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We studied the expression of nuclear factor-κ B inducing kinase in human samples from patients with graft-versus-host disease. We also explored the effect of nuclear factor-κ B inducing kinase in a murine model of graft-versus-host disease using donor cells from aly/aly mice (deficient in nuclear factor-κ B inducing kinase) and C57BL/6 mice (control). ResultsWe detected expression of nuclear factor-κ B inducing kinase in T-lymphocytes in the pathological lesions of patients with acute graft-versus-host disease. Mice transplanted with aly/aly T lymphocytes did not develop graft-versus-host disease at all, while mice receiving C57BL/6 cells died of a lethal form of the disease. Deficiency of nuclear factor-κ B inducing kinase did not affect the engrafting ability of donor T cells, but severely impaired their expansion capacity early after transplantation, and aly/aly T cells showed a higher proportion of apoptosis than did C57BL/6 T cells. Effector T lymphocytes were the T-cell subset most affected by nuclear factor-κ B inducing kinase deficiency. We also detected lower amounts of inflammatory cytokines in the serum of mice receiving aly/aly T cells than in the serum of mice receiving C57BL/6 T cells. ConclusionsOur results show that nuclear factor-κ B inducing kinase has a role in graft-versus-host disease by maintaining the viability of activated alloreactive T lymphocytes.Key words: NF-κB, NF-κB inducing kinase, NIK, graft-versus-host disease.Citation: Sánchez-Valdepeñas C, Casanova L, Colmenero I, Arriero M, González A, Lozano N, González-Vicent M, Díaz MA, Madero L, Fresno M and Ramírez M. Nuclear factor-κ B inducing kinase is required for graft-versus-host disease. Haematologica 2010;95(12):2111-2118. doi:10.3324/haematol.2010 This is an open-access paper. © F e r r a t a S t o r t i F o u n d a t i o n Nuclear factor-κ B inducing kinase is required for graft-versus-host disease

IntroductionAcute myeloblastic leukaemia (AML) constitutes the second most common haematological malignancy in the paediatric population. Current treatment regimens are based on the administration of polychemotherapy, combining high doses of cytarabine with anthracyclines and topoisomerase inhibitors. Allogeneic haematopoietic stem cell transplantation (HSCT) is an option for high-risk patients with AML (and for intermediate-risk patients if a sibling donor is available). With this strategy, AML survival has increased substantially; however, it has remained stagnant at approximately 60%, with relapse being the principal culprit. The predominant role of the immune system and natural killer (NK) cells in controlling paediatric AML has gained importance within the context of HSCT. In this protocol, we propose incorporating this cell therapy as an adjuvant treatment through the infusion of activated and expanded haploidentical NK (NKAE) cells in paediatric patients with AML who are in cytological remission after completing consolidation therapy, and with no indication for HSCT.Methods and analysisPatients up to 30 years of age, diagnosed with AML, in their first cytological remission, who have completed both the induction and the consolidation phases of chemotherapy and do not meet the criteria for allogeneic HSCT are eligible. The patients will receive two doses of NKAE cells once a week, using a GMP K562-mbIL15-41BBL stimulus from a haploidentical donor and interleukin 2 subcutaneously. The patients will then be followed up for 36 months to assess the primary endpoint, which is the probability of relapse after NK cell infusion.Ethics and disseminationThis clinical trial was approved by the Clinical Research Ethics Committee of La Paz University Hospital and The Spanish Agency of Medicines and Medical Devices. Findings will be disseminated through peer-reviewed publications, conference presentations and community reporting.Trial registration numberEudraCT code: 2015-001901-15, ClinicalTrials.gov Identifier:NCT02763475.

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RESUMEN Introducción:En el momento actual, los tumores sólidos refractarios al tratamiento convencional constituyen la principal causa de muerte en la edad pediátrica. Por tanto, es necesario desarrollar y consolidar nuevos tratamientos. Las células Natural Killer (NK) constituyen la primera línea de defensa del sistema inmune frente al desarrollo de células tumorales. Planteamos una nueva estrategia de terapia celular antitumoral en niños con cánceres refractarios, inmunoterapia con células NK estimuladas con interleucina 15 (IL-15). Pacientes y Métodos: En 22 pacientes pediátricos con tumores sólidos refractarios y en controles sanos determinamos mediante citometría de flujo multiparamétrica y fluorescencia resuelta en el tiempo, el fenotipo y la actividad citotóxica de las células NK, respectivamente. En ratones inmunodeficientes desarrollamos un modelo de neuroblastoma metastático muy agresivo y terapia de rescate con células Natural Killer estimuladas con IL-15. Resultados: Los pacientes pediátricos con cáncer refractario tienen un mayor porcentaje de células NK bright y una menor actividad citotóxica. La estimulación con IL-15 mejora la citotoxicidad in vitro y disminuye la carga tumoral in vivo. Conclusiones: Las células NK estimuladas con IL-15 constituyen una prometedora estrategia antitumoral. INTRODUCCIÓNLos tumores sólidos en su totalidad constituyen el cáncer infantil más frecuente en la edad pediátrica 1 . Aproximadamente más de la mitad de los pacientes pediátricos con tumores sólidos tienen enfermedad avanzada a su diagnóstico 2 . Siendo el pronóstico muy desfavorable en los pacientes con enfermedad metastásica 3 . El pronóstico es particularmente pobre en los pacientes con enfermedad metastá-sica en hueso, médula ósea, y en las recaídas, donde prácticamente todos los pacientes fallecen por progresión de la enfermedad. Por ejemplo, para pacientes con Sarcoma de Ewing refractario la tasa de supervivencia a largo plazo es actualmente menor del 20% y menor del 10% si la recaída sucede dentro de los 2 primeros años 4,5 . Las estrategias de quimioterapia de segunda línea en este tipo de pacientes son realmente poco exitosas, habiéndose alcanzado el techo terapéutico. Es por esto que son necesarias nuevas aproximaciones terapéuticas que supongan una alternativa a la quimioresistencia de estos tumores.El papel del sistema inmune en el reconocimiento tumoral y en su eliminación es conocido desde hace décadas. Su potencial es tal, que la mayoría de las personas sanas eliminan células tumorales a diario gracias a un eficaz sistema inmune 6 . Se han descrito en pacientes con cáncer, alteraciones del sistema inmune adaptativo como aumento de células T reguladoras, disminución de células T CD8 efectoras, aumento de citocinas reguladoras como IL-10 7 . Sin embargo el papel del sistema inmune innato no ha sido estudiado sistemáticamente. En los últimos años el conocimiento en la inmunobiología del cáncer ha identificado a las células Natural

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Introduction Phyllodes tumors (PTs) are uncommon fibroepithelial breast tumors that occur in middle-aged women, and they tend to vary in biologic behavior. Surgical management is the standard therapy for the condition, but factors associated with recurrence remain unclear. The aim of this study was to evaluate clinical and surgical characteristics related to PT recurrences. Methods This retrospective cohort study included patients in southern Colombia who were diagnosed with PT and managed at a level I teaching and referral hospital over a nine-year period. Factors associated with recurrence were determined by Cox regression analysis. Results This study included 61 patients; their median age was 46 years [interquartile range (IQR): 39-55 years]. Pathologically, 37 tumors (60.7%) were classified as low-grade. The median tumor size was 7 cm (IQR: 4-11.5 cm). Thirty-nine (63.9%) patients underwent quadrantectomy. Nine patients (14.8%) experienced tumor recurrence, with the median time to recurrence being one year (IQR: 0.5-2 years). Distant metastasis was observed in four patients (6.6%) at a median of nine months (IQR: 0.4-2.5 years). Univariate analyses showed that patients with high-grade tumors [hazard ratio (HR): 2.90, p = 0.148] and those who underwent mastectomy (HR: 2.90, p = 0.460) were at higher risk of recurrence. Conclusion PT recurrence may be associated with biological features, the extent of local excision, tumor size, and negative margins. However, multicenter data are needed to confirm these findings.