymphoma (ALCL) is unknown. ANHL0131 examined whether a maintenance regimen including vinblastine compared to the standard APO (doxorubicin, prednisone, vincristine, methotrexate, 6-mercaptopurine) regimen would result in superior event-free survival. PROCEDURE: One hundred and twenty five eligible patients were enrolled. Induction was identical for both arms. Post induction patients were randomized to receive APO with vincristine every 3 weeks or a regimen that substituted vincristine with weekly vinblastine (APV). RESULTS: There was no difference between the patients randomized to the APO versus APV arms in either event free survival (EFS) or overall survival (OS) (three year EFS 74% vs. 79%, P = 0.68 and three years OS of 84% vs. 86%, P = 0.87, respectively). Patients in the APV arm required dose reduction secondary to myelosuppression and had a higher incidence of neutropenia as well as infection with neutropenia compared to those in the APO arm (P < 0.001, P = 0.019, respectively). CONCLUSIONS: Treatment with weekly vinblastine instead of every three week vincristine as part of multi-agent maintenance therapy did not result in improvement in EFS or OS. Weekly vinblastine was associated with increased toxicity. (ClinicalTrials.gov Identifier NCT00059839).
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Linfoma Anaplásico de Células Grandes/tratamiento farmacológico , Adolescente , Adulto , Niño , Preescolar , Doxorrubicina/administración & dosificación , Femenino , Estudios de Seguimiento , Humanos , Lactante , Linfoma Anaplásico de Células Grandes/mortalidad , Linfoma Anaplásico de Células Grandes/patología , Masculino , Mercaptopurina/administración & dosificación , Metotrexato/administración & dosificación , Estadificación de Neoplasias , Prednisona/administración & dosificación , Pronóstico , Tasa de Supervivencia , Vinblastina/administración & dosificación , Vincristina/administración & dosificación , Adulto JovenRESUMEN
Like all organisms on the planet, environmental microbes are subject to the forces of molecular evolution. Metagenomic sequencing provides a means to access the DNA sequence of uncultured microbes. By combining DNA sequencing of microbial communities with evolutionary modeling and phylogenetic analysis we might obtain new insights into microbiology and also provide a basis for practical tools such as forensic pathogen detection. In this work we present an approach to leverage phylogenetic analysis of metagenomic sequence data to conduct several types of analysis. First, we present a method to conduct phylogeny-driven Bayesian hypothesis tests for the presence of an organism in a sample. Second, we present a means to compare community structure across a collection of many samples and develop direct associations between the abundance of certain organisms and sample metadata. Third, we apply new tools to analyze the phylogenetic diversity of microbial communities and again demonstrate how this can be associated to sample metadata. These analyses are implemented in an open source software pipeline called PhyloSift. As a pipeline, PhyloSift incorporates several other programs including LAST, HMMER, and pplacer to automate phylogenetic analysis of protein coding and RNA sequences in metagenomic datasets generated by modern sequencing platforms (e.g., Illumina, 454).
RESUMEN
Anaplastic Large Cell Lymphoma (ALCL) is the most common mature T-cell neoplasm in children and adolescents. ALCLs comprise approximately 15% of all non-Hodgkin lymphomas (NHL) in children and adolescents and commonly present with advanced systemic disease. Dissimilar from ALCL in adults, ALCL in children is nearly universally anaplastic large cell lymphoma kinase (ALK) positive. Despite the relative rarity of the disease, a great deal of insight into the pathogenesis of ALCL has been learned by researching the essential oncogenic role of ALK. Many different treatment strategies have been utilized with similar event free survival (EFS) rates of 65-75%. This review will provide an overview of the pathology, clinical features, prognostics factors, and treatment for children and adolescents with ALK positive ALCL.
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Linfoma Anaplásico de Células Grandes/mortalidad , Linfoma Anaplásico de Células Grandes/patología , Linfoma Anaplásico de Células Grandes/terapia , Adolescente , Adulto , Quinasa de Linfoma Anaplásico , Niño , Preescolar , Supervivencia sin Enfermedad , Femenino , Humanos , Lactante , Linfoma Anaplásico de Células Grandes/metabolismo , Masculino , Proteínas de Neoplasias/metabolismo , Proteínas Tirosina Quinasas Receptoras/metabolismo , Tasa de SupervivenciaRESUMEN
Anaplastic lymphoma kinase (ALK) is an oncogenic tyrosine kinase that is deregulated due to a variety of molecular mechanisms in pediatric cancer. They include chromosomal translocations, activation mutations, and gene amplifications. Since the initial discovery of ALK as an oncogenic tyrosine kinase involved in the chromosomal translocation t(2, 5)(p23;q35) in 1994, more than 20 translocation partners of ALK have been identified in various cancers. Furthermore, deregulation of ALK tyrosine kinase activity is critical for the pathogenesis of several other pediatric tumors, including neuroblastomas and inflammatory myofibroblastic tumors. The recent discovery of ALK translocations in adult lung cancer patients (non-small cell lung cancer) has accelerated the development of inhibitors of ALK tyrosine kinase as therapeutic agents. While excellent clinical response has been observed in many patients, the acquisition of clinical resistance to ALK inhibition highlights the need for development of second-generation ALK kinase inhibitors and/or combination therapies that target downstream signaling mediators or antibody drug conjugates. This article provides an update on the spectrum of ALK-driven tumors in the pediatric population and the potential therapies which target these tumors.