Paniculitis pancreática como primer signo de adenocarcinoma de páncreas con metástasis hepáticas

Pancreatic panniculitis is a rare septal-lobular entity. It is characterized by the appearance of erythematous-violaceous lesions or ulcerated subcutaneous nodules, sometimes painful, more frequently located in the lower extremities. Pancreatic panniculitis is associated with pancreatic disorders and sometimes manifests as the first sign of concomitant pancreatic pathology: acute or chronic pancreatitis, pancreatic carcinoma, pancreatic pseudocysts, traumatic pancreatitis… The diagnosis is confirmed by pathological analysis. We present the case of a 78-year-old man with subcutaneous nodules on the legs without other accompanying symptoms with a diagnosis of pancreatic panniculitis and findings of pancreatic adenocarcinoma with liver metastases in complementary tests.La paniculitis pancreática es una entidad septal-lobulillar poco común. Se caracteriza por la aparición de lesiones eritemato-violáceas o nódulos subcutáneos ulcerados a veces dolorosos localizados más frecuentemente en extremidades inferiores. Está asociada a trastornos pancreáticos y en ocasiones se manifiesta como primer signo de patología pancreática concomitante: pancreatitis aguda o crónica, carcinoma pancreático, pseudoquistes pancreáticos, pancreatitis traumática… El diagnóstico se confirma mediante análisis anatomopatológico. Se presenta el caso de un varón de 78 años con nódulos subcutáneos en extremidades inferiores sin otros síntomas, con diagnóstico de paniculitis pancreática y hallazgos de adenocarcinoma de páncreas con metástasis hepáticas en pruebas complementarias

High p27 protein levels in chronic lymphocytic leukemia are associated to low Myc and Skp2 expression, confer resistance to apoptosis and antagonize Myc effects on cell cycle

Myc (c-Myc) counteracts p27 effects, and low p27 usually correlates with high Myc expression in human cancer. However there is no information on the co-expression of both genes in chronic lymphocytic leukemia (CLL). We found a lack of correlation between RNA and protein levels of p27 and Myc in CLL cells, so we determined the protein levels by immunoblot in 107 cases of CLL. We observed a high p27 protein expression in CLL compared to normal B cells. Ectopic p27 expression in a CLL-derived cell line resulted in cell death resistance. Surprisingly, Myc expression was very low or undetectable in most CLL cases analyzed, with a clear correlation between high p27 and low Myc protein levels. This was associated with low Skp2 expression, which is consistent with the Skp2 role in p27 degradation and with SKP2 being a Myc target gene. High Myc expression did not correlate with leukemia progression, despite that cell cycle-related Myc target genes were upregulated. However, biochemical analysis showed that the high p27 levels inhibited cyclin-Cdk complexes even in Myc expressing CLL cells. Our data suggest that the combination of high p27 and low Myc is a marker of CLL cells which is mediated by Skp2

Cancer genomics paves the way to targeted therapy.

RESUMEN: La lucha contra el cáncer es aún un desafío mayor, con cerca de 14 millones de nuevos casos de cáncer al año y más de 8 millones de muertes anuales atribuidas al cáncer. Con la ayuda de múltiples servicios clínicos del HUMV y otras Instituciones, trabajamos para demostrar la hipótesis de que análisis integrados de genómica y secuenciación dirigida de alta profundidad en especímenes quirúrgicos de rutina puede generar datos firmes y relevantes sobre la complejidad molecular, composición subclonal, índice mutacional, firmas mutacionales y mutaciones precisas en genes con implicaciones terapéuticas; así generando una herramienta diagnóstica robusta que permita predecir sensibilidad a terapias específicas. In este proyecto, hemos podido demostrar que los estudios genómicos del cáncer demuestran dianas útiles para la intervención terapéutica y que la combinación de múltiples terapias inactivando rutas oncogénicas convergentes representa una opción plausible para pacientes con cáncer avanzado.ABSTRACT: Cancer is still a mayor challenge with something more than 14M new cases per year in the world and more of 8M patients dying yearly because of cancer. With the collaboration of multiple clinical services at the HUMV and other clinical institutions, we are working to demonstrate the hypothesis that genomics integrative analysis and high-depth targeted mutational analysis in routine cancer specimens may generate consistent, relevant data informing about molecular complexity, subclonal composition, mutational rate, mutational signatures and precise mutations in genes with therapeutic implications; thus generating a robust, solid, diagnostic tool that may allow to predict the sensitivity to specific therapies. In this project we have been able to demonstrate that cancer genome studies do demonstrate actionable targets, and that the combination of multiple therapies targeting convergent pathways represent a plausible option for advanced cancer patients

Chronic lymphocytic leukemia cells in lymph nodes show frequent NOTCH1 activation

Chronic lymphocytic leukemia (CLL) is the most common adult leukemia in the Western world. Pathogenic mechanisms involve multiple external events (such as microenvironmental and antigenic stimuli) and internal events (genetic and epigenetic alterations) that are associated with the transformation, progression and evolution of CLL. CLL is characterized by an accumulation of mature B cells in peripheral blood, bone marrow and lymphoid tissues. Extracellular stimuli play an important role in the development and maintenance of neoplastic cells. B-CLL cells proliferate and activate pathogenic signaling pathways in anatomical structures known as proliferation centers, which are usually more conspicuous in involved lymph nodes.1 Its clinical course is quite heterogeneous, whereby some patients progress rapidly and have short survival, whereas others have a more stable clinical course that may not need treatment for years.This work was supported by grants from the Ministerio de Economía y Competitividad (MINECO) (SAF2013-47416-R) Instituto de Salud Carlos III (ISCIII)- FEDER – MINECO- AES (CP11/00018, PI10/00621, RD012/0036/0060), and Asociación Española contra el Cancer (AECC). MS-B is supported by a Miguel Servet contract from ISCIII-FEDER (CP11/00018). Salary support to SG is provided by CP11/00018, from ISCIII-FEDER. JG-R is supported by a predoctoral grant from the Fundación Investigación Puerta de Hierro.S

Molecular basis of targeted therapy in T/NKcell lymphoma/leukemia: A comprehensive genomic and immunohistochemical analysis of a panel of 33 cell lines

T and NK-cell lymphoma is a collection of aggressive disorders with unfavorable outcome, in which targeted treatments are still at a preliminary phase. To gain deeper insights into the deregulated mechanisms promoting this disease, we searched a panel of 31 representative T-cell and 2 NK-cell lymphoma/leukemia cell lines for predictive markers of response to targeted therapy. To this end, targeted sequencing was performed alongside the expression of specific biomarkers corresponding to potentially activated survival pathways. The study identified TP53, NOTCH1 and DNMT3A as the most frequently mutated genes. We also found common alterations in JAK/STAT and epigenetic pathways. Immunohistochemical analysis showed nuclear accumulation of MYC (in 85% of the cases), NFKB (62%), p-STAT (44%) and p-MAPK (30%). This panel of cell lines captures the complexity of T/NK-cell lymphoproliferative processes samples, with the partial exception of AITL cases. Integrated mutational and immunohistochemical analysis shows that mutational changes cannot fully explain the activation of key survival pathways and the resulting phenotypes. The combined integration of mutational/expression changes forms a useful tool with which new compounds may be assayed

Targeted therapies in peripheral T-cell lymphoma : study of histological features, immunophenotypic and molecular

RESUMEN: Los linfomas T periféricos (PTCLs) constituyen un grupo heterogéneo de entidades caracterizadas por un pronóstico muy pobre y escasa respuesta a la terapia. Sus bases moleculares se desconocen aún, y urge la necesidad de identificar nuevos marcadores que permitan la aplicación de terapias dirigidas que lleven a una mejora en el pronóstico de estos pacientes, objetivo de la presente tesis, que se centra en tres patologías y dianas terapéuticas, llegando a las siguientes conclusiones: (1) El Linfoma Anaplásico de Células grandes cutáneo primario con translocación del locus IRF4-DUSP22 presenta rasgos histológicos específicos que traducen la presencia del reordenamiento y permiten realizar la selección de pacientes y la aplicación de terapias dirigidas. (2) La mayoría de los PTCLs expresan CD30 de forma variable, con una buena correlación con los niveles de mRNA, y son potenciales candidatos para el tratamiento con Brentuximab Vedotin. (3) Las mutaciones de JAK son frecuentes en los Linfomas T cutáneos (CTCLs), y potencialmente susceptibles de inhibición con ruxolitinib.ABSTRACT: T-cell Lymphomas (PTCLs) are a very heterogeneous group of non-Hodgkin Lymphomas (NHLs), with a dismal prognosis and whose molecular basis are still poorly understood. The aim of this thesis is the identification of morphologic and immunophenotypic markers contributing to PTCLs diagnosis and targeted treatment. This study includes three points with the conclusions below: (1) Primary cutaneous anaplastic large cell lymphoma with IRF4-DUSP22 translocation exhibit peculiar histological features allowing the recognition of this molecular alteration and patient’s selection for targeted therapy. (2) Most PTCLs express CD30 in a heterogeneous way, with a good correlation with mRNA levels, and these patients are potential candidates for directed therapy with Brentuximab Vedotin. (3) JAK mutations are frequent in Cutaneous T-cell lymphomas (CTCLs), and can be inhibited with ruxolitinib. Specific therapies, either with monoclonal antibodies or targeted therapy, will lead to an improvement of this patients poor outcome.A las agencias que han financiado los proyectos de investigación en los que se enmarcan los originales de esta tesis: Asociación Española Contra el Cáncer (AECC) y Instituto de Salud Carlos III del Ministerio Español de Economía y Competencias (MINECO and RTIC) MINECO, (SAF2013-­‐47416-­‐R and RD06/0020/0107-­‐RD012/0036/0060)) to MAP (SAF2013-­‐47416-­‐R) ISCIII-­‐ MINECO-­‐AES-­‐FEDER así como al Plan Nacional I+D+I: 2012-­‐2015-­‐PI12/00357, 2011-­‐2014-­‐ CP11/00018), and 2014-­‐2017-­‐FIS PI14/01784

Unsupervised hierarchical clustering analysis with 26 immunomarkers.

<p>Each row represents a single cell line; each column represents a single immunomarker. Blue (score 0); white, weak immunostaining (score 1); light red (score 2); red, strong immunoreactivity (score 3); grey, missing data.</p

Mutational landscape of TCL cell lines.

<p>The results of targeted deep sequencing of 16 genes in 20 T-ALL (black), 5 ALCL (dark grey), 3 CTCL (medium grey), 2 NK (light grey), 2 ATLL (diagonal lines) and one T-LGL (dots) cell lines. Mutated genes (rows) are arranged in decreasing order of mutation frequency. Cell lines (columns) are arranged from left to right on the basis of their mutational frequency following gene ranking. HTLV-1-positive cell lines (green) and translocation t(2;5)(p23;q35) (ALK +, dark blue) are showed.</p

Mapping of variants in a TCL gene panel.

<p>Schematic of the alterations encoded by SNVs in <i>TP53</i>, <i>NOTCH1</i>, <i>DNMT3A</i>, <i>JAK1</i>, <i>JAK3</i>, <i>STAT3</i> and <i>STAT5B</i>. Type of variation and disease are represented by color and shape, respectively. TAD: transactivation domain; PRD: proline-rich domain; TD: tetramerization domain; C-term: C-terminal domain; HD: heterodimerization domain; TM: transmembrane domain; RAM: Rbp-associated molecule domain; ANK: ankyrin domain; PEST: proline (P), glutamic acid (E), serine (S), threonine (T) degradation domain; ZNF: zinc-finger domain; Mtase: methyltransferase domain.</p