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El cancer papilar de tiroides es el tipo de neoplasia mas frecuente de la glandula tiroides. Su principal via de diseminacion es la via linfatica, en concreto a los ganglios del cuello. Pese a que su incidencia se encuentra en un progresivo incremento, es considerado un tipo de tumor de buen pronostico, tanto por su bajo porcentaje de recurrencia como por su supervivencia. Sin embargo, no todas las cuestiones en relacion a su diagnostico y tratamiento estan resueltas. Por un lado nos encontramos con un alto porcentaje de adenopatias subclinicas no diagnosticadas en el estudio preoperatorio y que van a influir en dicho pronostico. Por otro lado no existe consenso sobre si se debe realizar o no la diseccion profilactica del compartimento cervical central a la hora de plantear la estrategia quirurgica, especialmente en los tumores pequenos. La biopsia selectiva del ganglio centinela (BSGC), pese a estar validado en el cancer de mama y el melanoma, no lo esta en el cancer papilar de tiroides. En nuestro estudio la hipotesis de trabajo se basa en obtener su validacion en este tipo de cancer de tiroides, lo que permitira su aplicacion clinica. De este modo proponemos que puede ayudar a resolver las cuestiones discrepantes anteriormente expuestas. Segun nuestros resultados conseguimos una detectabilidad del 96% con un porcentaje de falsos negativos del 7,5%, pudiendo considerar la tecnica validada. Ademas nos indica correctamente en el 92,5% de los casos cuando debemos realizar la diseccion ganglionar del cuello, limitandola solo a aquellas disecciones con finalidad terapeutica, evitando la profilactica y por tanto disminuyendo la morbilidad que este tipo de diseccion implica. Este hecho permite estadificar correctamente a cada paciente y por tanto estratificar el riesgo de recurrencia de forma ajustada, hecho que influye en la indicacion y dosificacion del tratamiento ablativo con 131I tras el tratamiento quirurgico.

The nuclear receptor PPAR-β/δ (PPARD) has essential roles in fatty acid catabolism and energy homeostasis as well as cell differentiation, inflammation, and metabolism. However, its contributions to tumorigenesis are uncertain and have been disputed. Here, we provide evidence of tumor suppressive activity of PPARD in prostate cancer through a noncanonical and ligand-independent pathway. PPARD was downregulated in prostate cancer specimens. In murine prostate epithelium, PPARD gene deletion resulted in increased cellularity. Genetic modulation of PPARD in human prostate cancer cell lines validated the tumor suppressive activity of this gene in vitro and in vivo. Mechanistically, PPARD exerted its activity in a DNA binding-dependent and ligand-independent manner. We identified a novel set of genes repressed by PPARD that failed to respond to ligand-mediated activation. Among these genes, we observed robust regulation of the secretory trefoil factor family (TFF) members, including a causal and correlative association of TFF1 with prostate cancer biology in vitro and in patient specimens. Overall, our results illuminate the oncosuppressive function of PPARD and understanding of the pathogenic molecular pathways elicited by this nuclear receptor.Significance: These findings challenge the presumption that the function of the nuclear receptor PPARβ/δ in cancer is dictated by ligand-mediated activation. Cancer Res; 78(2); 399–409. ©2017 AACR.

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Purpose To determine the rate of non-invasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) in a multi-institutional series from the Iberian Peninsula and describing this NIFTP cohort. Methods Retrospective study of papillary thyroid carcinoma (PTC) or well-differentiated tumours of uncertain malignant potential (WDT-UMP) diagnosed between 2005 and 2015 and measuring >= 5 mm in adult patients from 17 hospitals. Pathological reports were reviewed to determine the cases that fulfil the original criteria of NIFTP and histology was reassessed. Rates were correlated with the number of PTC and its follicular variant (FVPTC) of each institution. Demographic data, histology, management, and follow-up of the reclassified NIFTP cohort were recorded. Results A total of 182 cases with NIFTP criteria were identified: 174/3372 PTC (rate: 5.2%; range: 0-12.1%) and 8/19 WDT-UMP (42.1%). NIFTP rate showed linear correlation with total PTC (p: 0.03) and FVPTC (p: 0.007) identified at each centre. Ultrasound findings were non-suspicious in 60.1%. Fine-needle cytology or core biopsy diagnoses were undetermined in 49.7%. Most patients were treated with total thyroidectomy. No case had nodal disease. Among patients with total thyroidectomy, 89.7% had an excellent response evaluated 1 year after surgery. There were no structural persistence or relapses. Five patients showed residual thyroglobulin after 90 months of mean follow-up. Conclusions NIFTP rate is low but highly variable in neighbouring institutions of the Iberian Peninsula. This study suggests pathologist's interpretation of nuclear alterations as the main cause of these differences. Patients disclosed an excellent outcome, even without using the strictest criteria.

Prostate cancer is the second most common tumor and the fifth cause of cancer-related death among men worldwide. PC cells exhibit profound signaling and metabolic reprogramming that account for the acquisition of aggressive features. Although the metabolic understanding of this disease has increased in recent years, the analysis of such alterations through noninvasive methodologies in biofluids remains limited. Here, we used NMR-based metabolomics on a large cohort of urine samples (more than 650) from PC and benign prostate hyperplasia (BPH) patients to investigate the molecular basis of this disease. Multivariate analysis failed to distinguish between the two classes, highlighting the modest impact of prostate alterations on urine composition and the multifactorial nature of PC. However, univariate analysis of urine metabolites unveiled significant changes, discriminating PC from BPH. Metabolites with altered abundance in urine from PC patients revealed changes in pathways related to cancer biology, including glycolysis and the urea cycle. We found out that metabolites from such pathways were diminished in the urine from PC individuals, strongly supporting the notion that PC reduces nitrogen and carbon waste in order to maximize their usage in anabolic processes that support cancer cell growth.

To evaluate the performance of core-needle biopsy (CNB) in thyroid using a cohort of patients in which it was used as first choice. Our institutional review board approved this retrospective study. We reviewed all CNB performed in our center over a period of 11 years. Ultrasound-guided CNBs were performed using a spring-loaded 18-gauge biopsy needle. We used a classification with four diagnostic categories for CNB results: insufficient, benign, follicular lesion (indeterminate), and malignant. Final diagnosis was based on surgical diagnosis or follow-up of at least 2 years in non-operated patients. The study included 4412 CNB in 4112 nodules of 3768 patients, 300 of them repeated biopsies. Results were 148 insufficient (3.4%), 3706 benign (84%), 278 follicular lesions (6.3%), and 280 malignant (6.3%). Considering follicular lesion and malignancy CNB results as positive (both lead to the recommendation of surgery) sensitivity was 96% (CI 93.2–97.8) and specificity 93.7% (CI 92.9–94.5). Predictive positive value for a follicular lesion diagnosis was 12.2% and for a malignancy diagnosis, 98.6%. CNB likelihood ratio for malignancy of a malignant diagnosis was 841.9 (CI 315.8–2313.3), of a malignant/follicular lesion diagnosis was 23.4 (CI 20.1–27.3), and of a benign diagnosis was 0.04 (CI 0.02–0.07). Repeated CNB in 53 insufficient biopsies obtained 50 diagnostic results. Minor complications occurred in 2.2% of CNB, and major in four procedures (0.09%). CNB in thyroid nodules is accurate and has few complications and a low rate of non-diagnostic and indeterminate diagnoses. It can be an alternative method when FNAC has poor performance. Repeating biopsy is useful after non-diagnostic biopsies. • Core-needle biopsy of thyroid has a low ratio non-diagnostic and indeterminate results. • Core-needle biopsy results are highly reliable, especially benign results. • Complication rate of core-needle biopsy of thyroid is low.

The presence of lymph nodes metastasis in papillary thyroid cancer modifies the type of surgical resection as well as the indication of the treatment withObservational prospective cohort study of 55 patients who underwent papillary thyroid cancer without suspicion of lymph node involvement clinical or radiological, since February 2012 through February 2015, with a follow-up between 6 and 8 years. It was usedage, gender, histological, analytical and preoperative and postoperative staging. The sensitivity, specificity and predictive values of technique was calculated. The validation was determined by calculating the detectability and the false negative results of the test.In 53 of the 55 patients (96.36%) there was the sentinel node detection. The false negative were 4 patients (7.5%). Of the rest, after applying the SLNB, 24 (48.9%) were kept as N0, 14 (28.5%) became N1a and 11 (22.4%) were classified as N1b. The differences observed in the study were significant (P.05). The sensitivity was 86.21%, the specificity of 100%, the PPV was 100% and the NPV of 85.71%. The diagnostic accuracy was 92.45%.The SLNB is a valid technique for use in patients suffering from papillary thyroid cancer with a high diagnostic accuracy.

Introduction The BRAF V600E mutation is the most common genetic change in papillary thyroid carcinoma and is associated with a poorer clinical course. Usual methods for its study (DNA sequencing or molecular test based on PCR) are expensive and time-consuming. Recently, immunohistochemistry (IHC) for BRAF mutation has been introduced. Objective To compare the results of IHC and real time PCR (RT-PCR) in the detection of BRAF V600E mutation in papillary thyroid carcinoma. Analysis of clinical and pathological differences depending on RT-PCR results is included. Methods A prospective study was performed in 82 consecutive samples, 54 of them taken through a core needle biopsy. IHC was performed on tissue fixed for 24 h with 10% neutral formalin using the anti-BRAF V600E (VE-1) mouse monoclonal primary antibody and was rated as positive or negative. DNA was extracted from formalin-fixed, paraffin-embedded tissues by manual microdissection, and BRAF mutation was detected by RT-PCR using the Cobas ® 4800 BRAF V600 mutation test (Roche). Results Both techniques were concordant in 81 cases, and BRAF was positive in 49. Discordance appeared in a follicular variant showing positive IHC and negative RT-PCR, attributed to histological heterogeneity. Cost of materials for IHC was less than half of the cost for RT-PCR. Conclusions IHC appears to be a reliable, economical and easily available alternative to molecular biology techniques for routine detection of the BRAF V600E mutation in papillary thyroid carcinoma patients, provided optimal fixation conditions are used. It may be a useful technique in hospitals with no access to molecular biology techniques.

Cellular transformation and cancer progression is accompanied by changes in the metabolic landscape. Master co-regulators of metabolism orchestrate the modulation of multiple metabolic pathways through transcriptional programs, and hence constitute a probabilistically parsimonious mechanism for general metabolic rewiring. Here we show that the transcriptional co-activator peroxisome proliferator-activated receptor gamma co-activator 1α (PGC1α) suppresses prostate cancer progression and metastasis. A metabolic co-regulator data mining analysis unveiled that PGC1α is downregulated in prostate cancer and associated with disease progression. Using genetically engineered mouse models and xenografts, we demonstrated that PGC1α opposes prostate cancer progression and metastasis. Mechanistically, the use of integrative metabolomics and transcriptomics revealed that PGC1α activates an oestrogen-related receptor alpha (ERRα)-dependent transcriptional program to elicit a catabolic state and metastasis suppression. Importantly, a signature based on the PGC1α–ERRα pathway exhibited prognostic potential in prostate cancer, thus uncovering the relevance of monitoring and manipulating this pathway for prostate cancer stratification and treatment.

Prostate cancer is among the most frequent cancers in men, and despite its high rate of cure, the high number of cases results in an elevated mortality worldwide. Importantly, prostate cancer incidence is dramatically increasing in western societies in the past decades, suggesting that this type of tumor is exquisitely sensitive to lifestyle changes. Prostate cancer frequently exhibits alterations in the PTEN gene (inactivating mutations or gene deletions) or at the protein level (reduced protein expression or altered sub-cellular compartmentalization). The relevance of PTEN in this type of cancer is further supported by the fact that the sole deletion of PTEN in the murine prostate epithelium recapitulates many of the features of the human disease. In order to study the molecular alterations in prostate cancer, we need to overcome the methodological challenges that this tissue imposes. In this review we present protocols and methods, using PTEN as proof of concept, to study different molecular characteristics of prostate cancer.

Nature 547, 109–113 (2017); doi:10.1038/nature22964 In this Letter, there are errors in Extended Data Figs 5, 8 and 9, and the affiliation of an author. The affiliations for author Violeta Serra should include number 2 (CIBERONC, Instituto de Salud Carlos III, C/ Monforte de Lemos 3-5, Pabellon 11, Planta 0, 28029 Madrid, Spain).

Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#terms Activation of the PTEN-PI3K-mTORC1 pathway consolidates metabolic programs that sustain cancer cell growth and proliferation,. Here we show that mTORC1 regulates polyamine dynamics, a metabolic route that is essential for oncogenicity. Through the use of integrative metabolomics in a mouse model and human biopsies of prostate cancer, we identified alterations in tumours impacting on the production of decarboxylated S-adenosylmethionine (dcSAM) and polyamine synthesis. Mechanistically, this metabolic rewiring stems from mTORC1-dependent regulation of S-adenosylmethionine decarboxylase 1 (AMD1) stability. This novel molecular regulation was validated in murine and human cancer specimens. AMD1 was upregulated in prostate cancer specimens with activated mTORC1. Conversely, samples from a clinical trial with the mTORC1 inhibitor everolimus exhibited a predominant decrease in AMD1 immunoreactivity that was associated to a decrease in proliferation, in line with the requirement of dcSAM production for oncogenicity. These findings provide fundamental information about the complex regulatory landscape controlled by mTORC1 to integrate and translate growth signals into an oncogenic metabolic program.

The nuclear receptor PPAR-β/δ (PPARD) has essential roles in fatty acid catabolism and energy homeostasis as well as cell differentiation, inflammation, and metabolism. However, its contributions to tumorigenesis are uncertain and have been disputed. Here, we provide evidence of tumor suppressive activity of PPARD in prostate cancer through a noncanonical and ligand-independent pathway. PPARD was downregulated in prostate cancer specimens. In murine prostate epithelium, PPARD gene deletion resulted in increased cellularity. Genetic modulation of PPARD in human prostate cancer cell lines validated the tumor suppressive activity of this gene in vitro and in vivo. Mechanistically, PPARD exerted its activity in a DNA binding-dependent and ligand-independent manner. We identified a novel set of genes repressed by PPARD that failed to respond to ligand-mediated activation. Among these genes, we observed robust regulation of the secretory trefoil factor family (TFF) members, including a causal and correlative association of TFF1 with prostate cancer biology in vitro and in patient specimens. Overall, our results illuminate the oncosuppressive function of PPARD and understanding of the pathogenic molecular pathways elicited by this nuclear receptor. Significance: These findings challenge the presumption that the function of the nuclear receptor PPARβ/δ in cancer is dictated by ligand-mediated activation. Cancer Res; 78(2); 399–409. ©2017 AACR.

Resumen El oncocitoma y el carcinoma de celulas cromofobas son dos entidades perfectamente reconocidas en la clasificacion vigente de las neoplasias renales. Ambas neoplasias estan muy interrelacionadas y parece que se originan en la zona distal de la nefrona. A pesar de estar perfectamente definidas desde el punto de vista histologico, en la practica diaria los limites entre ambas neoplasias siguen siendo confusos y, desafortunadamente, la llegada de las nuevas tecnicas diagnosticas a nuestros laboratorios no ha resuelto el problema. La aproximacion actual consiste en considerar al conjunto de tumores oncociticos renales como un espectro de lesiones en el cual el oncocitoma y el carcinoma de celulas cromofobas son los dos extremos. Sin embargo, la experiencia clinica demuestra que hay demasiados casos a medio camino, en tierra de nadie, en los cuales el patologo se encuentra con grandes dificultades diagnosticas y con la imposibilidad de predecir su comportamiento biologico. El panorama se complica aun mas si se tiene en cuenta que el carcinoma renal de celulas claras muestra con cierta frecuencia citoplasmas eosinofilos granulares, lo cual hace aun mas problematico el diagnostico diferencial. En este trabajo se revisa de manera critica la literatura existente en este campo.

Resumen En este trabajo se revisa el concepto del carcinoma renal constituido por celulas claras, un hecho muy frecuentemente encontrado en la practica diaria en nuestro medio. Este abordaje es pertinente debido a que no todos los carcinomas renales con celulas claras al microscopio son autenticos carcinomas renales de celulas claras, sino que pueden ser otras entidades. Dicha aproximacion puramente morfologica no reniega de la nueva clasificacion de la OMS vigente, sino que la complementa. El trabajo esta dirigido mas al patologo general que se enfrenta a casos muy variados con alta presion asistencial, que al subespecialista acostumbrado a profundizar en casos complejos y con grandes medios tecnicos en el campo del cancer renal. Se revisa en primer lugar el carcinoma renal asociado a la enfermedad de von Hippel-Lindau porque muchas de las alteraciones geneticas que provocan esta enfermedad estan presentes en el carcinoma renal de celulas claras esporadico y con posterioridad, se hace lo mismo con los carcinomas renales de celulas claras esporadicos convencionales, los carcinomas familiares no asociados a la enfermedad de von Hippel-Lindau, los carcinomas con translocacion, el carcinoma papilar renal hereditario, algunos carcinomas asociados a Esclerosis Tuberosa y al sindrome de Birt-Hogg-Dube, el carcinoma de celulas cromofobas y el carcinoma asociado a enfermedad renal quistica.

Resumen Antecedentes La invasion de las vesiculas seminales es un dato histologico de mal pronostico en el cancer de prostata. En la mayor parte de los casos es un hallazgo accidental ya que los pacientes con signos clinicos o histologicos de enfermedad extraprostatica no se tratan mediante cirugia en la mayor parte de protocolos al uso. Nuestra intencion es cuantificar este hallazgo histologico en una serie homogenea de prostatectomias radicales y correlacionarlo con los hallazgos en las biopsias previas. Metodos Durante un periodo de 8 anos (1998-2005), 363 pacientes con cancer de prostata fueron tratados mediante prostatectomia radical en el Hospital de Basurto. Los pacientes fueron seleccionados para la cirugia en funcion de la combinacion de la estadificacion clinica, niveles de PSA serico y datos obtenidos de la biopsia previa. Los datos obtenidos en las prostatectomias se correlacionaron (rho de Spearman) con varios hallazgos histologicos procedentes de las biopsias. Resultados Se detecto invasion seminal en 37 pacientes (10,2%). La invasion microscopica de las vesiculas seminales se correlaciono con los milimetros totales de cancer (media 20 mm, ρ=0,397), con el numero de focos de tumor (media 3,8, ρ=0,383), con la invasion de ambos lados prostaticos (ρ=0,256), con el indice de Gleason >7 (ρ=0,306), con la invasion perineural (ρ=0,318), y con el PIN de alto grado (ρ=0,142) en las biopsias, y con el indice de Gleason >7 (ρ=0,357), con el PIN de alto grado (ρ=0,211), con la extension extraprostatica (ρ=0,480), y con la invasion de margenes quirurgicos (ρ=0,287), invasion perineural (ρ=0,847), y afectacion del apex (ρ=0,307), en las prostatectomias. Conclusiones La invasion de las vesiculas seminales es un hallazgo frecuente en las piezas de prostatectomia radical, incluso despues de una seleccion correcta de pacientes para cirugia. Este hallazgo histologico se correlaciona con parametros de volumen tumoral, con la invasion bilateral, y con otros parametros de mal pronostico en el cancer de prostata.

Extracellular vesicles (EV) are emerging structures with promising properties for intercellular communication. In addition, the characterization of EV in biofluids is an attractive source of non-invasive diagnostic, prognostic and predictive biomarkers. Here we show that urinary EV (uEV) from prostate cancer (PCa) patients exhibit genuine and differential physical and biological properties compared to benign prostate hyperplasia (BPH). Importantly, transcriptomics characterization of uEVs led us to define the decreased abundance of Cadherin 3, type 1 (CDH3) transcript in uEV from PCa patients. Tissue and cell line analysis strongly suggested that the status of CDH3 in uEVs is a distal reflection of changes in the expression of this cadherin in the prostate tumor. CDH3 was negatively regulated at the genomic, transcriptional, and epigenetic level in PCa. Our results reveal that uEVs could represent a non-invasive tool to inform about the molecular alterations in PCa.

To analyze the diagnostic accuracy of ultrasound-guided core-needle biopsy (CNB) of thyroid nodules.Of 3517 CNBs performed using an 18G spring-loaded device in one institution, we retrospectively reviewed 676 nodules in 629 consecutive patients who underwent surgery. CNB and pathological examination were compared. CNB diagnosis was standardized in four categories: insufficient (I), benign (B), follicular lesion (FOL), and malignant (M). Main outcome measures were predictive positive values (PPV), false positives (FP), and false negatives (FN).CNB showed a low rate of insufficient and FOL diagnoses (5.8 % and 4.5 %). On surgery, there were eight FNs in 374 benign CNBs and three FPs in 148 malignant CNBs. The 154 nodules classified as FOL in CNB included, at surgery, 122 neoplasms; 28 of them malignant. PPV for malignancy of a malignant CNB was 98 %, and for a CNB diagnosis of FOL 18.2 %. Sensitivity for malignancy if CNB of FOL and M are considered positive was 95.6. Only one major complication was observed.CNB is reliable, safe, and accurate to evaluate thyroid nodules and can be an alternative technique to FNA. It has low rate of non-diagnostic and undetermined cases, with high sensitivity and PPV.Thyroid core-needle biopsy (CNB) has high sensitivity and PPV. Pitfalls of CNB are rare. Pitfalls are due to cystic cancer, histological heterogeneity, and mistakes in analysis. CNB is a reliable, safe, and accurate method to approach thyroid nodules. CNB can be used primarily or after insufficient or indeterminate FNA.

Nature Cell Biology 18, 645–656 (2016); published online 23 May 2016; corrected after print 22 May 2017 In the original version of this Article, the name of author James David Sutherland was coded wrongly, resulting in it being incorrect when exported to citation databases. This has now been corrected, though no visible changes will be apparent.

BACKGROUND: The plasmacytoid variant is a rare and controversial subtype of myoepithelioma that lacks myogenic differentation and the cytologic findings of which have not been reported previously. CASE: A 46-year-old man presented with a painless tumor located in the soft palate. Fine needle aspiration cytology (FNAC) showed odd-shaped cellular aggregates and single cells with round nuclei and finely granular cytoplasm resembling plasma cells together with strands of metachromatic stroma. The light, immunohistochemical and ultrastructural studies performed on the surgical specimen confirmed the initial cytologic diagnosis. CONCLUSION: Recognition of the cytologic findings of plasmacytoid myoepithelioma on needle aspirates allows a reliable and quick diagnosis that prompts correct management.

Aquagenic keratoderma is an infrequent condition characterized by translucent, smooth-surfaced papules and plaques and prominent eccrine ducts. It is limited to the palms and appears or becomes more pronounced after exposure to water. Histopathologically, hyperkeratosis and dilation of the eccrine ducts are seen. This condition has been described in adolescents and young women. We present the case of a 31-year-old woman with rheumatoid arthritis who had begun treatment with celecoxib one month before the onset of her cutaneous symptoms. Similar changes have been described in association with cystic fibrosis, and a case induced by rofecoxib has also been reported. Higher levels of sodium in the skin associated with celecoxib could increase the keratin's ability to take in water, and this may cause the clinical symptoms.

Urine extracellular vesicles are a valuable low-invasive source of information, especially for the cells of the genitourinary tract. In the search for biomarkers, different techniques have been developed to isolate and characterize the cargo of these vesicles. In the present work, we compare five of these different isolation methods (three commercial isolation kits, ultracentrifugation, and lectin-based purification) and perform miRNA profiling using a multiplex miRNA assay. The results showed high correlation through all isolation techniques, and 48 out of 68 miRNAs were detected above the detection limit at least 10 times. The results obtained by multiplex assay were validated through Taqman qPCR. In addition, using this technique combined with a clinically friendly extracellular vesicle (uEV)-enrichment method, we performed the analysis of selected miRNAs in urine from patients affected with bladder cancer, benign prostate hyperplasia, or prostate cancer. Importantly, we found that those miRNAs could be detected in almost 100% of the samples, and no significant differences were observed between groups. Our results support the feasibility of analyzing exosomes-associated miRNAs using a methodology that requires a small volume of urine and is compatible with a clinical environment and high-throughput analysis.

The presence of CB1 and CB2 cannabinoid receptors and their physiological role in the kidney has been described in animal models but not in humans. Our aim in this study was to evaluate the presence of these receptors in human kidney, adult and fetal. For this purpose, RT-PCR, western-blot and immunohisto-chemical assays were performed. RT-PCR confirmed the presence of CB1 receptor mRNA receptor and the absence of the CB2 receptor mRNA in adult and fetal kidney. Western-blot and immunohistochemical assays revealed the presence of the CB1 cannabinoid receptor protein, which displayed a similar distribution in fetal and adult kidneys. Proximal and distal convoluted tubule cells and intercalated cells in the collecting ducts showed marked positivity. Conversely, the CB2 cannabinoid receptor protein was consistently negative in all cases. Our data suggest a possible implication of the endocannabinoid system in the physiology and development of the human kidney.

Renal cancer is one of the ten most common malignant tumours in humans and its histological classification, best clinical management and treatment strategies are continuously debated. Roughly 10% of renal carcinomas are papillary renal cell carcinomas (RCCs), a histologically well characterized tumour subtype that is linked to alterations on chromosomes 7 and 17. Peptidases are proteolytic enzymes known to be involved in oncological processes, although their precise role in renal cancer is poorly understood.Eighteen papillary RCCs were selected for the study. Tumour and normal tissue samples were frozen for enzymatic analysis. The catalytic activity for a pool of peptidases (EC numbers: 3.4.11.14; 3.4.11.2; 3.4.11.6; 3.4.11.21; 3.4.11.7; 3.4.14.5; 3.4.24.11; 3.4.21.26; 3.4.19.3) was measured fluorometrically.Statistically significant decreases were observed in the following cell surface activities: EC.3.4.11.2 (six-fold decrease in tumour vs. non-tumour); 3.4.11.6 (five-fold decrease); 3.4.11.7 (eight-fold decrease); 3.4.24.11 (four-fold decrease). No significant alterations were observed in the soluble activities.These data confirm the involvement of cell-surface peptidases in the mechanisms underlying RCC aetiogenesis and suggest that the peptidase activity profile in the RCC may be a diagnostic/prognostic marker.

Objective: To characterize a large series of renal cell carcinomas (RCCs) in young patients and to compare the data obtained to previously published data. Patients and Methods: A total of 130 RCCs diagnosed in patients Results: Histologically, tumors were classified as clear cell (50.7%), papillary (8.5%), chromophobe (14.6%), unclassified (16.9%) and clear cell papillary (9.3%) RCCs. Organ-confined disease (OCD) was detected in 83.6% of the cases. Tumor size and Fuhrman’s grade were statistically correlated (Spearman’s ρ = 0.391). CD10 (p = 0.000), CK7 (p = 0.000), CD15 (p = 0.016), CD117 (p = 0.000), 34βE12 cytokeratin (p = 0.034) and e-cadherin (p = 0.000) immunostaining significantly differentiated the five histological categories. Conclusions: OCD was more common in young RCC patients. The clear cell phenotype accounted for only 50% of RCCs in this age group, with an increasing number of chromophobe and unclassified RCCs. Clear cell RCCs with a papillary growth pattern accounted for a significant proportion of the cases.

Aquagenic keratoderma is an infrequent condition characterized by translucent, smooth-surfaced papules and plaques and prominent eccrine ducts. It is limited to the palms and appears or becomes more pronounced after exposure to water. Histopathologically, hyperkeratosis and dilation of the eccrine ducts are seen. This condition has been described in adolescents and young women. We present the case of a 31-year-old woman with rheumatoid arthritis who had begun treatment with celecoxib one month before the onset of her cutaneous symptoms. Similar changes have been described in association with cystic fibrosis, and a case induced by rofecoxib has also been reported. Higher levels of sodium in the skin associated with celecoxib could increase the keratin's ability to take in water, and this may cause the clinical symptoms.

10529 Background: Pathogenesis in GIST could be related to cancer stem cell hypothesis (highly chemo resistant, very uncommon complete responses, kit is stem cell marker) even though no stem cell component in GIST has been yet demonstrated. Wnt signaling regulates proliferation in some normal and cancer stem cells as it occurs with intestinal epithelium. We have explored the prognostic significance of several Wnt signaling pathway and related molecules. To investigate the prognostic significance of β-Catenin, CDC25A, ROR2, p53, CUL4A, AKT-p and VEGFR-3 by immunohistochemical (IHC) analysis in TMA specimens of 101 non-gastric GIST. Methods: Data of diagnostic, therapeutic and follow-up procedures stem from the GIST Registry of GEIS. Cytoplasmic and/or membrane staining was deemed positive for ROR-2, VEGFR-3 and p-AKT antibodies whereas nuclear staining was positive for β-Catenin, CDC25A, CUL4A and p53 antibodies. IHC positive cases were considered if they displayed staining in at least 10% of cells. Statistical analyses for correlation of protein expression with known prognostic variables (mitoses, size) were performed with Mann-Whitney U test. Results: A subset of 101 non-gastric localized GIST patients was selected (90 intestinal, 15 others: mainly rectum and omentum). The median age was 62 y with gender distribution of 59M/42F and the median of follow-up was 36 months. The positivity for each protein was distributed as follows: ROR-2 63%, p-AKT 55%, β-Catenin 53%, VEGFR-3 22%, CDC25A 20%, p53 8% and CUL4A 7%. A statistically significant correlation was found between mitoses and β-Catenin (median 5 if negative/ 10 if positive, p=0.028); VEGFR-3 (median 5 if negative/21 if positive, p=0.002); CUL4A (median 6 if negative/60 if positive, p= 0.027). Additionally, tumor size was statistically correlated with VEGFR-3 (median 7 if negative/11 if positive, p=0.007). Conclusions: VEGFR-3, β-Catenin and CUL4A are correlated with the highest proliferative non-gastric GIST. These findings deserve further analysis and lead to potential new molecular therapeutic targets in GIST. This study was partially granted by Buesa Grant of GEIS.