INTRODUCCIÓN El 50% de los pacientes con neoplasias linfoides no se curan tras tratamiento estándar con quimioterapia y/o radioterapia, lo que hace imprescindible ensayar nuevos fármacos con diferentes mecanismos de acción. La interleukina 2 (IL2) es una citoquina fundamental en la repuesta inmune normal del individuo, que, in vitro, activa a las células NK (“natural killer” o asesinas naturales) produciendo un efecto antitumoral. En ensayos clínicos fase I-II con IL2 a dosis altas endovenosa se han observado respuestas en varios tipos de tumores, entre ellos las neoplasias linfoides. OBJETIVOS Valorar la tolerancia, los cambios inmunes in vivo y la eficacia de dosis bajas de IL2 subcutánea (sc) como tratamiento de mantenimiento en pacientes con neoplasias linfoides en remisión completa con alto riesgo de recaída PACIENTES Y METODOS El ensayo fue aprobado por el Comité Ético del Institut Catalá d’Oncologia. Se incluyeron pacientes diagnosticados de leucemia linfoblástica aguda (LLA), linfomas no-Hodgkin (LNH) y linfomas de Hodgkin (LH) en segunda remisión o posterior o en primera remisión con factores de mal pronóstico. El tratamiento consistió en IL2 4,5 x106 UI / día sc de lunes a viernes durante 12 semanas de forma ambulatoria. Se realizaron estudios de subpoblaciones linfocitarias en sangre periférica mediante inmunofenotipo, actividad citotóxica ex vivo mediante la técnica de liberación en 4 horas de cromo y niveles de diferentes citoquinas mediante enzimoinmunoensayo. Los resultados se compararon con los de 43 donantes sanos. Se realizó un estudio de casos y controles para evaluar diferencias en la supervivencia libre de enfermedad (SLE). RESULTADOS Se incluyeron 15 pacientes: 3 LLA, 7 LNH, 5 LH, con una mediana de edad de 39 años (límites 15-63). Un paciente no completo el tratamiento por progresión. La dosis se redujo en 4 pacientes por toxicidad, en 3 de ellos por astenia grado 3. El tratamiento indujo los siguientes cambios in vivo: eosinofilia (p=0,009), proliferación de células NK de 11% a 35% de los linfocitos (p=0,0006), y aumento de la actividad citotóxica tipo LAKe (células asesinas efectoras activadas por linfoquinas) de 6x10-3 UL/ml a 80x 10-3 UL/ml (p=0,02). Estos efectos alcanzaron el pico máximo a las 4 semanas de tratamiento y se mantuvieron estables durante el mismo. El aumento de células NK se correlacionó con el aumento de la actividad LAKe (r=0,96, p<0,0001). En un estudio de casos y controles compararon los 15 casos (mediana de SLE: 11,1 meses) con 22 controles históricos (mediana de SLE: 9,7 meses) y no se observaron diferencias significativas (p=0.9). CONCLUSIONES El tratamiento con IL2 sc a dosis bajas durante 12 semanas estimula la proliferación de células NK, lo que genera actividad citotóxica in vivo, en pacientes con neoplasias linfoides. En nuestro estudio, la demostración de diferencias significativas en la supervivencia es difícil dado el escaso número de pacientes tratados. Sin embargo, la intensa inmunomodulación que se alcanza, así como la poca toxicidad asociada, constituyen un primer paso para continuar explorando la inmunoterapia en pacientes con neoplasias linfoides

Los nódulos tiroideos son un problema clínico frecuente, correspondiendo a carcinomas sólo el 10%, por lo que es importante realizar un diagnóstico prequirúrgico correcto. Aunque la PAAF es en la actualidad la herramienta más útil para el diagnóstico preoperatorio, presenta limitaciones importantes, fundamentalmente en las lesiones foliculares. Por tanto, la existencia de marcadores que puedan mejorar la exactitud diagnóstica de las lesiones tiroideas es esencial. Varios estudios demostraron la sobreexpresión de galectina-3 en células tiroideas malignas, identificándolo como un posible marcador de malignidad tiroidea. Analizamos la expresión de galectina-3 de manera retrospectiva en 239 muestras de tejido tiroideo procedente de intervenciones quirúrgicas (95 benignas, 75 malignas y 69 casos de tejido tiroideo normal), y prospectivamente en 92 extensiones citológicas de material procedente de PAAF (10 normales, 50 benignas y 32 malignas).

Se realizó el estudio anátomo-histopatológico de muestras de vejiga urinaria, así como hígado, riñón y bazo, de 41 vacunos con cuadros lesionales de una enfermedad conocida en la provincia de Oxapampa (Pasco) como “Hematuria“ o “Intoxicación por Machicura“. Estos fueron obtenidos a partir de la inspección de 173 animales en el camal municipal de esta provincia, buscando correlacionar esta enfermedad local con la Hematuria Vesical Enzoótica Bovina (HVEB), enfermedad del ganado vacuno de distribución mundial. En el presente trabajo, se reporta que las lesiones halladas en la vejiga urinaria fueron multifocales en el 85.37% (35/41), siendo las más frecuentes las formaciones nódulo-vasculares ulceradas, en 82.93% (34/41). En el diagnóstico histopatológico se empleó las tinciones Hematoxilina - Eosina (H.E.), e histoquímicas de Hale para mucopolisacáridos ácidos y tricrómico de Masson para tejido conectivo fibroso y/o muscular, con presencia de colágeno. Las lesiones microscópicas reportadas, corresponden a diversos procesos, tales como: los proliferativos donde destacaron los polipoides con 58.54% (24/41); entre los procesos circulatorios, resaltaron los hemorrágicos con 68.29% (28/41) y las yemas de proliferación vascular o “nidos angioblásticos” en el 46.34% (19/41); en los procesos inflamatorios fue importante la cistitis no supurativa con 70.73% (29/41). Por otro lado, los procesos neoplásicos se presentaron en el 68.30% (28/41), siendo el 41.70% de tipo epitelial y 58.30% no epitelial. Los epiteliales fueron representados por carcinomas in situ con 26.83% (11/41) y papilomas mucosos 9.76% (4/41) al igual que los carcinomas transicionales de Grado I, mientras que los no epiteliales, el hemangiosarcoma fue la neoplasia más frecuente con 34.15% (14/41), hemangiomas con 24.39% (10/41) y mixosarcoma con 14.63% (6/41). Finalmente, en una sola oportunidad se registraron: papiloma racemoso, rabdomiosarcoma, leiomiosarcoma, hemangiopericitosarcoma, carcinoma tubular, carcinoma escamoso, linfoma y una metástasis linfoide. El presente trabajo concluye que el proceso conocido como “Hematuria“ en Oxapampa, es realmente la HVEB, haciéndose el reporte oficial de esta enfermedad en nuestro país, basados en el estudio anátomo-histopatológico, asimismo se amplían los procesos reportados hasta el momento en las investigaciones sobre esta enfermedad. Esta gran variedad de lesiones vesicales, vienen a ser indicadores de una marcada alteración de los procesos celulares fisiológicos, los cuales estarían siendo originados por una o varias sustancias carcinogénicas como el Ptaquilósido (Pq), que ha sido aislado en diversos estudios del Pteridium aquilinum (Pa), helecho presente en la región del problema, pero que necesita de investigación toxicológica futura. / Anatomo-histopathologic study of urinary bladder, liver, kidney and spleen samples from 41 zebu and crossbreeding cattle with different lesions of a disease commonly named as “hematuria“ or Machicura´s intoxication in the Oxapampa province (Pasco) were done. Samples from 173 necropsied animals of abbatoir from the Municipality of this province in order to correlate Machicura´s intoxication with Bovine Enzootic Vesical Haematuria ( BEVH ), a world wide disease were obtained. It was found that the urinary bladder lesions were multifocal in 85.37% (35/41). The histopathologic diagnosis with Hematoxiline – Eosine (HE) stain, Hale´s histochemical stain for acid mucopolysaccharide and Masson trichromic for fibrous connective tissue with collagen or muscular was done. The most important microscopic lesions were proliferative polips ( 58.54% ); the circulatory process were hemorragia ( 68.29% ) and vascular proliferation or “angioblastic nests” ( 46.34% ); in the inflammatory process, the non suppurative cystitis ( 70.73% ) was the most important finding. On the other side, 68.30% were of neoplastic process and 41.70% of epithelial origen compared to 58.30% of non epithelial type. The epithelial type were composed of in situ carcinoma (26.83% ) and mucous papilomas ( 9.76 % ) the same as transitional cell carcinoma of Grade I; the non epithelial neoplastic type were distributed as follow: 34.45% by hemangiosarcoma, the most frecuent neoplasia, 24.39% by hemangioma and 14.63% by mixosarcoma. Finally, a racemous papiloma, squamous cell carcinoma, tubular carcinoma, rhabdomyosarcoma, leiomyosarcoma, hemangiopericytosarcoma, lymphoma and a lymphoid metastasis were observed in one opportunity. The conclusion was that the well known process of hematuria that occured in Oxapampa was the same as BEVH and the official report of this disease in our country based on anatomo-histopathologic study was done. The great variety of vesical lesions were the indicators of the marked alterations of the normal biological cell process that could be originated by one or various carcinogenic sustances as the ptaquiloside ( Pq ) which was isolated from the Pteridium aquilinum ( Pa ) a bracken fern presented in the studied region, but a lot of toxicologic studies need to be done.

Prostate cancer is the second leading cause of cancer deaths among men. Targeted analyses of DNA from prostate cancers have identified recurrent somatic alterations that promote tumor growth and survival. Only recently, however, has the comprehensive analysis of cancer genomes become possible due to rapid advances in DNA sequencing technology.

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El linfoma difuso de células grandes (LDCGB) es la neoplasia linfoide agresiva más frecuente en el mundo occidental. Sin embargo, es una entidad nosológica heterogénea de difícil caracterización por técnicas convencionales. Por otro lado, desde los años ochenta sabemos que es una enfermedad con potencial curativo. La introducción de la inmunoquimioterapia con rituximab (IQTR) ha supuesto el mayor avance en el tratamiento de este tipo de linfoma, incrementando las tasas de remisión y de forma más importante la supervivencia de los pacientes. No obstante, un 25-30% de los pacientes serán refractarios al tratamiento o recaerán. En este grupo de pacientes es prioritaria la identificación de factores pronósticos clínicos y biológicos que permitan caracterizar grupos de riesgo y establecer posibles dianas terapéuticas. Esta tesis doctoral ha permitido profundizar un poco más en la caracterización biológica, clínica y pronostica del LDCGB. El primer trabajo ha contribuido a estudiar los LDCGB de origen primario extraganglionar como una variante particular con características diferentes de las formas ganglionares. Así estos pacientes presentan con mayor frecuencia características pronosticas favorables al diagnóstico (estadio temprano, niveles séricos bajos de LDH, e IPI de bajo riesgo), así como en la evolución (tasa de RC, SLP y SG superior). La segunda contribución del primer trabajo yace en cuestionar el papel de la inmunoquimioterapia en el tratamiento de los LDCGB extraganglionares. En esta entidad, quizás por las características iniciales de buen pronóstico, no observamos un incremento significativo de la supervivencia en aquellos pacientes tratados con IQTR. Ello podría suponer una ausencia de beneficio en estos pacientes, o simplemente que el número de pacientes para las diferentes localizaciones extraganglionares no es suficiente para detectar las diferencias que existen. En el segundo trabajo hemos estudiado la reproducibilidad de la caracterización molecular del LDCGB mediante técnicas de inmunohistoquímica. En la actualidad, los estudios de expresión genotípica (GEP) han permitido dividir al LDCGB en dos subgrupos centrogerminal (CGB) y activado (ABC) con impacto en el pronóstico, teniendo este último una menor supervivencia. Sin embargo, estas técnicas no son aplicables a la práctica clínica habitual dada su complejidad y elevado coste. Por ello, se han realizado intentos de remedar esta información utilizando diferentes algoritmos inmunohistoquímicos (Hans, Colomo, Muris, Choi y Tally) basados en la información extraída de los GEP. Estos algoritmos han establecido dos grupos inmunofenotípicos centrogerminal (CGB) y no-CGB. Sin embargo, nuestros resultados cuestionan el valor de los estudios de inmunohistoquímica como remedo de los perfiles de expresión genotípica. Aunque se encontró una correlación significativa entre los GEP y los diferentes algoritmos inmunohistoquímicos los valores predictivo negativo y positivo fueron relativamente bajos para los cinco algoritmos utilizados. De hecho, 30-50% de los LDCGB de origen CGB y 15-25% de los ABC fueron incorrectamente localizados por la inmunohistoquímica. Además, en términos de supervivencia global ninguno de los 5 algoritmos fue capaz de definir grupos con impacto en el pronóstico. / Diffuse large B-cell lymphoma (DLBCL), although considered a single category in the WHO classification, most likely includes different clinicopathologic entities difficult to separate with the standard techniques. From the clinical standpoint, the introduction of the immunochemoterapy in the treatment of DLBCL has dramatically improved the outcome of these patients with respect to chemotherapy alone. However, a significant proportion of these patients (20-30%) is refractory or eventually relapses. Nowadays, the identification of factors, either biological or clinical, that could recognize poor risk patients is a priority. Different prognostic factors for response and survival have been described in DLBCL, but in the rituximab era, the role of the biological prognostic factors is yet to be determined. In this sense, the first paper studies the main characteristics of the DLBCL extranodal primary origin. These patients more frequently show favorable prognostic features at diagnosis (early stage, low serum LDH and IPI low risk), as well as in evolution. Moreover, this paper questions the role of the immunochemotherapy in the extranodal DLBCL treatment. We observed lack of benefit in these patients, or simply the number of patients for different extranodal sites is not sufficient to detect differences. In the second paper we studied the reproducibility of the DLBCL molecular characterization by means of immunohistochemical studies. Currently, gene expression profiling studies (GEP) have allowed to separated the DLBCL in two subgroups, germinal centre (GCB) and activated (ABC) with the latter having a poorer outcome. However, molecular techniques are not applicable to the routine clinical practice because of its complexity and high cost. Therefore, attempts have been made to mimic this information using different algorithms immunohistochemical (Hans, Colomo, Muris, Choi and Tally) based on information extracted from the GEP. Nevertheless, in the present study none of the five immunohistochemical algorithms were able to accurately predict the GEP subtype or to separate molecular groups with prognostic value. In summary, this study allows to characterize the DLBCL-EN as a variant of good prognosis with a limited benefit of the immunochemotherapy. On the other hand, the DLBCL stratification based on immunohistochemical algorithms (GCB and non-GCB) should be viewed very cautiously.

The aim of this research was to assemble sufficient experimental evidence about candidate gene transcript expression changes between non-neoplastic and neo- plastic colorectal tissues to justify future assay development involving promis- ing leads. To achieve this aim, this thesis explores the hypothesis that gene expression-based biomarkers can be used to accurately discriminate colorectal neoplastic tissues from non-neoplastic controls. This hypothesis was tested by first analysing multiple, large, quality controlled data sets comprising gene expression measurements across colorectal phenotypes to discover potential biomarkers. Candidate biomarkers were then subjected to validation testing using a custom-design oligonucleotide microarray applied to independently derived clinical specimens. A number of novel conclusions are reached based on these data. The most important conclusion is that a defined subset of genes expressed in the colorectal mucosa are reliably differentially ex- pressed in neoplastic tissues. In particular, the apparently high prediction accu- racy achieved for single gene transcripts to discriminate hundreds of neoplastic and non-neoplastic tissues provides compelling evidence that the resulting can- didate genes are worthy of further biomarker research. In addition to addressing the central hypothesis, additional contributions are made to the field of colorectal neoplasia gene expression profiling. These contributions include: The first systematic analysis of gene expression in non-diseased tissues along the colorectum To better understand the range of gene expression in non-diseased tissues, RNA extracts taken from along the longitudinal axis of the large intestine were studied. The development of quality control methodologies for high dimen- sional gene expression data Complex data collection platforms such as oligonucleotide microarrays introduce the potential for unrecognized confound- ing variables. The exploration of quality control parameters across five hundred microarray experiments provided insights about quality control techniques. The design of a custom microrray comprised of oligonucleotide probe- sets hybridising to RNA transcripts differentially expressed in neo- plastic colorectal specimens A custom design oligonucleotide microarray was designed and tested combining the results of multiple biomarker discovery projects. Introduction of a method to filter differentially expressed genes dur- ing discovery that may improve validation efficiencies of biomarker discovery based on gene expression measurements Differential expression discovery research is typically focused only on quantitative changes in transcript concentration between phenotype contrasts. This work introduces a method for generating hypotheses related to transcripts which may be quali- tatively “switched-on” between phenotypes. Identification of mRNA transcripts which are differentially expressed between colorectal adenomas and colorectal cancer tissues Transcripts differentially expressed between adenomatous and cancerous RNA extracts were discovered and then tested in independent tissues. In conclusion, these results confirm the hypothesis that gene expression profiling can discriminate colorectal neoplasia (including adenomas) from non-neoplastic controls. These results also establish a foundation for an ongoing biomarker development program.

The pathology of a disfiguring and debilitating fatal disease affecting a high proportion of the wild population of Tasmanian Devils (Sarcophilus harrisii) that was discovered is described. The disease, named devil facial tumour disease (DFTD), has been identified in devils found across 60% of the Tasmanian landscape. The prevalence of this disease was extremely variable, possibly reflecting seasonal trapping success. Between 2001 and 2004, 91 DFTD cases were obtained for pathological description. Grossly, the tumours presented as large, solid, soft tissue masses usually with flattened, centrally ulcerated and exudative surfaces. They were typically multi-centric, appearing first in the oral, face or neck regions. Histologically, the tumours were composed of circumscribed to infiltrative nodular aggregates of round to spindle-shaped cells often within a pseudocapsule and divided into lobules by delicate fibrous septae. They were locally aggressive and metastasised in 65% of cases. There was minimal cytological differentiation amongst the tumour cell population under light and electron microscopy. The diagnostic values of a number of immunohistochemical stains were employed to further characterise up to 50 representative cases. They were negative for cytokeratin, epithelial membrane antigen, von Willebrand factor, desmin, glial fibrillary acid protein, CD16, CD57, CD3 and LSP1. DFTD cells were positive for vimentin, S-100, melan A, neuron specific enolase, chromogranin A and synaptophysin. In conclusion, the morphological and immunohistochemical characteristics together with the primary distribution of the neoplasms indicate that DFTD is an undifferentiated neoplasm of neuroendocrine histogenesis.

Orientador: Noeme Sousa Rocha / Banca: Julio Lopes Sequeira / Banca: Alaor Aparecido Almeida / Banca: Maria Aparecida Custódio Domingues / Banca: Vera Maria Villamil Martins / Resumo: Dos tumores diagnosticados nas cadelas as neoplasias mamárias apresentam a maior incidência. Essas neoplasias podem ser influenciadas por fatores internos e externos como os contaminantes ambientais. Apesar das evidências da toxicidade dos piretróides, seu potencial cancerígeno ainda não foi suficientemente esclarecido, havendo a necessidade de investigação de sua participação no câncer de mama. Este estudo teve por objetivo investigar possíveis relações entre resíduos de piretróides e carcinoma de mama espontâneo de cadelas correlacionando-os com o grau de agressividade da neoplasia. Foram selecionadas 50 cadelas divididas em cinco grupos com 10 animais cada. O Grupo Controle foi formado por cadelas que apresentavam diagnóstico negativo para neoplasia em mama; os grupos Luminal A, Luminal B, Superexpressão de HER-2 e Basal foram formados por cadelas que apresentaram carcinoma em mama classificado pela imunoistoquimica como Luminal A, Luminal B, Superexpressão de HER-2 e Basal, respectivamente. O grau de agressividade dos carcinomas foi avaliado por imunoistoquímica mediante a expressão de HER-2, p63 e receptor de Estrógeno. A determinação da concentração de resíduos piretróides aletrina, cipermetrina, deltametrina e tetrametrina da mama e do tecido adiposo adjacente à mama foi realizada por Cromatografia Líquida de Alta Eficiência. A intensidade de dano no DNA foi avaliada pelo Teste do Cometa. Das 50 cadelas, seis apresentaram resíduos de um ou mais piretróides nas amostras das mamas avaliadas e 10 apresentaram resíduos desse inseticida nas amostras de tecido adiposo. O piretróide mais frequente foi a deltametrina. A distribuição de cada resíduo investigado entre os grupos avaliados e entre as amostras de mama e de tecido adiposo em um mesmo animal foi heterogênea. Não há evidência estatística de que os piretróides estejam envolvidos na ... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: From all tumors that are diagnosed in female dog, the mammary neoplasia is the one that has the highest incidence. This sort of neoplasia may be influenced by both internal and external factors. Good examples of external factors are the environment contaminants. In spite of knowing the evidences of pyrethroid toxicity, it is not sufficiently clarified yet its cancer potential, thus leaving room for further investigation regarding its participation in the mammary tumor formation. This study aims at investigating not only the possible relationships between pyrethroid residue and spontaneous mammary carcinoma in female dog, but also correlating the degree of aggressiveness of such neoplasia. 50 female dog were selected and divided into five groups containing 10 animals each. Control group contained female dog that presented negative results for mammary neoplasia; female dog that presented mammary carcinoma and were immunohistochemically diagnosed as Luminal A, Luminal B, HER-2 Super-expression and Basal, were divided into groups bearing their respective tumor name. Carcinoma aggressiveness degree was immunohistochemically assessed concerning its expression of HER-2, p63 and Estrogen receptor. In order to define pyrethroid residue concentration for alethrin, cypermethrin, deltamethrin, and tetramethrin on mammary and mammary adjacent adipose tissue it was performed High-Performance Liquid Chromatography. The intensity of DNA damage was assessed via Comet Assay. From the 50 female dog, six have presented residue of one or more pyrethroids in mammary samples, and 10 presented residue of this insecticide in adipose tissue samples. The most frequently found pyrethroid residue was deltamethrin. Residue distribution among groups, and both mammary and adipose tissue of the same individual presented heterogeneous results. There is no statistical evidence showing that pyrethroids may be involved in ... (Complete abstract click electronic access below) / Doutor

BACKGROUND: Cervical cancer has historically been a major cause of mortality for women worldwide. Over the last 50 years, thanks to advances in screening technologies and the implementation of standardized management algorithms, the incidence of cervical cancer in the United States has been declining. LITERATURE REVIEW: In the most recent set of algorithms, the 2012 Updated Consensus Guidelines for the Management of Abnormal Cervical Cancer Screening Tests and Cancer Precursors, the authors conclude that there is high-level evidence to support extended screening intervals for women who are at average-risk for cervical cancer and who have a history of negative screening tests. However, there is large population of women with a history of abnormal screening tests, and their risk of recurrent disease is not well understood. Additionally, the predictive value of the available screening tests for this cohort of women is unknown. The authors of the 2012 Guidelines warn that there is insufficient evidence for optimal management of these women, the current guidelines are based on expert opinion only, and studies providing high-level evidence are lacking. PROPOSED PROJECT: This thesis proposes a systematic literature review of the existing evidence regarding to what extent women who are treated for cervical abnormalities at baseline are at an increased risk for persistent or recurrent disease in the future. Journal articles will be gathered from three different databases and abstracts will be screened for duplicity and relevancy. After article selection, the quality of evidence presented in each paper will be evaluated using the GRADE system to facilitate a methodical and accurate comparison of the existing evidence. Finally, a scheme for data abstraction from the articles will be outlined. CONCLUSIONS: The results of this systematic literature review will serve multiple purposes, including identifying what research has been done since the latest revision of management guidelines, and aiding in the revision of the algorithms for the population of women who have had abnormal screening test results. It will also identify persistent gaps in the body of knowledge regarding this cohort of patients, and guide the development of additional research studies to fill those gaps. SIGNIFICANCE: Determining the risk of recurrent disease in women with abnormal cervical cancer screening tests will serve to more optimally manage this cohort of women. This will allow providers to effectively monitor patients for the recurrence of cervical disease, while also minimizing the risks associated with overscreening.