Linfomas cutáneos con expresión de CD30. Clasificación, pronóstico y terapias dirigidas

La expresión de CD30 en linfocitos tumorales ha cobrado importancia desde la aparición de Brentuximab Vedotin (BV), un fármaco que utiliza este receptor como diana terapéutica y ha demostrado resultados prometedores en muchos pacientes. La expresión de este marcador no es infrecuente en los linfomas cutáneos tanto B como T, y no ha sido por el momento estudiada en profundidad en muchos de ellos. Esta tesis tiene como objetivo revisar aspectos de la clasificación de los linfomas cutáneos, tanto clínica como fenotípica y molecular, centrándonos en algunos cuya expresión de CD30 resulta significativa y poco estudiada hasta la fecha y en los que estas nuevas características fenotípicas y moleculares pueden ser relevantes para una mejor clasificación pronóstica y terapéutica de los pacientes. En el primer trabajo realizamos una revisión general de las alteraciones géneticas, epigenéticas y moleculares más relevantes descritas en procesos linfoproliferativos T CD30 positivos primarios cutáneos hasta la fecha y su posible potencial como dianas terapéuticas. El segundo trabajo identifica características morfológicas e inmunofenotípicas que ayudan a reconocer linfomas anaplásicos con reordenamientos de DUSP-22, identificando como características comunes en éstos la presencia de marcadores T y la ausencia de marcadores citotóxicos y de la vía de JAK/STAT. En el tercer trabajo describimos una serie de 9 pacientes con lesiones linfoproliferativas CD30+ y EBV+ que amplían el espectro clínico-patológico de la úlcera mucocutánea EBV+ (UMC-EBV+).Por último, en el cuarto artículo discutimos las principales características clínicas, histológicas y moleculares de una serie de 13 casos de linfoma B primario cutáneo de la zona marginal (PCMZL) con presencia de más de un 10% de células grandes CD30+ con morfología Hodgkin-like, y analizamos su relación con la progresión clínica e histológica de la enfermedad, así como con otras características inmunofenotípicas. 1. WillemzeR, Cerroni L, Kempf W, et al. The 2018 update of the WHO-EORTC classification for primary cutaneous lymphomas. Blood.2019;133(16):1703-17142. CerroniL. Sin lymphoma: the illustrated guide. In. Foruth ed. The Atrium, Southern Gate, Chchester, West Sussex, PO198SQ,UK: John Wiley & Sins;2014.3. Parrilla Castellar ER, Jaffe ES, Said JW, et al. ALK-negative anaplastic large cell lymphoma is a genetically heterogeneous diseaswith widely disparate clinical outcomes. Blood. 2014; 124(9):1473-1480. 4. Swerdlow SH CE, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J. WHO Classiffication of tumoours of haematopoietic and lymphoid tissues. Revised 4th edition ed. Lyon: IARC;2017.5. Mitteldorf C, Kempf W. Cutaneous pseudolymphoma-A review on the spectrum and a proposal for a new classidication. J Cutan Pathol. 20196. Onaindia A, Montes-Moreno S, Rodríguez-Pinilla SM, et al. Primary cutaneous anaplastic large cell lymphomas with 6p25.3 reaarangements exhibit particular histological features. Histopathology. 2015;66(6):846-855.7. Dojcinov SD, Venkataraman G, Raffeld M, Pittaluga S, Jaffe ES. EBV positive mucocutaneous ulcer- a study of 26 cases associated with various sources of immunosuppression. Am J Surg Pathol. 2010; 34(3):405-417.8. Servitje O, Gallardo F, Estrach , et al. Primary cutanoeus marginal zone B-cell lympho,a: a clinical, histopathological, immunophenotypic and molecular genetic study of 22 cases. Br J Dermatol. 2002; 147(6): 1147-1158.9. Servitje O, Muniesa C, Benavente Y, et al. Primary cutaneous marginal zone B-cell lymphoma: response to treatment and disease-free survival in a series of 137 patients.J Am Acad Dermatol. 2013; 69(3):357-365.<br /

Lymphotropic viruses EBV, KSHV and HTLV in Latin America: Epidemiology and associated malignancies. A literature-based study by the RIAL-CYTED

The Epstein-Barr virus (EBV), Kaposi sarcoma herpesvirus (KSHV) and human T-lymphotropic virus (HTLV-1) are lymphomagenic viruses with region-specific induced morbidity. The RIAL-CYTED aims to increase the knowledge of lymphoma in Latin America (LA), and, as such, we systematically analyzed the literature to better understand our risk for virus-induced lymphoma. We observed that high endemicity regions for certain lymphomas, e.g., Mexico and Peru, have a high incidence of EBV-positive lymphomas of T/NK cell origin. Peru also carries the highest frequency of EBV-positive classical Hodgkin lymphoma (HL) and EBV-positive diffuse large B cell lymphoma, not otherwise specified (NOS), than any other LA country. Adult T cell lymphoma is endemic to the North of Brazil and Chile. While only few cases of KSHV-positive lymphomas were found, in spite of the close correlation of Kaposi sarcoma and the prevalence of pathogenic types of KSHV. Both EBV-associated HL and Burkitt lymphoma mainly affect young children, unlike in developed countries, in which adolescents and young adults are the most affected, correlating with an early EBV seroconversion for LA population despite of lack of infectious mononucleosis symptoms. High endemicity of KSHV and HTLV infection was observed among Amerindian populations, with differences between Amazonian and Andean populations.Fil: Chabay, Paola Andrea. Gobierno de la Ciudad de Buenos Aires. Instituto Multidisciplinario de Investigaciones en Patologías Pediátricas. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto Multidisciplinario de Investigaciones en Patologías Pediátricas; Argentina. Gobierno de la Ciudad de Buenos Aires. Hospital General de Niños "Ricardo Gutiérrez"; ArgentinaFil: Lens, Daniela. Universidad de la Republica. Facultad de Medicina. Hospital de Clínicas "dr. Manuel Quintela".; UruguayFil: Hassan, Rocio. National Cancer Institute “José Alencar Gomes da Silva”; BrasilFil: Rodríguez Pinilla, Socorro María. University Hospital, Fundación Jiménez Díaz; EspañaFil: Valvert Gamboa, Fabiola. Cancer Institute and National League against Cancer; GuatemalaFil: Rivera, Iris. Salvadoran Institute of Social Security; El SalvadorFil: Huamán Garaicoa, Fuad. Santiago de Guayaquil Catholic University; EcuadorFil: Ranuncolo, Stella Maris. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Oncología "Ángel H. Roffo"; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Barrionuevo, Carlos. National University of San Marcos; PerúFil: Morales Sánchez, Abigail. Children’s Hospital of Mexico Federico Gómez; MéxicoFil: Scholl, Vanesa. No especifíca;Fil: de Matteo, Elena Noemí. Gobierno de la Ciudad de Buenos Aires. Instituto Multidisciplinario de Investigaciones en Patologías Pediátricas. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto Multidisciplinario de Investigaciones en Patologías Pediátricas; Argentina. Gobierno de la Ciudad de Buenos Aires. Hospital General de Niños "Ricardo Gutiérrez"; ArgentinaFil: Preciado, María Victoria. Gobierno de la Ciudad de Buenos Aires. Instituto Multidisciplinario de Investigaciones en Patologías Pediátricas. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto Multidisciplinario de Investigaciones en Patologías Pediátricas; Argentina. Gobierno de la Ciudad de Buenos Aires. Hospital General de Niños "Ricardo Gutiérrez"; ArgentinaFil: Fuentes Pananá, Ezequiel M.. Children’s Hospital of Mexico Federico Gómez; Méxic

Simultaneous inhibition of pan-phosphatidylinositol-3-kinases and MEK as a potential therapeutic strategy in peripheral T-cell lymphomas

Obtained from Haematologica/the Hematology Journal website http://www.haematologica.orgPeripheral T-cell lymphomas are very aggressive hematologic malignancies for which there is no targeted therapy. New, rational approaches are necessary to improve the very poor outcome in these patients. Phosphatidylinositol- 3-kinase is one of the most important pathways in cell survival and proliferation. We hypothesized that phosphatidylinositol- 3-kinase inhibitors could be rationally selected drugs for treating peripheral T-cell lymphomas. Several phosphatidylinositol-3-kinase isoforms were inhibited genetically (using small interfering RNA) and pharmacologically (with CAL-101 and GDC-0941 compounds) in a panel of six peripheral and cutaneous T-cell lymphoma cell lines. Cell viability was measured by intracellular ATP content; apoptosis and cell cycle changes were checked by flow cytometry. Pharmacodynamic biomarkers were assessed by western blot. The PIK3CD gene, which encodes the δ isoform of phosphatidylinositol-3-kinase, was overexpressed in cell lines and primary samples, and correlated with survival pathways. However, neither genetic nor specific pharmacological inhibition of phosphatidylinositol-3-kinase δ affected cell survival. In contrast, the pan-phosphatidylinositol-3-kinase inhibitor GDC-0941 arrested all T-cell lymphoma cell lines in the G1 phase and induced apoptosis in a subset of them. We identified phospho-GSK3b and phospho-p70S6K as potential biomarkers of phosphatidylinositol-3-kinase inhibitors. Interestingly, an increase in ERK phosphorylation was observed in some GDC-0941-treated T-cell lymphoma cell lines, suggesting the presence of a combination of phosphatidylinositol-3-kinase and MEK inhibitors. A highly synergistic effect was found between the two inhibitors, with the combination enhancing cell cycle arrest at G0/G1 in all T-cell lymphoma cell lines, and reducing cell viability in primary tumor T cells ex vivo. These results suggest that the combined treatment of pan-phosphatidylinositol-3-kinase + MEK inhibitors could be more effective than single phosphatidylinositol-3-kinase inhibitor treatment, and therefore, that this combination could be of therapeutic value for treating peripheral and cutaneous T-cell lymphomas.This work was supported by grants from the Asociación Española Contra el Cáncer, Fondo de Investigaciones Sanitarias (PI051623, PI052800 and PI080856), RTICC (RD06/0020/0107) and Ministerio de Ciencia e Innovación (SAF2008-0387-1). EMS is supported by a grant from the Department of Education, Universities and Research of the Basque Government (BFI08.207). MSB is supported by a Contract Miguel Servet from Fondo de Investigaciones Sanitarias (CP11/00018

Peripheral T-cell lymphoma: Molecular profiling recognizes subclasses and identifies prognostic markers

Peripheral T-cell lymphoma (PTCL) is a clinically aggressive disease, with a poor response to therapy and a low overall survival rate of approximately 30% after 5 years. We have analyzed a series of 105 cases with a diagnosis of PTCL using a customized NanoString platform (NanoString Technologies, Seattle, WA) that includes 208 genes associated with T-cell differentiation, oncogenes and tumor suppressor genes, deregulated pathways, and stromal cell subpopulations. A comparative analysis of the various histological types of PTCL (angioimmunoblastic T-cell lymphoma [AITL]; PTCL with T follicular helper [TFH] phenotype; PTCL not otherwise specified [NOS]) showed that specific sets of genes were associated with each of the diagnoses. These included TFH markers, cytotoxic markers, and genes whose expression was a surrogate for specific cellular subpopulations, including follicular dendritic cells, mast cells, and genes belonging to precise survival (NF-κB) and other pathways. Furthermore, the mutational profile was analyzed using a custom panel that targeted 62 genes in 76 cases distributed in AITL, PTCL-TFH, and PTCL-NOS. The main differences among the 3 nodal PTCL classes involved the RHOAG17V mutations (P < .0001), which were approximately twice as frequent in AITL (34.09%) as in PTCL-TFH (16.66%) cases but were not detected in PTCL-NOS. A multivariate analysis identified gene sets that allowed the series of cases to be stratified into different risk groups. This study supports and validates the current division of PTCL into these 3 categories, identifies sets of markers that can be used for a more precise diagnosis, and recognizes the expression of B-cell genes as an IPI-independent prognostic factor for AITL

Recurrent presence of the PLCG1 S345F mutation in nodal peripheral T-cell lymphomas

This work was supported by grants from Asociación Española contra el Cancer (AECC), Ministerio de Economía y Competitividad (MINECO) (SAF2013-47416-R), Instituto Salud Carlos III (ISCIII) – Fondos FEDER, MINECO-AES(RD012/0036/0060, PI10/00621, CP11/00018). RM is supported by the Fundación Conchita Rábago de la Fundación Jiménez Díaz, Madrid (Spain). JG-R is supported by a predoctoral grant from the Fundacion Investigacion Biomedica Puerta de Hierro. Salary support to SG is provided by ISCIII-FEDER (CP11/00018). MS-B is supported by a Miguel Servet contract from ISCIII-FEDER (CP11/00018). The Instituto de Investigación Marqués de Valdecilla (IDIVAL) is partly funded by the Sociedad para el Desarrollo Regional de Cantabria (SODERCAN)

Clinical and pathological characteristics of peripheral T-cell lymphomas in a Spanish population: a retrospective study

We investigated the clinicopathological features and prognostic factors of patients with peripheral T-cell lymphoma (PTCL) in 13 sites across Spain. Relevant clinical antecedents, CD30 expression and staining pattern, prognostic indices using the International Prognostic Index and the Intergruppo Italiano Linfomi system, treatments, and clinical outcomes were examined. A sizeable proportion of 175 patients had a history of immune-related disorders (autoimmune 16%, viral infections 17%, chemo/radiotherapy-treated carcinomas 19%). The median progression-free survival (PFS) and overall survival (OS) were 7·9 and 15·8 months, respectively. Prognostic indices influenced PFS and OS, with a higher number of adverse factors resulting in shorter survival (P 15% of cells were positive in anaplastic lymphoma kinase-positive and -negative anaplastic large-cell lymphoma and extranodal natural killer PTCL groups. We observed PTCL distribution across subtypes based on haematopathological re-evaluation. Poor prognosis, effect of specific prognostic indices, relevance of histopathological sub-classification, and response level to first-line treatment on outcomes were confirmed. Immune disorders amongst patients require further examination involving genetic studies and identification of associated immunosuppressive factors.This study was sponsored by Takeda

Peripheral T-cell lymphoma with a T follicular-helper phenotype: A different entity? Results of the Spanish Real-T study

Nodal peripheral T-cell lymphoma (PTCL) with a T follicular helper phenotype (PTCL-TFH) is a new type of PTCL. We aimed to define its clinical characteristics and prognosis compared to PTCL not otherwise specified (PTCL-NOS) and angioimmunoblastic T-cell lymphoma (AITL). This retrospective observational study included 175 patients diagnosed with PTCL between 2008 and 2013 in 13 Spanish sites. Patient diagnosis was centrally reviewed, and patients were reclassified according to the World Health Organization (WHO) 2016 criteria: 21 patients as PTCL-NOS, 55 as AITL and 23 as PTCL-TFH. Median follow-up was 56.07 months (95% CI 38.7–73.4). Progression-free survival (PFS) and overall survival (OS) were significantly higher in patients with PTCL-TFH than in those with PTCL-NOS and AITL (PFS, 24.6 months vs. 4.6 and 7.8 months, respectively, p = 0.002; OS, 52.6 months vs. 10.0 and 19.3 months, respectively, p < 0.001). Histological diagnosis maintained an independent influence on both PFS (hazard ratio [HR] 4.1 vs. PTCL-NOS, p = 0.008; HR 2.6 vs. AITL, p = 0.047) and OS (HR 5.7 vs. PTCL-NOS, p = 0.004; HR 2.6 vs. AITL, p = 0.096), regardless of the International Prognostic Index. These results suggest that PTCL-TFH could have more favourable features and prognosis than the other PTCL subtypes, although larger series are needed to corroborate these findings.This work was supported by Takeda Farmacéutica España, S.A.Peer reviewe

Herramientas tecnológicas para la transformación pedagógica

27 cm.El presente libro es el segundo tomo de la serie que desarrolla un planteamiento frente a la práctica pedagógica de la investigación educativa interdisciplinar desde la transformación y el uso de tecnologías (provisional)