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Cryptorchidism is one of the most frequent problems encountered in pediatric urology. Its causes, associated lesions, and prognosis in terms of fertility have been a source of interest and discrepancies for pediatric pathologists and urological surgeons.

One of the most challenging areas in pediatric testicular pathology is the appropriate understanding and pathological diagnosis of disorders of sexual development (DSD), and in particular, the issue of gonadal dysgenesis. Here we present the main concepts necessary for their understanding and appropriate classification, with extensive genetic correlations.

Normal male development requires three conditions: (1) adequate differentiation of the fetal testis; (2) synthesis and secretion of testicular hormones; and (3) effective action of these hormones on target organs. This requires the combined action of the inhibitory anti-müllerian hormone (AMH, secreted by Sertoli cells) to block the development of the uterus and fallopian tubes from the müllerian duct, together with the trophic stimulus of testosterone (a Leydig cell product), which leads to virilization of the wolffian ducts. Additionally, the development of external genitalia depends on the conversion of testosterone to dihydrotestosterone by the enzyme 5-α-reductase. Failure of any of these mechanisms leads to deficient virilization or the so-called "male pseudohermaphroditism" syndromes.

Aims: To study the mechanisms of pluripotency induction, we compared gene expression in pluripotent embryonic germ cells (EGCs) and unipotent primordial germ cells (PGCs)., Results: We found 11 genes ≥1.5-fold overexpressed in EGCs. None of the genes identified was the Yamanaka genes but instead related to glycolytic metabolism. The prospect of pluripotency induction by cell metabolism manipulation was investigated by hypoxic culturing. Hypoxia induced a glycolytic program in PGCs in detriment of mitochondrial oxidative phosphorylation. We demonstrate that hypoxia alone induces reprogramming in PGCs, giving rise to hypoxia-induced EGC-like cells (hiEGLs), which differentiate into cells of the three germ layers in vitro and contribute to the internal cell mass of the blastocyst in vivo, demonstrating pluripotency. The mechanism of hypoxia induction involves HIF1α stabilization and Oct4 deregulation. However, hiEGL cannot be passaged long term. Self-renewal capacity is not achieved by hypoxia likely due to the lack of upregulation of c-Myc and Klf4. Gene expression analysis of hypoxia signaling suggests that hiEGLs have not reached the stabilization phase of cell reprogramming., Innovation and Conclusion: Our data suggest that the two main properties of stemness, pluripotency and self-renewal, are differentially regulated in PGC reprogramming induced by hypoxia.

Myxoid/round cell liposarcoma is a soft tissue sarcoma that is extremely rare in the brachial plexus. We report a case of a myxoid/round cell liposarcoma originating in the brachial plexus that was surgically resected and evolved well, with no deficit or recurrence after 2 years of follow-up. To date, there has been no other case of this sarcoma in the literature., (Copyright © 2014 Sociedad Española de Neurocirugía. Published by Elsevier España. All rights reserved.)

Pulmonary aspergillosis is a fungal infection usually caused by inhaling Aspergillus fumigatus spores. However, when we talk about aspergillosis, we normally refer to the spectrum of clinical and radiological findings that depend directly on the patient's immune status, on the prior existence of lung disease, and on the virulence of the infective organism. There are four types of pulmonary aspergillosis (aspergilloma, allergic bronchopulmonary aspergillosis, chronic necrotizing pulmonary aspergillosis, and invasive aspergillosis), and each type has its own distinct radiologic findings. We review the signs of pulmonary aspergillosis on multidetector computed tomography and we correlate them with patients' symptoms and immune responses. Likewise, we discuss the differential diagnoses., (Copyright © 2013 SERAM. Published by Elsevier Espana. All rights reserved.)

Abstract The testis is a complex organ that undergoes significant changes from puberty to adulthood. An accurate knowledge of its histology, ultrastructure and physiological-morphological maturation process is required in order to interpret the many variations within the normal and abnormal (pathological) conditions. Here we describe in detail the different testicular compartments, showing correlations with the process of spermatogenesis at the histological and ultrastructural level.

The stromal vascular fraction (SVF) of adipose tissue is an easy to obtain source of adipose tissue-derived stem cells (ADSCs). We and others have achieved significant but suboptimal therapeutic effects with ADSCs in various settings, mainly due to low rates of differentiation into specific cell types and with the downside of undesired side effects as a consequence of the undifferentiated ADSCs. These data prompted us to find new stem cell-specific markers for ADSCs and/or subpopulations with higher differentiation potential to specific lineages. We found a subpopulation of human ADSCs, marked by c-Kit positiveness, resides in a perivascular location, and shows higher proliferative activity and self-renewal capacity, higher telomerase activity and expression, higher in vitro adipogenic efficiency, a higher capacity for the maintenance of cardiac progenitors, and higher pancreatogenic and hepatogenic efficiency independently of CD105 expression. Our data suggests that the isolation of ADSC subpopulations with anti-c-Kit antibodies allows for the selection of a more homogeneous subpopulation with increased cardioprotective properties and increased adipogenic and endodermal differentiation potential, providing a useful tool for specific therapies in regenerative medicine applications., (Copyright © 2014 International Society of Differentiation. Published by Elsevier B.V. All rights reserved.)

Acute pancreatitis (AP) is a serious medical condition usually associated with severe upper abdominal pain. The purpose of our study is to assess the therapeutic consequences of contrast-enhanced computed tomography (CE-CT) and the predictive value of CRP for severe pancreatitis. We included patients with a threefold increase of plasma lipase who had received a CE-CT or had a CRP of =150 mg/dl. A total of 74 out of 283 patients got a contrast-enhanced CT scan; in 11 cases the CT was followed by endoscopic or surgical interventions as therapeutic consequences compared with 19 out of 50 control cases. 69 out of 283 patients (24,3%) had CRP >150 mg/dl within 48 hours after admission. 32 of them had SAP. The CRP cutoff of 150 mg/L had a sensitivity of 80% and a specificity of 65%. The positive predictive value for SAP in patients beyond the cutoff is 46.4%. The negative predictive value for SAP in patients below the cutoff was 89.5%. Our results support the opinion that an early CE-CT is usually not indicated. CRP helps to assess the course of AP; levels below 150 mg/dl between the first 48 h indicate a mild course in most of the cases.

Studies over the last years show an increase in testicular cancer, hypospadias and cryptorchidism in industrial countries, leading to the concept of testicular dysgenesis syndrome (TDS). It is hypothesized that TDS is caused by estrogen and antiandrogen exposure during fetal life, accompanied by incomplete maturation of testicular Sertoli cells (SC). However, it is not known if SC disruption is a primary cause or a response to fetal Leydig cell testosterone production changes. To determine if SC differentiation is directly affected by estrogens, we compared SC maturation between adult gender reassignment cases exposed to estrogen and antiandrogen therapy, and those of typical TDS in adult cryptorchidism. We found similar expression of immature SC markers M2A antigen, inhibin bodies and Anti Mullerian Hormone, and the absence of maturation marker androgen receptor in SC of both types of patients. These data supports the occurrence of true SC dedifferentiation caused by estrogen exposure in adult humans. Our data also suggests that SC maturation is directly disrupted in TDS., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Although many cancers initially respond to cisplatin (CDDP)-based chemotherapy, resistance frequently develops. Insulin-like growth factor-binding protein-3 (IGFBP-3) silencing by promoter methylation is involved in the CDDP-acquired resistance process in non-small cell lung cancer (NSCLC) patients. Our purpose is to design a translational-based profile to predict resistance in NSCLC by studying the role of IGFBP-3 in the phosphatidyl inositol 3-kinase (PI3K) signaling pathway. We have first examined the relationship between IGFBP-3 expression regulated by promoter methylation and activation of the epidermal growth factor receptor (EGFR), insulin-like growth factor-I receptor (IGFIR) and PI3K/AKT pathways in 10 human cancer cell lines and 25 NSCLC patients with known IGFBP-3 methylation status and response to CDDP. Then, to provide a helpful tool that enables clinicians to identify patients with a potential response to CDDP, we have calculated the association between our diagnostic test and the true outcome of analyzed samples in terms of cisplatin IC50; the inhibitory concentration that kills 50% of the cell population. Our results suggest that loss of IGFBP-3 expression by promoter methylation in tumor cells treated with CDDP may activate the PI3K/AKT pathway through the specific derepression of IGFIR signaling, inducing resistance to CDDP. This study also provides a predictive test for clinical practice with an accuracy and precision of 0.84 and 0.9, respectively, (P=0.0062). We present a biomarker test that could provide clinicians with a robust tool with which to decide on the use of CDDP, improving patient clinical outcomes.

Context: Steroidogenic factor-1 (SF-1/NR5A1) is a nuclear receptor that regulates adrenal and reproductive development and function. NR5A1 mutations have been detected in 46,XY individuals with disorders of sexual development (DSD) but apparently normal adrenal function and in 46,XX women with normal sexual development yet primary ovarian insufficiency (POI)., Objective: A group of 100 46,XY DSD and two POI was studied for NR5A1 mutations and their impact., Design: Clinical, biochemical, histological, genetic, and functional characteristics of the patients with NR5A1 mutations are reported., Setting: Patients were referred from different centers in Spain, Switzerland, and Turkey. Histological and genetic studies were performed in Barcelona, Spain. In vitro studies were performed in Bern, Switzerland., Patients: A total of 65 Spanish and 35 Turkish patients with 46,XY DSD and two Swiss 46,XX patients with POI were investigated., Main Outcome: Ten novel heterozygote NR5A1 mutations were detected and characterized (five missense, one nonsense, three frameshift mutations, and one duplication)., Results: The novel NR5A1 mutations were tested in vitro by promoter transactivation assays showing grossly reduced activity for mutations in the DNA binding domain and variably reduced activity for other mutations. Dominant negative effect of the mutations was excluded. We found high variability and thus no apparent genotype-structure-function-phenotype correlation. Histological studies of testes revealed vacuolization of Leydig cells due to fat accumulation., Conclusions: SF-1/NR5A1 mutations are frequently found in 46,XY DSD individuals (9%) and manifest with a broad phenotype. Testes histology is characteristic for fat accumulation and degeneration over time, similar to findings observed in patients with lipoid congenital adrenal hyperplasia (due to StAR mutations). Genotype-structure-function-phenotype correlation remains elusive.

Small cell lung cancer is the most aggressive lung cancer subtype. The standard treatment approach is based on cisplatin regimens. Although response rates to treatment are approximately 60-80%, the median survival is still very poor. Excision repair cross complementation group 1 (ERCC1) is an enzyme that removes cisplatin-induced DNA adducts and has been related with prognosis and cisplatin response. Topotecan is the standard treatment as second-line therapy and it is an inhibitor of topoisomerase I (TOP I). We selected 76 patients with small cell lung (SCLC) to analyze the ERCC1 and TOP I mRNA expression. ERCC1 was studied both by quantitative PCR and immunohistochemistry. A significant association was found between the inmunohistochemistry expression of ERCC1 and the lack of platinum response (p=0.001). Moreover, low levels of TOP I RNA were shown to be linked to cisplatin response (p=0.002). In the survival analysis, a significant correlation between a better PFS with a low TOP I RNA expression as well as a negative ERCC1 inmunostaining were found, in both cases with a significant p-value (p=0.02 and 0.009, respectively). In summary, our results suggest the use of ERCC1 immunohistochemistry and TOP I mRNA analysis to predict cisplatin response and prognosis in SCLC patients.

With the completion of the human genome sequence, biomedical sciences have entered in the "omics" era, mainly due to high-throughput genomics techniques and the recent application of mass spectrometry to proteomics analyses. However, there is still a time lag between these technological advances and their application in the clinical setting. Our work is designed to build bridges between high-performance proteomics and clinical routine. Protein extracts were obtained from fresh frozen normal lung and non-small cell lung cancer samples. We applied a phosphopeptide enrichment followed by LC-MS/MS. Subsequent label-free quantification and bioinformatics analyses were performed. We assessed protein patterns on these samples, showing dozens of differential markers between normal and tumor tissue. Gene ontology and interactome analyses identified signaling pathways altered on tumor tissue. We have identified two proteins, PTRF/cavin-1 and MIF, which are differentially expressed between normal lung and non-small cell lung cancer. These potential biomarkers were validated using western blot and immunohistochemistry. The application of discovery-based proteomics analyses in clinical samples allowed us to identify new potential biomarkers and therapeutic targets in non-small cell lung cancer.

Hearing loss is the most common symptom in patients with vestibular schwannoma (VS). In the past, compressive mechanisms caused by the tumoral mass and its growth have been regarded as the most likely causes of the hearing loss associated with VS. Interestingly, new evidence proposes molecular mechanisms as an explanation for such hearing loss. Among the molecular mechanisms proposed are methylation of TP73, negative expression of cyclin D1, expression of B7-H1, increased expression of the platelet-derived growth factor A, underexpression of PEX5L, RAD54B, and PSMAL, and overexpression of CEA. Many molecular mechanisms are involved in vestibular schwannoma development; we review some of these mechanisms with special emphasis on hearing loss associated with vestibular schwannoma.

Protein phosphorylation affects most eukaryotic cellular processes and its deregulation is considered a hallmark of cancer and other diseases. Phosphoproteomics may enable monitoring of altered signaling pathways as a means of stratifying tumors and facilitating the discovery of new drugs. Unfortunately, the development of molecular tests for clinical use is constrained by the limited availability of fresh frozen, clinically annotated samples. Here we report phosphopeptide analysis in human archival formalin-fixed, paraffin-embedded (FFPE) cancer samples based on immobilized metal affinity chromatography followed by liquid chromatography coupled with tandem mass spectrometry and selected reaction monitoring techniques. Our results indicate the equivalence of detectable phosphorylation rates in archival FFPE and fresh frozen tissues. Moreover, we demonstrate the applicability of targeted assays for phosphopeptide analysis in clinical archival FFPE samples, using an experimental workflow suitable for processing and analyzing large sample series. This work paves the way for the application of shotgun and targeted phosphoproteomics approaches in clinically relevant studies using archival clinical samples.

According to International Society for the Study of Vascular Anomalies classification, vascular anomalies are mainly divided into two groups: vascular tumors and vascular malformations. Nevertheless, a small group of patients present clinical and/or histopathologic overlapping features. We report a case of a 4-month-old boy that presented a vascular lesion on his right buttock with involvement of abdominal wall muscles, abdominal cavity and drainage to primitive iliac by a tortuous drainage vein. Surgery was performed and histopathology demonstrated a combined vascular malformation. Six months later he developed a thrombocytopenia and repeat magnetic resonance imaging revealed a new solid mass involving the majority of the abdominal cavity. At 18 months of age the patient developed a Kasabach-Merrit phenomenon and treatment with vincristine, interferon and then acetyl-salicilic acid and dypiridamol was started. No response in platelet counts was obtained and one more surgery was perfomed. On this occasion a histopathologic study revealed vascular malformation areas intermingled with areas of kaposiform hemangioendothelioma. This patient demonstrates the Kasabach-Merritt phenomenon with kaposiform hemangioendothelioma arising within a pre-existing combined vascular malformation., (© 2010 Wiley Periodicals, Inc.)

Aim: To study the ability of human adipose-derived mesenchymal stem cells (AMSCs) to survive over the short and long term, their biodistribution and their biosafety in vivo in tumor-prone environments., Methods: We subcutaneously injected human AMSCs from different human donors into immunodeficient SCID mice over both short- (2 and 4 mo) and long- (17 mo) term in young, and aged tumor-prone mice. Presence of human cells was studied by immunohistochemistry and polymerase chain reaction analysis in all organs of injected mice., Results: Subcutaneously injected AMSCs did not form teratomas at any time point. They did not migrate but remained at the site of injection regardless of animal age, and did not fuse with host cells in any organ examined. AMSCs survived in vivo for at least 17 mo after injection, and differentiated into fibroblasts of the subdermic connective tissue and into mature adipocytes of fat tissue, exclusively at the site of injection., Conclusion: Our results support the assertion that AMSC may be safe candidates for therapy when injected subcutaneously because of their long term inability to form teratomas.

Aims: To provide a marker for immature and dysgenetic Sertoli cells which allows easy identification in patients in which Sertoli cell maturation does not take place properly, such as those consulting for cryptorchidism, testicular tumours and infertility., Methods and Results: We performed immunohistochemistry against inhibin-α subunit and the endoplasmic reticulum marker Grp78 in normal human testes from fetal life to adulthood, and in several testicular lesions where Sertoli cell maturation is abnormal. We describe a pattern of inhibin immunostain (inhibin bodies of 2-9 μm in diameter at the Sertoli cells cytoplasm apical pole) in immature and dysgenetic Sertoli cells that facilitates their identification. Inhibin bodies were found in tubules with either no germ cells or only spermatogonia or carcinoma in situ (CIS) and seminoma cells, but not in tubules containing more advanced germ cells., Conclusions: Our data provide a new marker of immature and dysgenetic Sertoli cells. In addition, our data suggest that inhibin bodies represent a slower transit of inhibin through the endoplasmic reticulum, as inhibin bodies were associated with Grp78., (© 2011 Blackwell Publishing Limited.)

Spindle cell neoplasms arising in the testis are uncommon; most cases belong to the category of gonadal stromal tumors, and the presence of distinctive clinical and pathological features usually lead to a definitive diagnosis. In some instances, however, the diagnosis of these tumors can be challenging and special techniques are needed. The present study reports 2 unusual cases of primary intratesticular tumors showing a striking morphology, characterized by spindle to stellate cells in a lymphoid background. The diagnosis of interdigitating dendritic cell tumor and inflammatory myofibroblastic tumor was established in the 2 cases, and their probable origin in cells of the accessory immune system is discussed. Although both tumors share similar histological features, their immunohistochemical profiles were decisive for a definitive diagnosis.

Aims: To investigate the clinical and prognostic significance of Aurora B in laryngeal squamous cell carcinomas (LSCC)., Methods and Results: Aurora B protein expression was analysed in 259 LSCC. The proliferation index (Ki67) and the expression of other cell cycle control proteins, such as Aurora A, survivin and p53 was also determined. Aurora B was highly expressed in 55.4% of LSCC. High Aurora B expression levels were correlated with tumour recurrence (P=0.01), death from disease (P=0.05) and decreased disease-free survival (P=0.013) and overall survival (P=0.04). Survivin expression was neither associated with clinicopathological characteristics nor with survival. However, survivin expression in the nucleus paralleled Aurora B expression (P=0.014). Aurora A expression was associated significantly with increased tumour grade (P=0.008). Multivariate analysis indicated that Aurora B was an independent predictor for LSCC-specific disease-free survival [hazard ratio (HR), 2.10; 95% confidence interval (95% CI), 1.25-3.52 (P=0.005)] and overall survival [HR, 1.91; 95% CI 1.01-3.34 (P=0.023)]., Conclusions: Aurora B may be a novel prognostic biomarker for LSCC and a potential therapeutic target in this type of tumour., (© 2011 Blackwell Publishing Limited.)

Pulmonary hypertension is characterized by progressive involvement of the pulmonary vessels that leads to increased vascular resistance and consequently to right ventricular failure. Vascular lesions are a common factor in a wide spectrum of diseases, and their result, pulmonary hypertension, is a severe clinical condition with a poor prognosis that worsens the normal course of the diseases to which it is associated (COPD, collagen disease, sarcoidosis, and congenital or acquired heart disease). It is important for pulmonary hypertension to be diagnosed as early as possible because nowadays drugs can reduce mortality and improve the quality of life; furthermore, some types of pulmonary hypertension (e.g., chronic thromboembolism and those associated with some congenital heart diseases like left-to-right shunt) can be treated surgically. In cases of suspected pulmonary hypertension, imaging methods can confirm the diagnosis, suggest a cause, help choose the most appropriate treatment, and monitor the response to treatment. This review describes the approach to pulmonary hypertension using different imaging techniques; special emphasis is given to the role of multidetector CT (MDCT), which makes it possible to study all the organs in the thorax in a single acquisition. We review the radiological signs of pulmonary hypertension and the current (Dana Point) radiological criteria for classifying the type of hypertension based on alterations in the lung parenchyma, mediastinum, pleural spaces, and pericardium, as well as on the study of the chambers of the heart., (Copyright © 2010 SERAM. Published by Elsevier Espana. All rights reserved.)

Cyclin E is a key component of the cell cycle regulatory machinery, contributing to the activation of Cdk2 and the control of cell cycle progression at several stages. Cyclin E expression is tightly regulated, by periodic transcription and ubiquitin-mediated degradation. Overexpression of cyclin E has been associated with tumor development and poor prognosis in several tumor types, including germ cell tumors and both cyclin E and its partner Cdk2 are required for normal spermatogenesis. Here we have generated and characterized transgenic mice overexpressing a cyclin E mutant protein, resistant to ubiquitin-mediated proteolysis, in testicular germ cells, under the control of the human EF-1alpha promoter. The transgenic mice develop normally and live a normal life span, with no signs of testicular tumor development. The transgenic mice display however reduced fertility and testicular atrophy, due to reduced spermatogonial proliferation as a consequence of deregulated cyclin E levels. Overall our results show that deregulation of cyclin E expression contribute to infertility, due to inability of the spermatogonial cells to start the mitotic cycles prior to entering meiosis.

Congenital heart disease is relatively common among adults. Patients' conditions have generally been diagnosed previously and imaging tests are requested for follow-up or for complications of the anomaly or of its surgical correction. Classically, these patients were studied with echocardiography and cardiac catheterization, but multidetector CT and magnetic resonance imaging have changed the approach because these techniques show the anatomy of heart defects and their correction very clearly. We emphasize the importance of multidetector CT as a complementary technique for the study of congenital heart disease that is newly discovered in adults or for the follow-up of congenital heart disease that was surgically corrected during childhood. When vascular anomalies are present outside the heart or after palliative surgery, multidetector CT shows anatomical details that are difficult or impossible to see with echocardiography. We also emphasize the frequent association between pulmonary hypertension and congenital heart disease that can debut in adults., (Copyright © 2009 SERAM. Published by Elsevier Espana. All rights reserved.)

The occurrence of congenital epididymal malformations with a cystic component has not been fully characterized. Most epididymal cysts occur later in life and are likely acquired. In addition, congenital malformations of the male excretory system are extremely uncommon in fetuses and neonates, and epididymal dysplastic changes have not been reported in these cases. In this study, we report 20 cases (including 19 fetal/neonatal autopsies and one surgical specimen from an older child) showing the same spectrum of histological findings in the epididymis, characterized by cystic ductal dilation with dysplastic ducts of variable diameters and irregular shapes, with ill-defined walls. Efferent ductules also showed dysplastic features. In addition, 18 cases had either renal and/or urinary tract anomalies, including renal dysplasia (eight), pelvicaliceal dilation (eight), renal agenesis (four) and hypoplasia (one), ureteral agenesis (two) and hypoplasia (one), urethra and bladder agenesis (two), prostate agenesis (two), and autosomal recessive polycystic renal disease (two). Our observations led to the recognition of a peculiar, not previously described congenital lesion of the epididymis, and we propose the term cystic dysplasia of the epididymis for this anomaly. Similar to what is observed in other male genital system anomalies (including malformations of the rete testis, vas deferens, and seminal vesicles), most lesions occurred in association with renal and/or urinary tract malformations, suggesting a spectrum of congenital malformations. The shared embryological origin of these structures may explain their simultaneous occurrence, possibly related to disrupted mesonephric duct development.

Background: Cerebellar metastasis (CM) from papillary thyroid carcinoma (PTC) is exceptional with only 12 reported cases and usually carries a very poor prognosis. In the two previously reported patients in whom CM was detected before PTC, other distant or local metastases were already present by the time of PTC diagnosis. We report a patient found to have papillary thyroid microcarcinoma after surgical resection and histopathological study of a large solitary hemorrhagic CM, who showed no evidence of other metastatic sites and survived 7 years after initial diagnosis., Summary: A 65-year-old female patient with a history of surgical resection of a 7-cm cerebellar mass diagnosed with PTC metastasis, and adjuvant treatment with cranial external radiotherapy, was referred to us. The neck ultrasonography showed a solitary 4-mm right thyroid nodule. Histopathology after total thyroidectomy revealed a 2-mm papillary thyroid microcarcinoma, sclerosing variant, with capsule infiltration but no regional lymph node invasion. Although she received a total dose of 500 mCi of 131-I after surgery and the last two whole-body scans were normal, serum thyroglobulin levels progressively increased. The patient refused any further test or treatment other than basal blood sampling and suppressive therapy with levothyroxine and remained stable for 4 years until she started to complain about deviation of her walk. A computed tomography scan showed a regrowth of the metastasis. She suffered a sudden worsening of her neurological status because of a big intratumoral hemorrhage that required decompressive craniectomy and hematoma evacuation surviving 3 years more after this episode., Conclusions: To our knowledge, this is the first reported case of a solitary CM from an occult PTC, and also the first that developed an acute cerebellar hemorrhage years after cranial surgery, however, exhibiting the longest reported survival. This case highlights the importance of not only an appropriate initial treatment of the CM and primary PTC in these patients, but also a close follow-up, to avoid further complications and improve their prognosis.

Cisplatin-based chemotherapy is the paradigm of non-small-cell lung cancer (NSCLC) treatment; however, it also induces de novo DNA-hypermethylation, a process that may be involved in the development of drug-resistant phenotypes by inactivating genes required for drug-cytotoxicity. By using an expression microarray analysis, we aimed to identify those genes reactivated in a set of two cisplatin (CDDP) resistant and sensitive NSCLC cell lines after epigenetic treatment. Gene expression, promoter methylation and CDDP-chemoresponse were further analyzed in three matched sets of sensitive/resistant cell lines, 23 human cancer cell lines and 36 NSCLC specimens. Results revealed specific silencing by promoter hypermethylation of IGFBP-3 in CDDP resistant cells, whereas IGFBP-3 siRNA interference, induced resistance to CDDP in sensitive cells (P<0.001). In addition, we found a strong correlation between methylation status and CDDP response in tumor specimens (P<0.001). Thus, stage I patients, whose tumors harbor an unmethylated promoter, had a trend towards increased disease-free survival (DFS). We report that a loss of IGFBP-3 expression, mediated by promoter-hypermethylation, results in a reduction of tumor cell sensitivity to cisplatin in NSCLC. Basal methylation status of IGFBP-3 before treatment may be a clinical biomarker and a predictor of the chemotherapy outcome, helping to identify patients who are most likely to benefit from CDDP therapy alone or in combination with epigenetic treatment.

Plasma concentrations of inhibin are correlated with spermatogenetic function. Inhibin is secreted mainly by the Sertoli and Leydig cells of the testis. In the human epididymis, the location and function of inhibin are contentious. Thus, the aim of the present study was to determine the location of inhibin in the human epididymis. Investigations were performed in samples with normal testicular function at different stages of development, as well as in samples in which testicular function or the testicular-epididymal connection were altered. In fetal, newborn and infant testes, Sertoli and Leydig cells stained positive for inhibin, whereas no such staining was detected in the epididymides. Inhibin was located in both the Sertoli and Leydig cells, as well as in the epididymis, in the apical pole of mainly secretory cells in the efferent ducts. This staining pattern was not correlated with the staining pattern for macrophages. The main duct of the epididymis was negative for inhibin staining. In ischaemic atrophic testes, the few tubules in which Sertoli cells were present stained positive for inhibin, whereas the epididymides stained negative. In paediatric cryptorchidism, Sertoli and Leydig cells stained positive for inhibin, whereas the epididymides were negative. In adult cryptorchidism, Sertoli and Leydig cells stained positive for inhibin, even in tubules containing Sertoli cells only. Interestingly, inhibin was absent from the efferent ducts. In three cases undergoing hormonal treatment prior to subsequent gender change, Sertoli and Leydig cells stained positive for inhibin. In contrast, the efferent ducts were negative or only faintly positive in cases of shorter hormonal treatment. In all cases studied, the presence of inhibin in the efferent ducts was associated with its production in the testis, suggesting that the epididymis is not responsible for the production of inhibin in men. The pattern of inhibin staining does not correlate with that of macrophages, suggesting that inhibin is not degraded in the human epididymis. The data suggest that, in humans, inhibin is secreted by Sertoli cells into the seminiferous tubules and then travels towards the efferent ducts, where it is reabsorbed into the bloodstream.

Primary cardiac tumors are infrequent, less than 15-20% are malignant, and most of them are sarcomas. Primary recidivant cardiac osteosarcomas are extremely rare, only a few cases have been reported, and the prognosis is ominous. We report a case of a primary cardiac osteosarcoma in a 70-year-old woman who was admitted to the hospital for evaluation of congestive heart failure. Despite the wide resection of the tumor, a local and metastatic recurrence was diagnosed. In this report, we illustrate the utility of image techniques for the diagnosis and the monitoring of primary cardiac tumors, especially the role of bone scintigraphy. This technique is not a routine procedure for the cardiologist, but it has been very useful in this case in order to decide the optimal treatment.

Background: Proteomics is expected to play a key role in cancer biomarker discovery. Although it has become feasible to rapidly analyze proteins from crude cell extracts using mass spectrometry, complex sample composition hampers this type of measurement. Therefore, for effective proteome analysis, it becomes critical to enrich samples for the analytes of interest. Despite that one-third of the proteins in eukaryotic cells are thought to be phosphorylated at some point in their life cycle, only a low percentage of intracellular proteins is phosphorylated at a given time., Methodology/principal Findings: In this work, we have applied chromatographic phosphopeptide enrichment techniques to reduce the complexity of human clinical samples. A novel method for high-throughput peptide profiling of human tumor samples, using Parallel IMAC and MALDI-TOF MS, is described. We have applied this methodology to analyze human normal and cancer lung samples in the search for new biomarkers. Using a highly reproducible spectral processing algorithm to produce peptide mass profiles with minimal variability across the samples, lineal discriminant-based and decision tree-based classification models were generated. These models can distinguish normal from tumor samples, as well as differentiate the various non-small cell lung cancer histological subtypes., Conclusions/significance: A novel, optimized sample preparation method and a careful data acquisition strategy is described for high-throughput peptide profiling of small amounts of human normal lung and lung cancer samples. We show that the appropriate combination of peptide expression values is able to discriminate normal lung from non-small cell lung cancer samples and among different histological subtypes. Our study does emphasize the great potential of proteomics in the molecular characterization of cancer.

The activating mutation BRAF(V600E) is a frequent genetic event in papillary thyroid carcinomas (PTC) that predicts a poor prognosis, leading to loss of sodium/iodide symporter (NIS) expression and subsequent radioiodide-refractory metastatic disease. The molecular basis of such an aggressive behavior induced by BRAF remains unclear. Here, we show a mechanism through which BRAF induces NIS repression and promotes epithelial to mesenchimal transition and invasion based on the operation of an autocrine transforming growth factor (TGF)beta loop. BRAF induces secretion of functional TGFbeta and blocking TGFbeta/Smad signaling at multiple levels rescues BRAF-induced NIS repression. Although this mechanism is MAP/extracellular signal-regulated kinase (ERK) kinase (MEK)-ERK independent, secreted TGFbeta cooperates with MEK-ERK signaling in BRAF-induced cell migration, Matrigel invasion, and EMT. Consistent with this process, TGFbeta and other key components of TGFbeta signaling, such as TbetaRII and pSmad2, are overexpressed in human PTC, suggesting a widespread activation of this pathway by locally released TGFbeta. Moreover, this high TGFbeta/Smad activity is associated with PTC invasion, nodal metastasis, and BRAF status. Interestingly, TGFbeta is overexpressed in the invasive front, whereas NIS is preferentially expressed in the central regions of the tumors, suggesting that this negative correlation between TGFbeta and NIS occurs locally inside the tumor. Our study describes a novel mechanism of NIS repression in thyroid cancer and provides evidence that TGFbeta may play a key role in promoting radioiodide resistance and tumor invasion during PTC progression.

A total of 1482 adult ticks collected from vegetation and animals in central Spain in 2003-2005 were tested for the presence of Coxiella burnetii by polymerase chain reaction and subsequent reverse line blot hybridization (PCR-RLB). C. burnetii was identified in 7.7% of questing ticks (80/1039) and 3.4% of ticks collected from animals (15/443) belonging to four species: Hyalomma lusitanicum, Dermacentor marginatus, Rhiphicephalus sanguineus, and R. pusillus. These findings show an active role of ticks in maintaining C. burnetii in wild and peridomestic cycles in central Spain.

Objectives: To report the second case of solitary neurofibroma arising from the tunica albuginea in the literature and to show its imaging findings., Methods/results: We present a case of neurofibroma arising from the tunica albuginea in an adult patient not affected by neurofibromatosis. We describe the ultrasonographic and magnetic resonance imaging (MRI) features and the histopathological characteristics along with a brief bibliographic review., Conclusion: MRI may be useful to characterize paratesticular lesions. Neurofibroma should be included in the differential diagnosis when MRI depicts a well-circunscribed tumour with high-signal intensity on T2 and marked enhancement after gadolinium administration.

Systemic venous pressure is elevated in right heart failure, and this elevation may be reflected in pulsatile venous flow when there is significant tricuspid regurgitation. The presence of this systolic reversed flow in the femoral and popliteal veins may result in major difficulties for diagnosis and treatment. We report the case of a patient with signs and symptoms of acute ischemia of the right lower limb with palpable pulse in the groin and popliteal fossa. Tricuspid regurgitation was suspected by clinical examination, and Doppler ultrasonographic examination of the extremity revealed pulsatile flow in the femoral and popliteal veins while the iliac arterial axis was occluded. A preoperative angiogram revealed an underlying iliac artery thrombosis, which was successfully treated.

Estimates of the incidence of aortoenteric fistula as a sequela of surgery of the aorta range 1-2%. This complication is less common in patients who have had an aortic endograft implanted for aortoiliac aneurysm. We present three cases of aortoenteric fistula complicating endovascular treatment of abdominal aortic aneurysm (3/423 patients, 0.7% in our series).

Background: TWIST1 is a basic helix-loop-helix (bHLH) transcription factor that has been involved in tumor progression and metastasis in several cancer types, although no evidence has been provided yet on its implication in colorectal carcinogenesis., Methods: We examined the expression pattern of TWIST1 messenger RNA (mRNA) in 54 colorectal cancer biopsies compared with each respective adjacent normal mucosa by real-time reverse-transcriptase polymerase chain reaction (RT-PCR) methodology., Results: TWIST1 mRNA was found significantly overexpressed in colorectal cancer samples compared to nontumorous colon mucosa (P < 0.0001). Receiver operating characteristic (ROC) curve analysis demonstrated that TWIST1 mRNA levels are significantly increased in patients with nodal invasion and, interestingly, a significant correlation with patient sex was also found., Conclusions: Evidence for upregulation of TWIST1 mRNA in colorectal cancer is provided, suggesting its implication in the onset of malignant progression of this disease. In addition, significant higher levels of TWIST1 mRNA were found in men than in women, suggesting a possible transcriptional regulation of TWIST1 by sexual hormones. The use of TWIST1 as a new prognostic marker of advanced malignancy, and as a potential therapeutic target in colorectal cancer, is proposed.

Pluripotent cells can be isolated from the mammalian inner cell mass (ICM) of the embryo at the blastocyst stage, and maintained in culture as undifferentiated, embryonic stem cells (ES). These cells are an important model of mammalian development in vitro and are the focus of a great deal of research for their use in Cell Therapy. In vivo, shortly after the blastocyst stage, the ICM segregates into two layers: the hypoblast which will give rise to the yolk sac, and the epiblast. Epiblast stem cells, like ES cells, are pluripotent. The epiblast will differentiate very early into germ cell progenitors, the primordial germ cells (PGC). PGCs can give rise to embryonal carcinoma cells, the pluripotent stem cells of testicular tumors. During normal embryo development, PGCs migrate into the aorta-gonad-mesonephros region (AGM). Interestingly, this region also harbors the first wave of embryonic hematopoiesis. Subsequent waves of hematopoiesis involve AGM-hematopoietic stem cell (HSC) colonization of the fetal liver, thymus, spleen and ultimately, for adult hematopoiesis, the bone marrow (BM). The BM is also source of mesenchymal stem cells (MSCs). It is accepted that the AGM region cells give rise to the mesothelial cells which are the embryonic precursors of the HSC and MSC of the BM. Recent identification of a subpopulation of cells with markers typical of PGCs in the adult BM, which are capable of differentiating into HSCs, suggests that HSCs originate from a common precursor of PGCs and HSCs derived from the epiblast. Several groups have described the presence of stem cells with the same markers in epidermis, bronchial epithelium, pancreas, retina, hair follicle, heart and dental pulp among, other organs. This presence supports the hypothesis that during early development, epiblast/germ line-derived cells are deposited in various organs which persist into adulthood. The question remains whether these pluripotent stem cells are only developmental remnants or if they continuously contribute to the renewal of tissues, and thus can be reactivated for tissue regeneration without the need for stem cell transplantation for human cell therapies.