Revisión sistemática y metaanálisis sobre CK20, CD44, Ki67 y p53 como marcadores inmunohistoquímicos en el carcinoma in situ vesical / A systematic review and meta-analysis of CK20, CD44, Ki67 and p53 as immunohistochemical markers in bladder carcinoma in situ

Introducción: La displasia urotelial y el carcinoma in situ (CIS) están relacionados con la recurrencia y la progresión del carcinoma urotelial. Diferenciar el CIS y la displasia de la atipia reactiva suele ser difícil sobre la base de las características histológicas. La integración de los hallazgos histológicos con la inmunohistoquímica se utiliza en la práctica habitual para realizar el diagnóstico del CIS y, para ello, se utilizan los marcadores inmunohistoquímicos CK20, CD44, Ki67 y p53 como complemento al estudio histológico.En este trabajo, nos propusimos evaluar CK20, CD44, Ki67 y p53 como marcadores inmunohistoquímicos en pacientes con CIS, mediante una revisión sistemática y un metaanálisis.Materiales y métodosSe realizó una revisión sistemática con búsqueda en bases de datos electrónicas de estudios en inglés publicados desde enero de 2010 hasta abril de 2021. Se consideraron elegibles los estudios que evaluaban la expresión de CK20, CD44, Ki67 y p53 en el CIS.ResultadosEn total, 15 referencias fueron aptas para la revisión cuantitativa. La tasa global de expresión de CK20, CD44, Ki67 y p53 en el CIS fue del 43%, 31%, 44% y 38%, respectivamente.ConclusionesNuestro estudio apoya el consenso de la Sociedad Internacional de Patología Urológica de 2014 sobre la evaluación histológica como método de referencia para diagnosticar el CIS urotelial, y sugiere que una correlación muy estrecha entre los datos morfológicos, inmunohistoquímicos y clínicos es esencial para proporcionar el mejor manejo de los pacientes con carcinoma vesical. (AU)

Introduction: Urothelial dysplasia and carcinoma in situ (CIS) are related to recurrence and progression of urothelial carcinoma. Differentiating CIS and dysplasia from reactive atypia is often difficult based only on histological features. The integration of histological findings with immunohistochemistry is used in routine practice to make a diagnosis of CIS and, for this purpose, the immunohistochemical markers CK20, CD44, Ki67 and p53 are used to supplement histology.In this work, we aimed to assess CK20, CD44, Ki67 and p53 as immunohistochemical markers in patients with CIS through a systematic review and meta-analysis.Materials and methodsA systematic review was performed by searching electronic databases for English-language studies published from January 2010 to April 2021. Studies were considered eligible if they evaluated the CK20, CD44, Ki67 and p53 expression in CIS.ResultsIn total, 15 references were suitable for quantitative review. The overall rate of CK20, CD44, Ki67 and p53 expression in CIS was 43%, 31%, 44%, 38%, respectively.ConclusionsOur study supports the 2014 International Society of Urologic Pathology consensus that histological assessment remains the gold standard to diagnose urothelial CIS and suggests that a very close correlation between morphological, immunohistochemical and clinical data is essential to provide the best management for patients with bladder carcinoma. (AU)

Agenesia unilateral congénita de glándula lagrimal con sustitución por lipoma. Un caso raro de alacrimia congénita unilateral / Congenital unilateral absence of the lacrimal gland combined with lipoma. A rare case of unilateral congenital alacrima

El propósito de este artículo es describir un caso de agenesia lagrimal congénita unilateral en una niña de 7 años con síntomas oculares, ausencia de secreción lagrimal y una tumoración conjuntival en el ángulo superoexterno del ojo derecho. La agudeza visual era de 20/20 en ambos ojos. El ojo derecho presentaba secreción mucosa, erosiones y filamentos corneales. La anamnesis, la exploración física y las pruebas analíticas descartaron enfermedades sistémicas asociadas a la alacrimia congénita, así como enfermedades reumatológicas, inmunológicas o infecciosas. La resonancia nuclear magnética con diversas técnicas de supresión grasa mostró la ausencia de glándula lagrimal derecha y la presencia de una tumoración compatible con lipoma. Este caso, para nuestro conocimiento, representa la primera comunicación de una agenesia unilateral de glándula lagrimal combinada con un lipoma

The purpose of this report is to describe a case of a unilateral congenital absence of the lacrimal gland in a 7-year-old girl with ocular symptoms, no tear production and a conjunctival tumour at the supero-external angle of the right eye. The visual acuity was 20/20 in both the eyes. The right eye showed mucous secretion, corneal erosions and filaments. Anamnesis, physical examination and clinical tests ruled out systemic diseases associated with congenital alacrima, as well as rheumatic, immunological and infectious diseases. Nuclear magnetic resonance, with various fat suppression techniques, demonstrated the absence of the right lacrimal gland and the presence of a tumour compatible with lipoma. This case, to our knowledge, is the first report of unilateral absence of the lacrimal gland combined with lipoma

Prognostic and microRNA profile analysis for CD44 positive expression pediatric posterior fossa ependymoma

Background: Ependymoma is the third most common pediatric brain tumor and occurs most frequently in the posterior fossa. However, the lack of immortalized cell lines, xenografts, or animal models has significantly hindered the study of pediatric posterior fossa ependymoma (P-PF-EPN) pathogenesis. This prompted us to use clinical big data to study this rare disease. Methods: Application of the robust rank aggregation method revealed CD44 as a reliable biomarker in P-PF-EPN. 120 P-PF-EPN samples after surgical resection were selected for Kaplan-Merier and Cox proportion hazard regression survival analysis. Immunohistochemical analysis was performed to assess CD44 expression in the tumor samples. The miRNA profile was determined using a whole-genome miRNA microarray. The expression patterns of related mRNAs, miRNAs and proteins were validated by qRT-PCR or Western blotting. Results: CD44 was found to be an independent predictor of prognosis in survival analysis. It improved the accuracy of using LAMA2/NELL2 for classifying P-PF-EPN molecular subgroups. Fourteen miRNAs were underexpressed, and one miRNA was overexpressed in CD44-positive P-PF-EPNs. miR-543, miR-495-3p, miR-299-3p, miR-139-5p and miR-128-3p were identified to have CD44 positively co-regulated potential target oncogenes. Two PI3K-Akt signaling pathway related potential target oncogenes (VEGFA, CSF1) for miR-299-3p and miR-495-3p were validated overexpression in CD44 positive P-PF-EPNs. Abnormal activation of the PI3K-Akt pathway was confirmed in CD44-positive cases. Conclusions: CD44 is of great clinical significance as a prognostic biomarker. The survival difference between CD44 positive and negative P-PF-EPN is determined by a complex functional miRNA-mRNA-signaling pathway regulatory network

No disponible

Sarcoma de Kaposi conjuntival gigante por el virus de inmunodeficiencia humana: remisión total tras terapia antirretroviral y quimioterapia sistémica / Human immunodeficiency virus-associated giant conjunctival Kaposi's sarcoma: complete remission with antiretroviral therapy and systemic chemotherapy

CASO CLÍNICO: Paciente varón de 35 años con lesión conjuntival tumoral hemorrágica unilateral y otra contralateral poco elevada, de curso subagudo y asociadas a máculas cutáneas violáceas en extremidades y angiomas digestivos como primera manifestación de inmunodepresión por el virus de inmunodeficiencia humana (VIH). La biopsia cutánea, de mucosa estomacal y conjuntival confirmó el diagnóstico de sarcoma de Kaposi con resolución total de las lesiones con terapia antirretroviral y quimioterapia sistémica. CONCLUSIÓN: El sarcoma de Kaposi conjuntival asociado a infección por el VIH, incluso de grandes dimensiones, puede tener una buena respuesta al tratamiento antirretroviral y quimioterápico sistémicos sin necesidad adicional de terapia ocular local

CASE REPORT: A 35-year-old male patient with a large unilateral haemorrhagic conjunctival tumour lesion and another contralateral haemorrhagic conjunctival flat lesion associated with violaceous cutaneous macules on the extremities and angiomatous lesions in the upper gastrointestinal tract as initial clinical manifestation of HIV-related immunodeficiency. Cutaneous, gastric mucosal and conjunctival biopsy was consistent with Kaposi's sarcoma with complete remission after highly active antiretroviral therapy and systemic chemotherapy. CONCLUSION: HIV-related conjunctival Kaposi's sarcoma, even a large one, can have a good response to antiretroviral therapy and systemic chemotherapy without any additional topical eye treatment

Propuesta de algoritmo global de tratamiento del hallux rigidus según la medicina basada en la evidencia / Proposed global treatment algorithm for hallux rigidus according to evidence-based medicine

Introducción. El hallux rigidus es la artrosis más frecuente en el pie y tobillo. Existen numerosas revisiones respecto al tratamiento quirúrgico, pero escasas publicaciones que aborden la eficacia del tratamiento conservador. Objetivo. Presentar un algoritmo global de tratamiento completo para todos los grados de esta enfermedad. Métodos. Revisión sistemática de la evidencia disponible hasta octubre de 2013 utilizando las siguientes fuentes: Pubmed y PEDro database (physiotherapy evidence database) de artículos sobre tratamiento de hallux rigidus que comuniquen sus resultados y de los que pudieran obtenerse grados de recomendación. Resultados. Obtuvimos 112 artículos sobre tratamiento conservador y 609 sobre tratamiento quirúrgico. Finalmente solo 4 cumplían los criterios de inclusión. Conclusiones. El uso de ortesis a medida o modificaciones del calzado, la infiltración con hialuronato, la queilectomía en grados moderados y la artrodesis metatarsofalángica en grados avanzados, son los únicos procedimientos contrastados con grado de evidencia B o moderada en el tratamiento del hallux rigidus (AU)

Introduction. Hallux rigidus is the most common arthritis of the foot and ankle. There are numerous reviews on the surgical treatment, but few publications that address the effectiveness of conservative treatment. Objective. To present a comprehensive algorithm for treatment of all grades of this disease. Methods. Literature search in the following sources: Pubmed and PEDro database (physiotherapy evidence database) until October 2013 for articles on treatment hallux rigidus to record levels of evidence. Results. A total of 112 articles were obtained on conservative treatment and 609 on surgical treatment. Finally, only 4 met the inclusion criteria. Conclusions. The use of orthoses or footwear modifications, infiltration with hyaluronate, cheilectomy in moderate degrees and the metatarsophalangeal arthrodesis for advanced degrees, are the only procedures contrasted with grade B or moderate evidence in the treatment of hallux rigidus (AU)

Tratamiento de lesiones condrales agudas de espesor completo con ácido hialurónico de alto peso molecular; un modelo experimental / Treatment of acute full-thickness chondral defects with high molecular weight hyaluronic acid; an experimental model

Objetivo. Evaluar el efecto de 2 protocolos diferentes de ácido hialurónico (AH) intraarticular (hylan G-F20) sobre la regeneración del cartílago articular en lesiones condrales agudas de espesor completo. Material y método. Se realizaron lesiones condrales de espesor completo de 3 × 6 mm en los cóndilos femorales de conejos New Zealand, tratados con una dosis única o tres dosis de AH. Los animales fueron sacrificaron a las 12 semanas y el tejido regenerado fue evaluado mediante observación directa e histología con la escala ICRS. Resultados. Macroscópicamente, en ambos grupos tratados con AH los defectos se rellenaron con tejido irregular, con zonas similares al cartílago hialino y otras en las que se observaron áreas deprimidas con exposición de hueso subcondral. El análisis histológico demostró en ambos grupos tratados con AH un tejido similar al cartílago hialino comparado con el grupo control. Sin embargo, la puntuación de la escala Internacional Cartilage Repair Society (ICRS) no mostró diferencias entre los grupos tratados con AH. Conclusión. El uso de dosis única o 3 dosis de AH en lesiones condrales agudas tiene un beneficio limitado y similar en la regeneración del cartílago articular (AU)

Purpose. To evaluate the effect of 2 different protocols of intra-articular hyaluronic acid (HA, hylan G-F20) to articular cartilage regeneration in acute full-thickness chondral defects. Materials and methods. Full-thickness chondral defects of 3 mm × 6 mm were performed into the lateral femoral condyles of New Zealand rabbits, treated with a single or three doses of HA. The animals were sacrificed at 12 weeks and the regenerated tissue was evaluated by direct observation and histology with the ICRS scale. Results. Macroscopically, in both groups treated with HA the defects were filled with irregular tissue with areas similar to hyaline cartilage and others in which depressed areas with exposed subchondral bone were observed. Histological analysis showed in both groups treated with HA a hyaline-like cartilage compared to control group. However, the score of the International Cartilage Repair Society (ICRS) scale did not show differences between the groups treated with HA. Conclusion. The use of single dose or 3 doses of AH in acute chondral lesions has a limited and similar benefit in articular cartilage regeneration (AU)

Combined preoperative CEA and CD44v6 improves prognostic value in patients with stage I and stage II colorectal cancer

AIM: Combination of biomarkers may improve diagnosis and have better prognostic value than single markers. The purpose of this study was to investigate whether combined CEA and CD44v6 improves prognostic value in stage I and stage II (stage I/II) colorectal cancer (CRC). METHODS: Preoperative serum CEA level and the expression of CD44v6 in CRC tissues were examined by electrochemiluminescence immunoassay and immunohistochemistry, respectively. The association of CEA and CD44v6 with clinicopathological features and their possible prognostic values was analyzed. RESULTS: The preoperative elevated serum CEA level and positive CD44v6 expression were detected in 30.1 % (52/173) serum samples and 60.5 % (101/167) CRC tissues, respectively. Patients with an elevated-CEA level or a CD44v6-negative tumor had a worse disease-specific survival (DSS) than those with a normal-CEA level or CD44v6-positive tumor (P = 0.024, P = 0.012, respectively). Moreover, CD44v6 expression could be used in discriminating patients from good to poor prognosis in normal-CEA subgroup (P = 0.043), but not in elevated-CEA subgroup (P = 0.563). Multivariate analysis revealed that combined CEA and CD44v6 was an independent prognostic factor for patients with stage I/II CRC (P = 0.023). However, serum CEA level only retained a borderline significance for correlation with a worse DSS (P = 0.059), and CD44v6 expression alone was not an independent prognostic factor for DSS in multivariate analysis (P = 0.123). CONCLUSION: These results suggested that combined CEA/CD44v6 had better prognostic value than CEA or CD44v6 alone for patients with stage I/II CRC (AU)

No disponible

Estudio de expresión de marcadores de células madre neurales en neuroblastoma y correlación con factores pronóstico / Study of the expression of neural Stem Cell markers in neuroblastoma tumor samples and correlation with prognostic factors

INTRODUCCIÓN: En el neuroblastoma (NB), la existencia de células madre cancerosas (CMC) se ha relacionado con la presencia de metástasis, resistencia al tratamiento quimioterápico y recidiva. Nuestro objetivo es analizar la expresión de marcadores relacionados con proliferación y diferenciación de células progenitoras neurales en muestras de NB, y correlacionarlo con parámetros clínicos, histología, genética y respuesta al tratamiento. MATERIAL Y MÉTODOS: Realizamos un estudio experimental retrospectivo con muestras de neuroblastoma obtenidas mediante biopsia o exéresis tumoral entre 2010 y 2012 en nuestro hospital. Mediante inmunohistoquímica de fluorescencia analizamos la expresión de los marcadores: CD44, CD74, CD133, tirosina hidroxilasa, receptor de endotelina A (REA) y endotelina B (REB), p75, nestina y Phox2b, todos relacionados con la biología de células madre neurales. Posteriormente, relacionamos los niveles de expresión con variables clínicas. RESULTADOS: La expresión de nestina fue positiva en el 72,2% de las muestras y el REA en el 66,7%. Phox2b y CD74 fueron de menor expresión, siendo positiva en menos del 30%. Los marcadores CD44, REB y Phox2b se expresaban en tumores más agresivos. La expresión de REA se correlacionó de forma significativa con tumores de histología desfavorable (p= 0,01), amplificación del N-myc (p= 0,05) y recidiva/ progresión (p= 0,05). [Conclusión] La expresión de CD44, REB y REA se asoció con tumores más agresivos y factores de mal pronóstico. Estos marcadores están presentes en la membrana de células madre neurales, pudiendo ser útiles para identificar y aislar por citometría de flujo las CMCs del NB y para el estudio de nuevas dianas terapéuticas

INTRODUCTION: The existence of cancer stem cells (CSC) in neuroblastoma (NB) has been associated with the development of metastasis, resistance to chemotherapy and recurrence. Our objective is to analyze the expression of proliferation and differentiation markers of neural progenitor cells in NB samples, and to correlate this expression with clinical variables such as histology, genetics and response to conventional therapy. MATERIAL AND METHODS: We performed a retrospective-experimental study with neuroblastoma samples obtained from biopsies or tumor resections between 2010-2012 in our Hospital. Fluorescence immunohistochemistry was used to analyze the expression of the different markers: CD44, CD74, CD133, tyrosine hydroxylase, endothelin receptors type A (ETA) and B (ETB), p75, nestina y and Phox2b, all of them related to neural stem cell biology. The level of expression of the markers was then correlated with clinical variables. [Results] Nestin expression was positive in 72.2% of samples and ETA in 66.7%. PHOX2B and CD74 expression were lower, being positive in less than 30%. The markers CD44, ETB and PHOX2B were expressed in more aggressive tumors. ETA expression correlated significantly with unfavorable histology tumors (p= 0.01), N-myc amplification (p= 0.05) and recurrence/progression (p= 0.05). [Conclusion] The expression of CD44, ETB and ETA was associated with more aggressive tumors and poor prognostic factors. These markers are in the membrane of neural stem cells and may be useful to identify and isolate by flow cytometry CSCs of NB for the study of new therapeutic targets

Development and characterization of an isogenic cell line with a radioresistant phenotype

INTRODUCTION: Radiation resistance is a major cause of death in cancer patients. Cancer cells react during radiotherapy by re-programming specific cell functions that may confer resistance to radiation. The understanding of this complex process is hindered due to the lack of appropriate study models. We describe an experimental development of a radioresistant isogenic cancer cell line, and its molecular characterization. MATERIALS AND METHODS: A431-cultured cells were irradiated for 7 month until 85 Gy. Then, a selected single cell was left to grow as stable A431-R cell line. Clonogenic assay was used to determine cell survival, the α and β parameters of the LQ model, and the mean inactivation dose. The DNA repair ability of cells was evaluated by pulsed-field electrophoresis method. Differential effect of fractionated radiation was ultimately tested in xenografts. Furthermore, we used a wound healing assay, Western blot for EGFR, AKT and ERK1/2 and ELISA test for vascular endothelial growth factor (VEGF) secretion. Finally we explored CD44 marker and cell cycle distribution. RESULTS: The established A431-R cell line showed radiation resistance in clonogenic assays, repair of radiation-induced DNA fragmentation and xenografted tumours. The radiation resistance was associated with in vitro higher cell growth and migration, increased levels of former oncoproteins, and secretion of VEGF. CONCLUSIONS: In this model, the emergence of radiation resistance was associated with the acquisition of biological traits that support more aggressive behaviour of cancer cells. We have generated a model that will be useful for mechanistic studies and development of rational treatments against radiation resistance in cancer (AU)

Evidencia disponible relativa a la eficacia de diferentes agentes endovesicales restituidores de glucosaminoglicanos empleados en cistitis intersticial / Available Evidence About Efficacy of Different Restoring Agents of Glycosaminoglycans for Intravesical Use in Interstitial Cystitis

Objetivos: Comparación de los diferentes regímenes terapéuticos endovesicales a base de agentes restituidores de glucosaminoglicanos (AR-GAG) comercialmente disponibles en España en términos de efectividad clínica. Material y método: Análisis bibliográfico de los estudios publicados en Medline entre 1996 y 2012 sobre AR-GAG de aplicación vesical con énfasis en los resultados clínicos. Comparación post-hoc de la eficacia de dicho tratamiento en los estudios realizados en pacientes con cistitis intersticial en diferentes condiciones, mediante el cálculo de los tamaños de efecto para el análisis de mejora en la escala analógica visual (EAV) de dolor y la tasa de respuesta clínica. Cálculo del número necesario de pacientes a tratar (NNT) para los distintos agentes a partir de la odds ratio (OR) e implicaciones económicas asociadas. Resultados: La evidencia disponible es globalmente escasa. Un total de 38 artículos tratan de AR-GAG en diferentes indicaciones, 17 de ellos en cistitis intersticial y solamente 8 son subsidiarios de establecer comparación entre los resultados presentados. Los tratamientos empleados fueron placebo, ácido hialurónico de alto peso molecular al 0,8% (Cystistat®), condroitín sulfato sódico al 2% (Uracyst®) y una combinación de ácido hialurónico de bajo peso molecular al 1,6% más condroitín sulfato al 2% (Ialuril®), entre 6 y 12 instilaciones. Otro preparado de ácido hialurónico de bajo peso molecular (Uromac®) carece de evidencia científica alguna. Todos los elementos terapéuticos estudiados muestran disminución de la puntuación media de la EAV de dolor y aumento de la tasa de respuesta postratamiento. El NNT para los tratamientos estadísticamente ventajosos sobre placebo oscila entre 1,6 y 4,1. La comparación post-hoc de las tasas de respuesta establece que Cystistat® 12 instilaciones (OR: 18,8; IC 95%: 6,4-57,2; p=0,001) o 10 instilaciones (OR: 19,2; IC 95%: 5,3-75,3; p=0,001) son las pautas de tratamiento que obtienen máxima efectividad. En ambos casos el NNT fue 1,6. Conclusiones: Este estudio está sujeto a múltiples limitaciones inherentes a la naturaleza de su diseño; no obstante, muestra que, a pesar de que la literatura disponible es escasa, existen diferencias en cuanto a la efectividad clínica de los diferentes agentes y regímenes aplicados para el tratamiento endovesical de la cistitis intersticial. Estas diferencias conllevan también implicaciones de índole económica (AU)

Objectives: To compare the different endovesical therapeutic regimes in terms of clinical effectiveness based on glycosaminoglycan replenishment agents (RA-GAG) available on the market in Spain. Material and methods: A bibliographic analysis was made of the studies published in Medline from 1996 to 2012 on RA-GAG of application in the bladder, placing emphasis on the clinical results. A post-hoc comparison was made of the efficacy of this treatment in the studies conducted in patients with interstitial cystitis in different conditions by calculating the effect sizes to analyze improvement on the pain visual analogue scale (VAS) and clinical response rate. The number of patients needed to treat (NNT) for the different agents was calculated based on the odds ratio and associated economic implications. Results: The globally available evidence is scarce. There are 38 articles about RA-GAGs in different indications, 71 of them in interstitial cystitis and only 8 may assist in establishing a comparison between the results presented. The treatments used were placebo, 0.8% high molecular weight hyaluronic acid (Cystistat®), 2% chondroitin sulfate sodium (Uracyst®) and a combination of 1.6% low molecular weight hyaluronic acid plus 2% chondroitin sulfate (Ialuril®), between 6 and 12 instillations. Another low molecular weight hyaluronic acid preparation (Uromac®) lacks any scientific evidence. All the therapeutic elements studied show a mean score decrease on the pain VAS and increase in the rate of post-treatment response. The NNT for the treatments that are statistically more beneficial over placebo ranges from 1.6 and 4.1. The post-hoc comparison of the response rates has established that Cystistat® 12 instillations (OR 18.8; 95% CI 6.4-57.2; P=.001) or 10 instillations (OR 19.2; 95% CI 5.3-75.3; P=.001) are the treatment regimes that obtain maximum effectiveness. In both cases, the NNT was 1.6. Conclusions: This study has multiple limitations inherent to the nature of the design. However, although the available literature is scarce, it shows that there are differences regarding the clinical effectiveness of the different agents and regimes used for endovesical treatment of interstitial cystitis. These differences also entail economic type implications (AU)

CD44/CD24 breast cancer cells isolated from MCF-7 cultures exhibit enhanced angiogenic properties

BACKGROUND: Recent studies suggest that the relationship between cancer stem cells (CSCs) and the vascular niche may be bidirectional; the niche can support the growth and renewal of CSCs, and CSCs may contribute to the maintenance of the niche. There is little knowledge concerning the role of breast cancer stem cells in promoting tumor angiogenesis. AIM: For human breast cancers, CSCs have been shown to be associated with a CD44+/CD24- phenotype. We investigated the potential activities of CD44+/CD24- breast cancer stem cells in promoting tumor angiogenesis. METHODS: The expression of pro-angiogenic genes was determined by quantitative real-time RT-PCR. Endothelial cell migration assays were employed to evaluate effects of conditioned media from CD44+/CD24- on human umbilical vein endothelial cells. A chorioallantoic membrane (CAM) assay was used to study the potential of CD44+/CD24- cells to promote angiogenesis. RESULTS: In our study, CD44+/CD24- cells expressed elevated levels of pro-angiogenic factors compared with CD44+/CD24+ cells. CD44+/CD24- cell-conditioned media significantly increased endothelial cell migration. Breast cancer cell lines enriched with CD44+/CD24- cells were more pro-angiogenic in the CAM assay than hose lacking a CD44+/CD24- subpopulation. CD44+/CD24- cells sorted from MCF-7 cell lines were more pro-angiogenic in a CAM assay than CD44+/CD24+ cells. Furthermore, the VEGF concentration was significantly higher in CD44+/CD24- cell-conditioned media than in CD44+/CD24+ cell-conditioned media. The pro-angiogenic effect of CD44+/CD24- cells on endothelial cells was abolished by bevacizumab. CONCLUSION: Our findings demonstrate that CD44+/CD24- breast cancer stem cells have substantial pro-angiogenic potential and activity. This provides new insights to explore in the development of targeted therapies (AU)

A role for cancer stem cells in drug resistance and metastasis in non-small-cell lung cancer

The cancer stem cell (CSC) theory is currently a very important field in cancer research. This theory states that tumours are organised in a hierarchical manner with a subpopulation of limited number called CSCs with the ability to self-renew and undergo asymmetrical divisions, giving rise to a differentiated progeny that represents most of the tumour populations. CSCs are metastatic and chemoresistant, two features that very likely contribute to the poor response of locally advanced lung cancer. CSCs have been identified in non-small-cell lung cancer cell lines as well as those from patient primary samples. A correlation has been found in terms of chemoresistance and bad prognosis in patient-derived samples enriched with CSCs, indicating that these cells are an important target for future therapy combinations. Therefore, understanding the biology and exploring cell markers and signalling pathways specific for CSCs of lung cancer may help in achieving progress in the treatment of the disease (AU)

Uso de marcadores moleculares para la predicción de la metástasis axilar en cánceres de mama con diámetro igual o inferior a 1 cm (pT1a, b) / No disponible

La tasa de invasión ganglionar axilar que presentan los cánceresde mama de diámetro igual o inferior a 1 cm es baja,pero no despreciable. Ello obliga a la realización sistemáticadel estudio de la axila, ya sea mediante linfadenectomía clásica,o la técnica del ganglio centinela. Si fuéramos capaces depredecir la metastatización axilar con un grado de fiabilidadaceptable (superior al 95%), podríamos restringir la ampliaciónde la cirugía a aquellas pacientes que verdaderamente sebenefician de ella, y limitarnos a la extirpación del tumor en el80-90% restante.Hemos estudiado 145 cánceres invasores de mama unifocalescon diámetro igual o inferior a 1 cm (pT1a,b) operadosen nuestro centro. En todos los casos fue practicada linfadenectomíaaxilar completa o, más recientemente, estudio delganglio centinela (28/145 casos). Un total de 20 pacientes(13,8%) presentaron metástasis en los ganglios axilares (rango:1-23 ganglios afectados). Además de los parámetros histológicosclásicos, en todos los casos se determinó mediante inmunohistoquímicala expresión de receptores hormonales (REy RP), el marcador de proliferación Ki67, el oncogén c-erb-B2y el gen oncosupresor mutado p53. También mediante inmunohistoquímica,se valoró la expresión de CD44std en 69 casos,cuya ausencia se asocia con la metastatización axilar, y decomplejos uPA-PAI en 54 casos, cuya presencia en cáncerescon receptores de progesterona se asocia igualmente con lainvasión de los ganglios axilares en tumores T1.De todas las variables estudiadas, las únicas que se correlacionaronde manera estadísticamente significativa y directa con lainvasión ganglionar de la axila fueron un índice de proliferaciónKi67 superior al 10% (r = 0,18, p = 0,034) y la ausencia de expresiónde CD44std (r = 0,28; p = 0,022). De manera significativae inversa se correlacionaron con las metástasis ganglionaresde la axila el grado histológico 1 (r = - 018; p = 0,041) y elgrado nuclear 1 (r = - 0,18; p = 0,036).Estos datos parecen indicar que células tumorales altamenteproliferativas, y además capaces de desanclarse de sus vecinas,son aquellas que inician el proceso de metastatización axilaren el cáncer de mama ya desde sus estadios más precoces.Recíprocamente, tumores de 1 cm de diámetro o menos, biendiferenciados, prácticamente nunca presentan metástasis axilares

The axillary nodal invasion rate of breast cancers with a diameterof 1 cm or less is low, but not negligible. Therefore itis mandatory to study the axilla systematically, either by meansof a classical lymphadenectomy or the sentinel node technique.If we were able to predict axillary metastases with anacceptable degree of certainty (above 95%), we could restrictthe extended surgery to those patients really benefiting fromit, and limit it to the tumor excision alone in the remaining 80-90%.We have studied 145 unifocal invasive breast cancers witha diameter of 1 cm or less (pT1a,b) operated upon at our center.In all cases we performed a complete axillary dissection,or in more recent times a sentinel node study (28/145 cases).A total of 20 patients (13.8%) showed metastasis in the axillarynodes (range; 1-23 affected nodes). In addition to classicalhistological parameters, in all cases we determined by meansof immunohistochemistry the expression of hormone receptors(ER & PR), the Ki67 proliferation marker, the c-erb-B2oncogene and the mutant p53 tumor suppressor gene. Alsoby means of immunohistochemistry we evaluated the expressionof CD44std in 69 cases, the absence of which is associatedwith axillary metastasis, and of uPA-PAI complexes in 54cases, the presence of which in cancers expressing progesteronereceptors is equally associated with axillary nodal invasionin T1 tumors.Of all studied variables, the only ones correlating in a statisticallysignificant way with axillary nodal invasion were a Ki67 proliferationindex above 10% (r = 0.18, p = 0.034) and the absenceof expression of CD44std (r = 0.28; p = 0.022). Histologic grade 1 (r = - 018; p = 0.041) and nuclear grade1 (r = - 0.18; p = 0.036) correlated inversely in a significant waywith axillary metastasis.These data seem to indicate that highly proliferating tumorcells, which are additionally capable of detaching themselvesfrom their neighbors, are the ones initiating the axillarymetastatic process in breast cancer already at its earlieststages. Reciprocally, well differentiated tumors of 1 cm or lessalmost never show axillary metastases

Estudio inmunohistoquímico del carcinoma epidermoide de labio / Epidermoid carcinoma of the lip: An immunohistochemical study

Objetivos: Determinar la sobreexpresión de las proteínas cerb-B2, p53, bcl-2, Ki67 y CD44varV6 y establecer su valorpronóstico en el carcinoma epidermoide de labio.Diseño del estudio: Estudio inmunohistoquímico de las proteínasp53, c-erb-B2, bcl-2, ki67 y CD44varV6 en 79 carcinomasepidermoides de labio diagnosticados y tratados a lo largo deun periodo de 20 años. Los datos obtenidos fueron sometidosa análisis estadístico uni y multivariante.Resultados: La inmunotinción fue positiva en el 75% de los casospara la proteína c-erb-B2, en el 70,6% para la proteína p 53, enel 3,8% para la proteína bcl-2 y en el 89,9% para la molécula deadhesión cd44varV6. La expresión proteica de ki67 osciló entreun mínimo de 0% y un máximo de 6,29%. Los factores inmunohistoquímicosanalizados no presentaron valor pronóstico enel carcinoma epidermoide de labio, y solamente los pacientesafectados por este tipo de tumores que expresaban la moléculade adhesión CD44varV6 se asociaron de forma significativa conuna mayor supervivencia mediante el análisis de Kaplan-Meier.Conclusiones: Las técnicas inmunohistoquímicas analizadaspara el estudio anatomopatológico del carcinoma epidermoidede labio no deberían realizarse rutinariamente, dado su mayorcoste y su menor utilidad en la práctica clínica diaria

Objectives: To determine the expression of the c-erb-B2, p53,bcl-2, Ki67 and CD44varV6 proteins, and to establish theirprognostic value in epidermoid carcinoma of the lip.Study design: Immunohistochemical study of the c-erb-B2,p53, bcl-2, Ki67 and CD44varV6 proteins in 79 epidermoidcarcinomas of the lip, diagnosed and treated over a period of 20years. The data obtained were subjected to uni- and multi-variatestatistical analyses.Results: Immunostaining was positive in 75% of cases for c-erb-B2 protein, in 70.6% for p53 protein, in 3.8% for bcl-2 proteinand in 89.9% for adhesion molecule CD44varV6. Ki67 proteinexpression varied between a minimum of 0% and a maximum of6.29%. Most immunohistochemical factors analyzed presentedno prognostic value for epidermoid carcinoma of the lip. Onlythose patients affected by this type of tumor that expressed theadhesion molecule CD44varV6 were significantly associatedwith a greater survival calculated by means of Kaplan-Meieranalysis.Conclusions: The immunohistochemical techniques analyzedfor the anatomicopathological study of epidermoid carcinomaof the lip should not routinely be used due to their high cost andlow utility in daily clinical practice

Expresión de CD44v6 en carcinomas ductales infiltrantes de mama con negatividad de receptores de estrógenos y de progestágenos / CD44v6 expression in er-negative and PgR-negative infiltrating ductal breast carcinomas

No disponible

pS2 citosólica y proliferación celular en carcinomas ductales infiltrantes de mama hormonodependientes / Cytosolic pS2 levels and cellular proliferation in ER-positive and PgR-positive infiltrating ductalcarcinomas of the breast

Objetivo: La proteína pS2 (TFF1/pS2) es una molécula inducida por los estrógenos en los carcinomas mamarios. Nosotros hemos querido estudiar su expresión en carcinomas ductales infiltrantes de mama RE + y RP + , correlacionarla con otros parámetros clínico-biológicos y conocer su impacto en la evolución. Material y metodos: La pS2 citosólica fue determinada utilizando un IRMA (CIS. BioInternational. Francia). Hemos analizado, además, las concentraciones citosólicas de catepsina D y activador del plasminógeno tipo tisular (t-AP), así como las del receptor del factor de crecimiento epidérmico (EGFR), oncoproteína erbB2, CD44v5 y CD44v6 en las membranas celulares. El tamaño tumoral, grado histológico (GH), afectación axilar, metástasis a distancia, ploidía, índice de DNA y fase de síntesis celular (FS) fueron también considerados. Resultados: Los tumores pS2-positivos (> 5ng/mg prot.) mostraron mayores concentraciones de catepsina D (p:0,0043) y t-AP (p:0,0089) y fueron, asimismo, menos frecuentemente GH3 (p:0,0231), FS > 7 % (p:0,0005) y FS > 14 % (p:0,0014). Durante el período de seguimiento (i: 1-147; 50,1+/­31,7; mediana 37 meses) los tumores pS2 positivos mostraron menor número de recidivas (5/101 vs 6/69; p:0,059), pero no de muertes por el tumor (1/101 vs 2/6); ns). Conclusiones: Nuestros resultados apoyan la relación inversa de la pS2 con la proliferación celular en los tumores RE+ y RP+, lo cual puede sugerir una nueva función biológica distinta a la de indicadora de la hormonodependencia. Sin embargo, necesitamos tener mayor tiempo de seguimiento para poder precisar si ello incide directamente en la evolución ulterior del tumor

Objective: The trefoil factor 1 (TFF1/pS2) is an estrogen-induced molecule in breast tumours. We wanted to study its expression in ER+ and PgR+ infiltrating ductal carcinomas of the breast (IDCs), and to correlate it with other clinical-biological parameters and the outcome. Material and methods: Cytosolic pS2 levels were measured using an IRMA (CIS. Biointernational. France) in 170 tumors. Likewise we determined the cytosolic levels of cathepsin D and tissue-type plasminogen activator (t-PA), as well as the concentrations of the epidermal growth factor receptor (EGFR), erbB2 oncoprotein, CD44v5 and CD44v6 on cell surfaces. Also the tumour size, histological grade (HG), axillary lymph node involvement, distant metastasis, ploidy, DNA index and of cellular synthesis phase (SP) was taken in account.Results: The pS2-positive (> 5 ng(/mg prot.) tumours showed higher concentrations of cathepsin D (p: 0.0043) and t-PA (p: 0.0089) than the pS2-negative ones. Likewise, they were less frequently HG3 (p: 0.0231), SP > 7 % (p: 0.0005) and SP > 14 % (p:0.0014). During the follow-up time (r: 1-147; 50,1+/­31,7; median 37 months) the pS2-positive tumors showed a less number of recurrences (5/101 vs 6/69; p: 0.059) but not of deaths by the tumor (1/101 vs 2/69). Conclusions: These results support an inverse relationship between pS2 positivity and cellular proliferation in IDCs and suggest a new role of this protein (different of the hormonodependence) in the biology of these breast carcinomas, while further studies will be required to establish the impact of this finding on their outcome

Valor clínico-biológico de la concentración citosólica de ácido hialurónico en adenocarcinomas pulmonares CD44v6 positivos / Clinico-biological value of the cytosol concentration of hyaluronic acid in CD44v6-positive lung adenocarcinomas

• Propósito: El objetivo de este estudio ha sido analizar la influencia de la concentración citosólicade ácido hialurónico (AH) sobre las características clínico-biológicas de adenocarcinomas de pulmónCD44v6 positivos.• Material y métodos: El grupo estudio incluyó 34 muestras tumorales. Dosificamos las concentracionescitosólicas de AH, pS2, catepsina D, t-AP, NSE, cyfra 21.1, CA125 y fracción libre de lahormona gonadotrófica coriónica. También determinamos las concentraciones de EGFR, proteína oncogénicaerbB2, CD44s y CD44v5 en las membranas celulares. Se tuvo presente, asimismo, el estadioclínico, grado histológico, ploidía, índice de DNA y fase de síntesis celular (FS).• Resultados: En el grupo tumoral los valores del índice AH/CD44v6 oscilaron entre 8.5 y 5999(mediana 107) y fueron superiores (p: 0.004) a los observados en 10 muestras de tejido pulmonarnormal de los mismos pacientes. Los adenocarcinomas pulmonares AH/CD44v6 positivos (>107; medianadel grupo) mostraron mayores concentraciones de proteína oncogénica erbB2 (p:0.020) y superioresvalores de FS (p: 0.009) e índice de DNA (p: 0.024). Asimismo, fueron más frecuentementeFS+ (>15 %) (p: 0.026).• Conclusiones: Los resultados obtenidos parecen resaltar la importancia de la concentración citosólicade AH en los adenocarcinomas pulmonares CD44v6 positivos, de tal modo que altos valoresen el índice AH/CD44v6 se asocian con una mayor proliferación e indiferenciación celular, lo cualunido a mayores concentraciones de proteína oncogénica erbB2, sugiere un subgrupo de tumorescon un posible diferente comportamiento. Sin embargo, dada el reducido número de enfermos incluídos,creemos que son necesarios más estudios para poder confirmar nuestros hallazgos

• Purpose: To study the influence of the cytosol hyaluronic acid (HA) concentrations on theclinical and biological features of CD44v6-positive lung adenocarcinomas (LAs).• Material and methods: The study included 34 tissue samples. We determined theconcentration of HA, p52, cathepsin D, t-PA, NSE, cyfra 21.1, CA125, and free beta subunit ofhuman chorionic gonadotrophin in the cytosol, and of EGFR, erbB2 oncoprotein, CD44s and CD44v5on the cell surface. Other parameters considered were clinical stage, histological grade (HG), ploidy,DNA index, and S-phase cell fraction (SF) measured by flow cytometry.• Results: In the tumoral group the HA/CD44v6 index values varied from 8.5 to 5,999 (107,median for the entire group) and were significantly higher (p 0.004) than those observed in 10samples of normal lung tissue obtained from the same patients. The HA/CD44v6-positive (>107)adenocarcinomas had higher concentrations of erbB2 oncoprotein (p: 0.02), and greater values ofglobal SF (p: 0.009) and DNA index (p: 0.024). They were also more frequently SF+ (>15 %).• Conclusions: The results stand out the importance of the cytosol concentration of hyalurinicacid in the CD44v6-positive lung adenocarcinomas, in such a way that high values of theHA/CD44v6 index are associated with a higher proliferation and cellular undifferentiation, which,joined to the higher concentration of erbB2 protein, suggest a subgroup of tumors with a possiblydifferent (poorer ?) outcome. Nevertheless, given the limited number of studied patients, furtherstudies are necessary to confirm our findings

El CA125 citosólico en adenocarcinomas pulmonares. Nuevos aspectos biológicos / CA125 Cytosolic levels in lung adenocarcinomas. New biological aspects

Introducción: El CA125 sérico es útil marcador de los carcinomas no mucinosos de ovario, pero puede incrementarse en otros tumores, entre los cuales están los no microcíticos de pulmón. Nosotros hemos querido estudiar, en adenocarcinomas pulmonares, su concentración citosólicas y correlacionarlas con la pS2, CD44s, CD44v5 y CD44v6, todas ellas con interés fisiopatológico en aquellos tumores. Pacientes y mótodos: El grupo estudio incluyó 55 pacientes (33 varones) afectos de adenocarcinomas pulmonares.El CA125 y la pS2 citosólicos fueron determinados mediante sendos IRMAS (CIS. Biointernational.Francia), mientras que las concentraciones de CD44s, CD44v5 y CD44v6 en las membranas celulares fueron dosificadas mediante EIAS (Bender Diagnostics. Austria). Otros parámetros considerados fueron el estadio clínico, ploidía y la fase de síntesis celular. Resultados: Las concentraciones citosólicas de CA125 oscilaron entre 1 y 225 U/mg prot. (mediana 80.5) y fueron superiores (p: 0,002) a las observadas en 16 muestras de tejido pulmonar normal de los mismos pacientes (i:1-32,5; mediana 6,7 U/mg prot.). Cuando los adenocarcinomas fueron clasificados en función de la concentración de CA125, tomando como dinteles los percentiles 25 (7,2 U/mg prot.) y 75 (320 U/mg prot.), pudimos observar que los tumores con altos valores antigénicos mostraron mayor positividad para el CD44v6 (p: 0,002) y menor para el CD44s (p: 0,053); asimismo, tuvieron tendencia a ser más frecuentemente pS2 + (p: 0,09). Conclusiones: Los resultados anteriores nos inducen a las siguientes consideraciones: 1) en los adenocarcinomas pulmonares las concentraciones citosólicas de CA125 son superiores a las constatadas en el tejido pulmonar normal de los mismos pacientes; 2) los adenocarcinomas pulmonares con altas concentraciones de CA125 presentan una mayor positividad para el CD44v6 y menor para el CD44s, mostrando, además, una tendencia a ser más frecuentemente pS2 +. Todo ello apoya su interés como indicador de un peor pronóstico en este subtipo histológico pulmonar

Introduction: CA125 is a useful serum tumor marker in patients with non-mucinous ovarian cancer, but there may be high serum levels in other malignant tumors, among them the non-small cell lung cancers. We decided to study the cytosolic levels of CA125 in lung adenocarcinomas and compare them with pS2, CD44s, CD44v5 and CD44v6, all of them with biological interest in this subtype of lung carcinomas. Subjects and methods: The study group included 55 patients (33 males) having lung adenocarcinomas. CA125 and cytostolic pS2 were measured by both IRMAS methods (CIS. Biointernational. France). The concentrations of CD44 standard (CD44s), CD44v5 and CD44v6 on cell surfaces were dosed by EIAS (Bender Diagnostics. Austria). Clinical stage, ploidy and S-phase cellular fraction were also taken into account. Results: In the 55 lung adenocarcinomas, cytosolic CA125 levels ranged between 1 and 225 U/mg prot. (median 80.5) and were higher (p:0.002) than those observed in 16 normal lung tissues from the same patients (r: 1-32.5; median 6.7 U/mg prot.). When the 25th (7.2 U/mg prot.) and 75th (320 U/mg prot.) percentiles were used as clinical cut-offs, we found that the cases with high antigenic levels showed a greater positivity for CD44v6 (p:0.002) and a reduced positivity for CD44 standard (p:0.053). Likewise, they showed a tendency towards being pS2 + (p:0.09) more frequently. Conclusions: Our results lead us to draw the following conclusions: 1) Cytosolic CA125 levels in lung adenocarcinomas were higher than those observed in normal tissues from the same patients. 2) Lung adenocarcinomas with high cytosolic CA125 concentrations had a greater positivity for CD44v6, a reduced positivity for CD44s and were more frequently pS2 +. These associations support the usefulness of the cytosolic CA125 levels as an indicator of poor outcome in this subtype of lung carcinomasIntroduction: CA125 is a useful serum tumor marker in patients with non-mucinous ovarian cancer, but there may be high serum levels in other malignant tumors, among them the non-small cell lung cancers. We decided to study the cytosolic levels of CA125 in lung adenocarcinomas and compare them with pS2, CD44s, CD44v5 and CD44v6, all of them with biological interest in this subtype of lung carcinomas. Subjects and methods: The study group included 55 patients (33 males) having lung adenocarcinomas. CA125 and cytostolic pS2 were measured by both IRMAS methods (CIS. Biointernational. France). The concentrations of CD44 standard (CD44s), CD44v5 and CD44v6 on cell surfaces were dosed by EIAS (Bender Diagnostics. Austria). Clinical stage, ploidy and S-phase cellular fraction were also taken into account. Results: In the 55 lung adenocarcinomas, cytosolic CA125 levels ranged between 1 and 225 U/mg prot. (median 80.5) and were higher (p:0.002) than those observed in 16 normal lung tissues from the same patients (r: 1-32.5; median 6.7 U/mg prot.). When the 25th (7.2 U/mg prot.) and 75th (320 U/mg prot.) percentiles were used as clinical cut-offs, we found that the cases with high antigenic levels showed a greater positivity for CD44v6 (p:0.002) and a reduced positivity for CD44 standard (p:0.053). Likewise, they showed a tendency towards being pS2 + (p:0.09) more frequently. Conclusions: Our results lead us to draw the following conclusions: 1) Cytosolic CA125 levels in lung adenocarcinomas were higher than those observed in normal tissues from the same patients. 2) Lung adenocarcinomas with high cytosolic CA125 concentrations had a greater positivity for CD44v6, a reduced positivity for CD44s and were more frequently pS2 +. These associations support the usefulness of the cytosolic CA125 levels as an indicator of poor outcome in this subtype of lung carcinomas

Expresión de CD44v6 en carcinomas escamosos de pulmón. Asociación con altas concentraciones de EGFR, proteína erbB2 y elevada proliferación celular / CD44v6 expression in lung squamous carcinoma. Association with elevated concentrations of EDFR, erbB2 protein and high cell proliferation

- Propósito: el CD44v6 es una isoforma variante del CD44 involucrada en la diseminación metastática de ciertos tumores. Nosotros hemos querido analizar su expresión en carcinomas escamosos de pulmón y correlacionarla con otros parámetros clínico-biológicos de utilidad clínica.- Material y método: el CD44v6 fue determinado mediante un EIA (Bender Diagnostics. Austria), cuyo dintel de positividad fue establecido en 5 ng/mg prot. En las membranas celulares determinamos, asimismo, las concentraciones del receptor del factor de crecimiento epidérmico (EGFR) y proteína erbB2. También se ha tenido presente el estadio clínico, grado histológico (GH), ploidía y fase de síntesis celular (FS).- Resultados: en los carcinomas escamosos de pulmón, la positividad para el CD44v6 fue apreciada en 76 de los 95 casos (80 por ciento). Los tumores CD44v6 positivos presentaron mayores concentraciones de EGFR (p:0,007), proteína erbB2 (p:0,056) y valores globales de FS (p:0,011). Asimismo, cursaron más frecuentemente con FS + (>15,4 por ciento) (p:0,041).- Conclusiones: los resultados anteriores nos inducen a las siguientes consideraciones: 1) la expresión de CD44v6 se observa en un alto porcentaje de los carcinomas escamosos de pulmón; 2) Su asociación con altas concentraciones de EGFR, proteína erbB2 y una proliferación celular elevada sugieren que pueda reflejar un peor comportamiento y evolución de estos tumores (AU)

Consumo de ácido acetilsalicílico en pacientes con diabetes mellitus. Respuesta / Aspirin use in patients with diabetes mellitus. Reply

No disponible