Breast Carcinoma with Choriocarcinomatous Differentiation; a Rare Case

Objectives: Breast carcinoma with choriocarcinomatous differentiation is a rare entity, generally presenting with high-grade disease and an aggressive clinical course with overall survival of less than a year Case: A 69-year-old woman with a diagnosis of pT1N0M0 invasive ductal carcinoma with choriocarcinomatous differentiation received six cycles of adjuvant chemotherapy and is still disease free on the 23rd month after diagnosis, showing a better prognosis than most other cases reported in the literature. Conclusion: The reason for the poor prognosis for this type of breast carcinoma remains unclear. Standard chemotherapeutic agents administered for breast carcinoma may be used for choriocarcinomatous differentiation.

The regulation of cancer cell invasive behaviour by Chloride Interacellular Channel 3 (CLIC3) and Transglutaminasae 2

A study into the role of secreted CLIC3 in tumour cell invasion. The initiation and progression of cancers is thought to be linked to their relationship with a population of activated fibroblasts, which are associated with tumours. I have used an organotypic approach, in which plugs of collagen I are preconditioned with fibroblastic cells, to characterise the mechanisms through which carcinoma-associated fibroblasts (CAFs) influence the invasive behaviour of tumour cells. I have found that immortalised cancer-associated fibroblasts (iCAFs) support increased invasiveness of cancer cells, and that this is associated with the ability of CAFs to increase the fibrillar collagen content of the extracellular matrix (ECM). To gain mechanistic insight into this phenomenon, an in-depth SILAC-based mass proteomic analysis was conducted, which allowed quantitative comparison of the proteomes of iCAFs and immortalised normal fibroblast (iNFs) controls. Chloride Intracellular Channel Protein 3 (CLIC3) was one of the most significantly upregulated components of the iCAF proteome. Knockdown of CLIC3 in iCAFs reduced the ability of these cells to remodel the ECM and to support tumour cell invasion through organotypic plugs. A series of experiments, including proteomic analysis of cell culture medium that had been preconditioned by iCAFs, indicated that CLIC3 itself was a component of the iCAF secretome that was responsible for the ability of iCAFs to drive tumour cell invasiveness. Moreover, addition of soluble recombinant CLIC3 (rCLIC3) was sufficient to drive the extension of invasive pseudopods in cancer cell lines, and to promote disruption of the basement membrane in a 3D in vitro model of the ductal carcinoma in situ (DCIS) to invasive ductal carcinoma (IDC) transition. My investigation into the mechanism through which extracellular CLIC3 drives tumour cell invasiveness led me to focus on the relationship between CLIC3 and the ECM modifying enzyme, transglutaminase-2 (TG2). Through this, I have found that TG2 physically associates with CLIC3 and that TG2 is necessary for CLIC3 to drive tumour cell invasiveness. These data identifying CLIC3 as a key pro-invasive factor, which is secreted by CAFs, provides an unprecedented mechanism through which the stroma may drive cancer progression.

Sialadenoma Papilliferum with Inverted Pattern in a Young Patient: A Case Report

BACKGROUND: Sialadenoma papilliferum (SP) is a rare, benign neoplasm of salivary gland origin which manifests as an exophytic papillary excrescence of the mucosa. Indeed, SP is both an exophytic proliferation of papillary stratified squamous epithelium above the mucosal surface and an endophytic salivary ductal proliferation beneath the mucosa. It arises predominantly in minor salivary glands and usually affects patients in the age range of 32-87 years, with reports in young patients being exceedingly rare.

Caracterización clínico epidemiológica del cáncer de mama en el Hospital Nacional Rosales

El cáncer de mama es el más frecuente en mujeres con 1.38 millones de casos nuevos para el 2008 (23%) y el segundo más frecuente en general (10.9%). Es el más frecuente tanto en países desarrollados como en desarrollo (690 000 casos nuevos). En El Salvador es la segunda causa de cáncer y la tercera causa de muerte por cáncer. El riesgo de enfermar es superior en las mujeres de países con nivel socioeconómico alto, pero el riesgo de morir es mayor entre las mujeres que habitan países pobres. Se realiza este estudio para conocer el comportamiento de esta patología en nuestra población. Materiales y métodos: Se realizó un estudio descriptivo de seguimiento de una cohorte con cáncer de mama, tratados en el Hospital Nacional Rosales en un periodo de tiempo. Resultados: Se encontró una muestra de 132 pacientes. La edad media fue 54.61 años (DS +13.61). 55 pacientes (41.7%) provenían del departamento de San Salvador. De 119 pacientes en que se obtuvo datos de paridad se encontró una mediana de 3 hijos. 15.52% tenían antecedentes familiares. El 91.7% consultaron por presencia de tumor, con una mediana de consulta de 6 meses. Biopsia fue el método diagnostico en 84.41% de las pacientes. El tipo Ductal invasor fue el más frecuente (78.8%) y el estadio de presentación más frecuente fue IIb y IIIa correspondiendo al 50% de la población total. 5 pacientes no fueron sometidos a ninguna terapia quirúrgica, 20% recibido neoadyuvancia, 50% adyuvancia y 35.6% tamoxifeno. Hubo una pérdida de vista al año del 31% de pacientes, y en los restantes se obtuvo una sobrevida del 97.8%.

Carcinoma de mama en trabajadora expuesta a radiaciones ionizantes

Caso clínico. M.A., de 40 años de edad, es técnico especialista de radiodiagnóstico del hospital. Es una trabajadora profesionalmente expuesta a radiaciones ionizantes categoría A. Es diagnosticada de carcinoma ductal infiltrante de mama derecha. Tratamiento: tumorectomía, quimioterapia (Taxotere), Radioterapia con acelerador lineal (50 Grays) y braquiterapia con Iridio-192 (8 Grays). A los 18 meses es alta médica y acude a la consulta de Medicina del Trabajo para examen de salud tras ausencia por larga enfermedad. Consultado el Cuadro de Enfermedades Profesionales (Real Decreto 1299/2006) y el Protocolo de vigilancia sanitaria específica para radiaciones ionizantes del Ministerio de Sanidad, no aportan información útil para definir los criterios de aptitud. Se revisa historia clínica de la paciente y bibliografía y se concluye: la trabajadora es calificada APTA para el puesto de trabajo de técnico especialista de radiodiagnóstico.

Variaciones en el proceso de confirmación diagnóstica entre unidades de cribado poblacional de cáncer de mama

Objetivo: Analizar las variaciones en el proceso de confirmación diagnóstica entre unidades de cribado, las variaciones en los resultados de cada episodio y la relación entre las tasas de las diferentes pruebas de confirmación diagnóstica y las de detección de lesiones. Método: Estudio observacional de las variaciones de las tasas estandarizadas de pruebas diagnósticas y de detección de lesiones, en 34 unidades de cribado de los programas poblacionales de detección precoz de cáncer de mama, de tres comunidades autónomas, en el periodo de 2002 a 2011. Resultados: Las razones de variación entre los percentiles 25-75 en las tasas de realización de pruebas diagnósticas oscilaron entre 1,68 (recitaciones) y 3,39 (punción-aspiración con aguja fina). En las tasas de detección de lesiones benignas, carcinoma ductal in situ y cáncer invasivo fueron, respectivamente, 2,79, 1,99 y 1,36. Se encontró una relación positiva entre las tasas de realización de pruebas y las tasas de detección en punción-aspiración con aguja fina y lesiones benignas (R²: 0,53), punción-aspiración con aguja fina y carcinoma invasivo (R²: 0, 28), biopsias cerradas y lesiones benignas (R²: 0,64), biopsias cerradas y carcinoma ductal in situ (R²: 0,61), y biopsias cerradas y carcinoma invasivo (R²: 0,48). Conclusiones: Se observaron variaciones en la realización de pruebas invasivas entre las unidades de detección precoz de cáncer de mama de mayor magnitud que las de detección de lesiones. Las unidades con más pruebas de punción-aspiración con aguja fina tienen mayores tasas de detección de lesiones benignas, y las que realizan más biopsias cerradas detectan más lesiones benignas y cáncer.

Carcinoma colóide do pâncreas : a propósito de um caso não associado a neoplasia mucinosa papilar intraductal

Trabalho Final do Curso de Mestrado Integrado em Medicina, Faculdade de Medicina, Universidade de Lisboa, 2014

An investigation of the relationship between the components of tumour microenvironment, signal transduction pathways and outcome in breast cancer

Breast cancer, the most commonly diagnosed type of cancer in women, is a major cause of morbidity and mortality in the western world. Well-established risk factors of breast cancer are mostly related to women’s reproductive history, such as early menarche, late first pregnancy and late menopause. Survival rates have improved due to a combination of factors, including better health education, early detection with large-scale use of screening mammogram, improved surgical techniques, as well as widespread use of adjuvant therapy. At initial presentation, clinicopathological features of breast cancer such as age, nodal status, tumour size, tumour grade, and hormonal receptor status are considered to be the standard prognostic and predictive markers of patient survival, and are used to guide appropriate treatment strategies. Lymphovascular invasion (LBVI), including lymphatic (LVI) and blood (BVI) vessel invasion, has been reported to be prognostic and merit accurate evaluation, particularly in patients with node negative tumours who might benefit from adjuvant chemotherapy. There is a lack of standard assessment and agreement on distinguishing LVI from BVI despite the major challenges in the field. A systematic review of the literatures, examining methods of detection and the prognostic significance of LBVI, LVI and BVI, was carried out. The majority of studies used haematoxylin and eosin (H&E) and classical histochemistry to identify LVI and BVI. Only few recent studies used immunohistochemistry (IHC) staining of the endothelium lining lymphatic and blood vessels, and were able to show clear differences between LVI and BVI. The prognostic significance of LBVI and LVI was well-documented and strongly associated with aggressive features of breast tumours, while the prognostic value and the optimal detection method of BVI were unclear. Assessment and prognostic value of LBVI on H&E sections (LBVIH&E) was examined and compared to that of LVI and BVI detected using IHC with D2-40 for LVI (LVID2–40) and Factor VIII for BVI (BVIFVIII) in patients with breast cancer including node negative and triple negative patients (n=360). LBVIH&E, LVID2–40 and BVIFVIII were present in 102 (28%), 127 (35%) and 59 (16%) patients respectively. In node negative patients (206), LBVIH&E, LVID2–40 and BVIFVIII were present in 41 (20%), 53 (26%) and 21 (10%) respectively. In triple negative patients (102), LBVIH&E, LVID2–40 and BVIFVIII were present in 35 (29%), 36 (35%) and 14 (14%) respectively. LBVIH&E, LVID2–40 and BVIFVIII were all significantly associated with tumour recurrence in all cohorts. On multivariate survival analysis, only LVID2–40 and BVIFVIII were independent predictors of cancer specific survival (CSS) in the whole cohort (P=0.022 and P<0.001 respectively), node negative (P=0.008 and P=0.001 respectively) and triple negative patients (P=0.014 and P<0.001 respectively). Assessment of LVI and BVI by IHC, using D2-40 and Factor VIII, improves prediction of outcome in patients with node negative and triple negative breast cancer and was superior to the conventional detection method. Breast cancer is recognised as a complex molecular disease and histologically identical tumours may have highly variable outcomes, including different responses to therapy. Therefore, there is a compelling need for new prognostic and predictive markers helpful of selecting patients at risk and patients with aggressive diseases who might benefit from adjuvant and targeted therapy. It is increasingly recognised that the development and progression of human breast cancer is not only determined by genetically abnormal cells, but also dependent on complex interactions between malignant cells and the surrounding microenvironment. This has led to reconsider the features of tumour microenvironment as potential predictive and prognostic markers. Among these markers, tumour stroma percentage (TSP) and tumour budding, as well as local tumour inflammatory infiltrate have received recent attention. In particular, the local environment of cytokines, proteases, angiogenic and growth factors secreted by inflammatory cells and stromal fibroblasts has identified crucial roles in facilitating tumour growth, and metastasis of cancer cells through lymphatic and/or blood vessel invasion. This might help understand the underlying process promoting tumour invasion into these vessels. An increase in the proportion of tumour stroma and an increase in the dissociation of tumour cells have been associated with poorer survival in a number of solid tumours, including breast cancer. However, the interrelationship between these variables and other features of the tumour microenvironment in different subgroups of breast cancer are not clear. Also, whether their prognostic values are independent of other components of the tumour microenvironment have yet to be identified. Therefore, the relationship between TSP, clinicopathological characteristics and outcome in patients with invasive ductal breast cancer, in particular node negative and triple negative disease was examined in patients with invasive ductal breast cancer (n=361). The TSP was assessed on the haematoxylin and eosin-stained tissue sections. With a cut-off value of 50% TSP, patients with ≤50% stroma were classified as the low-TSP group and those with >50% stroma were classified as the high-TSP group. A total of 109 (30%) patients had high TSP. Patients with high TSP were old age (P=0.035), had involved lymph node (P=0.049), Her-2 positive tumours (P=0.029), low-grade peri-tumoural inflammatory infiltrate (P=0.034), low CD68+ macrophage infiltrate (P<0.001), low CD4+ (P=0.023) and low CD8+ T-lymphocytes infiltrate (P=0.017), tumour recurrence (P=0.015) and shorter CSS (P<0.001). In node negative patients (n=207), high TSP was associated with low CD68+ macrophage infiltrate (P=0.001), low CD4+ (P=0.040) and low CD8+ T-lymphocytes infiltrate (P=0.016) and shorter CSS (P=0.005). In triple negative patients (n=103), high TSP was associated with increased tumour size (P=0.017) high tumour grade (P=0.014), low CD8+ T-lymphocytes infiltrate (P=0.048) and shorter CSS (P=0.041). The 15-year cancer specific survival rate was 79% vs 21% in the low-TSP group vs high-TSP group. On multivariate survival analysis, a high TSP was associated with reduced CSS in the whole cohort (P=0.007), node negative patients (P=0.005) and those who received systemic adjuvant therapy (P=0.016), independent of other pathological characteristics including local host inflammatory responses. Therefore, a high TSP in invasive ductal breast cancer was associated with recurrence and poorer long-term survival. The inverse relation with the tumour inflammatory infiltrate highlights the importance of the amount of tumour stroma on immunological response in patients with invasive ductal breast cancer. Implementing this simple and reproducible parameter in routine pathological examination may help optimise risk stratification in patients with breast cancer. Similarly, the relationship between tumour budding, clinicopathological characteristics and outcome was examined in patients with invasive ductal breast cancer (n=474), using routine pathological sections. Tumour budding was associated with several adverse pathological characteristics, including positive lymph node (P=0.009), presence of LVI (P<0.001), and high TSP (P=0.001) and low-grade general peri-tumural inflammatory infiltrative (P=0.002). In node negative patients, a high tumour budding was associated with presence of LVI (P<0.001) and low-grade general peri-tumural inflammatory infiltrative (P=0.038). On multivariate survival analysis, tumour budding was associated with reduced CSS (P=0.001), independent of nodal status, tumour necrosis, CD8+ and CD138+ inflammatory cells infiltrate, LVI, BVI and TSP. Furthermore, tumour budding was independently associated with reduced CSS in node negative patients (P=0.004) and in those who have low TSP (P=0.003) and high-grade peri-tumoural inflammatory infiltrative (P=0.012). A high tumour budding was significantly associated with shorter CSS in luminal B and triple negative breast cancer subtypes (all P<0.001). Therefore, tumour budding was a significant predictor of poor survival in patients with invasive ductal breast cancer, independent of adverse pathological characteristics and components of tumour microenvironment. These results suggest that tumour budding may promote disease progression through a direct effect on local and distant invasion into lymph nodes and lymphatic vessels. Therefore, detection of tumour buds at the stroma invasive front might therefore represent a morphologic link between tumour progression, lymphatic invasion, spread of tumour cells to regional lymph nodes, and the establishment of metastatic dissemination. Given the potential importance of the tumour microenvironment, the characterisation of intracellular signalling pathways is important in the tumour microenvironment and is of considerable interest. One plausible signalling molecule that links tumour stroma, inflammatory cell infiltrate and tumour budding is the signal transducer and activator of transcription (STAT). The relationship between total and phosphorylated STAT1 (ph-STAT1), and total and ph-STAT3 tumour cell expression, components of tumour microenvironment and survival in patients with invasive ductal breast cancer was examined. IHC of total and ph-STAT1/STAT3 was performed on tissue microarray of 384 breast cancer specimens. Cellular STAT1 and cellular STAT3 expression at both cytoplasmic and nuclear locations were combined and identified as STAT1/STAT3 tumour cell expression. These results were then related to CSS and phenotypic features of the tumour and host. A high ph-STAT1 and a high ph-STAT3 tumour cell expression was associated with increased ER (P=0.001 and P<0.001 respectively) and PR (all P<0.05), reduced tumour grade (P=0.015 and P<0.001 respectively) and necrosis (all P=0.001). Ph-STAT1 was associated with increased general peri-tumoural inflammatory infiltrate (P=0.007) and ph-STAT3 was associated with lower CD4+ T-lymphocyte infiltrate (P=0.024). On multivariate survival analysis, including both ph-STAT1 and ph-STAT3 tumour cell expression, only high ph-STAT3 tumour cell expression was significantly associated with improved CSS (P=0.010) independent of other tumour and host-based factors. In patients with high necrosis grade, high ph-STAT3 tumour cell expression was independent predictor of improved CSS (P=0.021). Ph-STAT1 and ph-STAT3 were also significantly associated with improved cancer specific survival in luminal A and B subtypes. STAT1 and STAT3 tumour cell expression appeared to be an important determinant of favourable outcome in patients with invasive ductal breast cancer. The present results suggest that STATs may affect disease outcome through direct impact on tumour cells, and the surrounding microenvironment. The above observations of the present thesis point to the importance of the tumour microenvironment in promoting tumour budding, LVI and BVI. The observations from STATs work may suggest that an important driving mechanism for the above associations is the presence of tumour necrosis, probably secondary to hypoxia. Further work is needed to examine the interaction of other molecular pathways involved in the tumour microenvironment, such as HIF and NFkB in patients with invasive ductal breast cancer.

Diclofenaco comparado con ibuprofeno para el cierre de Ductus arterioso persistente, en recién nacidos prematuros

Introducción: El Ductus arterioso persistente (DAP), es uno de los defectos congénitos cardiacos más comunes, requiere manejo farmacológico y/o quirúrgico; presenta complicaciones hemodinámicas, respiratorias y muerte. Los medicamentos de elección para su manejo son indometacina e ibuprofeno, pero su costo y accesibilidad llevo al uso de diclofenaco como alternativa de manejo en algunos hospitales. Objetivo: Comparar respuesta al tratamiento con diclofenaco vs ibuprofeno en cierre de DAP. Materiales y Métodos: Estudio observacional analítico retrospectivo, que compara los resultados obtenidos al usar Diclofenaco e Ibuprofeno para el cierre del DAP en recién nacidos pretérmino. Se recolecto información de pacientes hospitalizados en la Unidad Neonatal de un Hospital II nivel de Bogotá. Se revisaron las historias clínicas de pacientes de edad gestacional entre 24 y 36 semanas por Ballard con los criterios para diagnóstico de DAP y recibieron tratamiento farmacológico con una de las siguientes opciones: Ibuprofeno 10 mg/Kg dosis inicial después 5mg/Kg a las 24 48 horas, o Diclofenaco 0.2 mg/Kg dosis cada 12 horas tres dosis. Se comparó el Diclofenaco y el Ibuprofeno para el tratamiento farmacológico de DAP en recién nacidos prematuros. Resultados: Fueron evaluados 103 pacientes, el diagnóstico de DAP se realizó con ecocardiograma transtorácico, el 66.6 % de los pacientes presentó cierre farmacológico con Diclofenaco y 69 % con Ibuprofeno, La mortalidad fue de 17.65 % con Diclofenaco y 11.54 % con ibuprofeno; en ambos casos asociadas a la prematurez. Conclusiones: El éxito farmacológico fue similar en ambos grupos, el diclofenaco es una alternativa interesante cuando la terapia convencional no esté disponible.

Development of machine learning methods for multi-modal biomarkers detection and integration

In medicine, innovation depends on a better knowledge of the human body mechanism, which represents a complex system of multi-scale constituents. Unraveling the complexity underneath diseases proves to be challenging. A deep understanding of the inner workings comes with dealing with many heterogeneous information. Exploring the molecular status and the organization of genes, proteins, metabolites provides insights on what is driving a disease, from aggressiveness to curability. Molecular constituents, however, are only the building blocks of the human body and cannot currently tell the whole story of diseases. This is why nowadays attention is growing towards the contemporary exploitation of multi-scale information. Holistic methods are then drawing interest to address the problem of integrating heterogeneous data. The heterogeneity may derive from the diversity across data types and from the diversity within diseases. Here, four studies conducted data integration using customly designed workflows that implement novel methods and views to tackle the heterogeneous characterization of diseases. The first study devoted to determine shared gene regulatory signatures for onco-hematology and it showed partial co-regulation across blood-related diseases. The second study focused on Acute Myeloid Leukemia and refined the unsupervised integration of genomic alterations, which turned out to better resemble clinical practice. In the third study, network integration for artherosclerosis demonstrated, as a proof of concept, the impact of network intelligibility when it comes to model heterogeneous data, which showed to accelerate the identification of new potential pharmaceutical targets. Lastly, the fourth study introduced a new method to integrate multiple data types in a unique latent heterogeneous-representation that facilitated the selection of important data types to predict the tumour stage of invasive ductal carcinoma. The results of these four studies laid the groundwork to ease the detection of new biomarkers ultimately beneficial to medical practice and to the ever-growing field of Personalized Medicine.