MYC and TP53 Alterations but Not MAPK Pathway Mutations Are Common Oncogenic Mechanisms in Follicular Dendritic Cell Sarcomas.

CONTEXT.­: Despite their stromal origin, follicular dendritic cells (FDCs) share many functions with hematopoietic system cells. FDC neoplasms are currently classified by the World Health Organization along with those of a histiocytic nature. However, the molecular alterations driving oncogenesis in FDC sarcomas (FDCSs) are beginning to be unveiled and do not seem to concur with those described in histiocytic neoplasms, namely MAPK pathway activation. OBJECTIVE.­: To identify molecular alterations driving tumorigenesis in FDCS. DESIGN.­: We investigated the role of MYC and TP53 in FDC-derived tumor oncogenesis and assessed comprehensively the status of the MAPK pathway in 16 FDCSs, 6 inflammatory pseudotumor (IPT)-like FDCSs, and 8 IPTs. RESULTS.­: MYC structural alterations (both amplifications and rearrangements) were identified in 5 of 14 FDCSs (35.7%), all associated with MYC overexpression. TP53 mutations were identified in 4 of 14 FDCSs (28.6%), all of which displayed intense and diffuse p53 expression. None of these alterations were identified in any IPT-like FDCSs or in IPT cases. No MAPK pathway gene alterations were identified in any of the cases studied. CONCLUSIONS.­: The presence of MYC and TP53 alterations and the lack of association with Epstein-Barr virus segregate classical FDCS from IPT-like FDCS, pointing at different oncogenic mechanisms in both entities. Our results suggest a possible oncogenic role of MYC and TP53 alterations in FDCS. The absence of MAPK pathway alterations confirms the lack of a significant role of this pathway in the oncogenesis of FDC-derived neoplasms.

Assessment of a New ROS1 Immunohistochemistry Clone (SP384) for the Identification of ROS1 Rearrangements in Patients with Non-Small Cell Lung Carcinoma: the ROSING Study.

INTRODUCTION: The ROS1 gene rearrangement has become an important biomarker in NSCLC. The College of American Pathologists/International Association for the Study of Lung Cancer/Association for Molecular Pathology testing guidelines support the use of ROS1 immunohistochemistry (IHC) as a screening test, followed by confirmation with fluorescence in situ hybridization (FISH) or a molecular test in all positive results. We have evaluated a novel anti-ROS1 IHC antibody (SP384) in a large multicenter series to obtain real-world data. METHODS: A total of 43 ROS1 FISH-positive and 193 ROS1 FISH-negative NSCLC samples were studied. All specimens were screened by using two antibodies (clone D4D6 from Cell Signaling Technology and clone SP384 from Ventana Medical Systems), and the different interpretation criteria were compared with break-apart FISH (Vysis). FISH-positive samples were also analyzed with next-generation sequencing (Oncomine Dx Target Test Panel, Thermo Fisher Scientific). RESULTS: An H-score of 150 or higher or the presence of at least 70% of tumor cells with an intensity of staining of 2+ or higher by the SP384 clone was the optimal cutoff value (both with 93% sensitivity and 100% specificity). The D4D6 clone showed similar results, with an H-score of at least 100 (91% sensitivity and 100% specificity). ROS1 expression in normal lung was more frequent with use of the SP384 clone (p < 0.0001). The ezrin gene (EZR)-ROS1 variant was associated with membranous staining and an isolated green signal FISH pattern (p = 0.001 and p = 0.017, respectively). CONCLUSIONS: The new SP384 ROS1 IHC clone showed excellent sensitivity without compromising specificity, so it is another excellent analytical option for the proposed testing algorithm.

Post-Operative Localization of Deep Brain Stimulation Electrodes in the Subthalamus Using Transcranial Sonography.

OBJECTIVES: The correct positioning of deep brain stimulation electrodes determines the success of surgery. In this study, we attempt to validate transcranial sonography (TCS) as a method for early postoperative confirmation of electrode location in the subthalamic nucleus (STN). MATERIALS AND METHODS: Nineteen patients diagnosed with Parkinson's disease were enrolled in the study. Postoperative TCS was applied to measure the distance between the implanted electrodes and the third ventricle in the axial plane. Whether the electrodes were positioned within or outside the substantia nigra (SN) was evaluated through measurements in the coronal plane. The obtained metrics through TCS were compared with those from postoperative computed tomography (CT) and magnetic resonance imaging (MRI). RESULTS: A statistically significant correlation between distances from electrode to third ventricle by TCS and CT/MRI (r = 0.75, p < 0.01) was observed. Distances from third ventricle to electrodes tips were different when sonographically they showed to be inside or outside the SN (p < 0.01). A cut-off value of 8.85mm in these distances was the most sensitive (100%) and specific (90.5%) to predict if electrodes were positioned inside the SN (CI 95% 0.81-10.30, p = 0.001). CONCLUSIONS: Transcranial sonography is a useful technique to reliably identify targeted positioning of deep brain stimulation electrodes in or out of the SN.

Actualización bibliográfica del mecanismo de lesión sin contacto del ligamento cruzado anterior / Noncontact anterior cruciate ligament injury mechanism. Bibliographic actualization

Introducción: La ruptura del Ligamento Cruzado Anterior (LCA) es una de las lesiones más frecuentes en el deporte, representa un alto costo para su tratamiento y un largo período de rehabilitación postoperatorio. A pesar de su alto impacto aún no se ha determinado con exactitud su mecanismo lesional. En este trabajo se hace un análisis exhaustivo de la bibliografía sobre el tema, exponiendo las diferentes propuestas de los autores, focalizando en las lesiones sin contacto del LCA. Si bien no pueden extraerse conclusiones inequívocas, la bibliografía parece indicar que no habría un único mecanismo lesional y éste podría estar determinado por las características anatómicas del paciente

Introduction: The Anterior Cruciate Ligament (ACL) rupture is one of the most frequent injuries in sports, represents a high cost for its treatment and a long period of postoperative rehabilitation. Despite its high impact, its mechanism of injury has still not been determined with accuracy. In this review an exhaustive analysis of the literatura on the subject is made, exposing the different proposals of the authors, focusing on the non-contact lesions of the ACL. Although no unequivocal conclusions can be drawn, the literature seems to indicate that there would not be a single mechanism of injury and this could be determined by the anatomical characteristics of the patient

Rare Neurodegenerative Diseases: Clinical and Genetic Update.

More than 600 human disorders afflict the nervous system. Of these, neurodegenerative diseases are usually characterised by onset in late adulthood, progressive clinical course, and neuronal loss with regional specificity in the central nervous system. They include Alzheimer's disease and other less frequent dementias, brain cancer, degenerative nerve diseases, encephalitis, epilepsy, genetic brain disorders, head and brain malformations, hydrocephalus, stroke, Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis (ALS or Lou Gehrig's Disease), Huntington's disease, and Prion diseases, among others. Neurodegeneration usually affects, but is not limited to, the cerebral cortex, intracranial white matter, basal ganglia, thalamus, hypothalamus, brain stem, and cerebellum. Although the majority of neurodegenerative diseases are sporadic, Mendelian inheritance is well documented. Intriguingly, the clinical presentations and neuropathological findings in inherited neurodegenerative forms are often indistinguishable from those of sporadic cases, suggesting that converging genomic signatures and pathophysiologic mechanisms underlie both hereditary and sporadic neurodegenerative diseases. Unfortunately, effective therapies for these diseases are scarce to non-existent. In this chapter, we highlight the clinical and genetic features associated with the rare inherited forms of neurodegenerative diseases, including ataxias, multiple system atrophy, spastic paraplegias, Parkinson's disease, dementias, motor neuron diseases, and rare metabolic disorders.

Acinic Cell Carcinoma of the Parotid Gland with Four Morphological Features.

Acinic cell carcinoma arising in salivary glands is a rare tumor, accounting for 2% to 5% of the primary neoplasms of the parotid gland. When these tumors are well-differentiated, the neoplasia has innocuous aspect, due to the similarity to normal parotid tissue. This makes the diagnosis difficult. Initially the malignancy of this tumor was uncertain; however, recent studies have declared it as malignant. The female / male ratio is 3:2. The nodule usually presents as solitary and well defined shape. Several authors have used different terms to describe histomorphological patterns of these tumors. Four descriptive categories (solid, microcystic, papillary-cystic and follicular) are useful for pathologists. Here we report a case of a 49 yr old man with a left parotid nodule of 5 cm. Parotidectomy was performed at the Hospital Universitario Miguel Servet, in Zaragoza (Spain). The microscopy showed a tumor with acinic semblance, having the four morphologic patterns previously described. The morphological and immunohistochemical study was consistent with the diagnosis of acinic cell carcinoma.

Cystatin C is differentially involved in multiple system atrophy phenotypes.

AIMS: As cystatin C (CysC) is involved in some forms of neurodegeneration, we investigated the possible relationship between CysC and multiple system atrophy (MSA), including its parkinsonian (MSAp) and cerebellar (MSAc) phenotypes. METHODS: Cystatin C gene (CST3) haplotypes were determined by PCR followed by KspI digestion in 50 MSA patients and 108 controls. CST3 and cathepsins B, D and L1 mRNA levels were studied in frozen post-mortem caudate nucleus and cerebellar samples of eight MSAp, four MSAc and 18 control brains and analysed by the ΔΔCt method. CysC immunohistochemistry was performed on three MSAp, three MSAc and three control cerebella. Additionally, determination of CST3 and cathepsins B, D and L1 mRNA levels and immunohistochemistry for CysC were carried out in cerebella from three patients with paraneoplastic cerebellar degeneration, three with spinocerebellar ataxia (type 3, SCA3) and three with cerebellar ischaemia (CI). RESULTS: In the set of blood samples, the CST3 B-haplotype was associated with MSAp (OR 4.86, confidence interval 1.84-13.3). High CST3 mRNA levels were found in MSAp caudate nuclei [expression change: 3.08 (2.98-3.18)] and MSAc cerebella [expression change: 2.44 (2.14-2.88)]. In the latter there was CysC over-expression in Purkinje cells, Bergmann glia and dentate nucleus neurones. No cathepsin increase was detected in MSA cerebella. High mRNA levels of CST3 and cathepsins B and L1 were observed in SCA3 and CI brains. CONCLUSIONS: CysC changes are differentially present in the parkinsonian and cerebellar forms of MSA and may play an important role in the pathogenesis of this neurodegenerative condition.

Cellular and molecular pathways triggering neurodegeneration in the spinocerebellar ataxias.

The autosomal dominant spinocerebellar ataxias (SCAs) are a group of progressive neurodegenerative diseases characterised by loss of balance and motor coordination due to the primary dysfunction of the cerebellum. To date, more than 30 genes have been identified triggering the well-described clinical and pathological phenotype, but the underlying cellular and molecular events are still poorly understood. Studies of the functions of the proteins implicated in SCAs and the corresponding altered cellular pathways point to major aetiological roles for defects in transcriptional regulation, protein aggregation and clearance, alterations of calcium homeostasis, and activation of pro-apoptotic routes among others, all leading to synaptic neurotransmission deficits, spinocerebellar dysfunction, and, ultimately, neuronal demise. However, more mechanistic and detailed insights are emerging on these molecular routes. The growing understanding of how dysregulation of these pathways trigger the onset of symptoms and mediate disease progression is leading to the identification of conserved molecular targets influencing the critical pathways in pathogenesis that will serve as effective therapeutic strategies in vivo, which may prove beneficial in the treatment of SCAs. Herein, we review the latest evidence for the proposed cellular and molecular processes to the pathogenesis of dominantly inherited spinocerebellar ataxias and the ongoing therapeutic strategies.

Jaagsiekte sheep retrovirus is not detected in human lung adenocarcinomas expressing antigens related to the Gag polyprotein of betaretroviruses.

A proportion of human lung adenocarcinomas (hLACs) express an antigen related to the major capsid protein (CA) of Jaagsiekte sheep retrovirus (JSRV), a Betaretrovirus that causes a transmissible lung cancer in sheep. In this study, we have investigated whether JSRV or related betaretroviruses are expressed in hLACs. Results obtained indicate that JSRV is not associated with human lung adenocarcinomas. However, a proportion of hLACs reacted positively in immunohistochemistry with antibodies specific towards different domains of the JSRV Gag suggesting that a bona fide retrovirus antigen could be expressed in these tumours. Further studies will be necessary to ascertain whether the detection of antigens cross-reacting with betaretrovirus Gag antisera in some hLACs is due to expression of a human endogenous retrovirus or, more unlikely, of an uncharacterized exogenous retrovirus.

Los hospitales de epidemias / Epidemic hospitals

En este trabajo histórico, el autor describe el desarrollo de los hospitales para la atención de los pacientes en las epidemias desde el tiempo de la Conquista de Guatemala. Se mencionan las fechas y las principales enfermedades que obligaron a establecer éstos centros y otros recientemente para infecciones especiales: Viruela: 1780, 1873, 1885 y 1891. Cólera:1837,1857 y 1991. Meningitis: 1904. Tifus exantem tico: 1899,1900 y 1905. Fiebre Amarilla: 1895, 1905 y 1918. Tuberculosis:desde 1924

Alteraciones renales en un lactante con glucogenosis tipo I / Renal alterations in a nursing infant with glycogenos type I

Introuducción. Las alteraciones en el metabolismo de los carbohidratos muestran un espectro clínico, bioquímico, histológico y ultraestructural variado. La glucogenosis tipo I puede presentar diversas manifestaciones hepáticas y ocasionalmente renales. Caso clínico. Niño de 1 año a 2 meses de edad, que presentó desde los 2 meses de vida glucogenosis hepática tipo I, con hallazgos histológicos y ultraestructurales característicos; desarrolló insuficiencia renal con leisones de glomeruloesclerosis focal y segmentaria, vacuolización epitelial tubular y nefritis tubulointersticial. Falleció de un cuadro de vías respiratorias y boncroaspiración. Conclusiones. El presente caso ilustra las alteraciones renales en un lactante con glucogenosis tipo I que evolucionó rápidamente a insuficiencia renal, lo que usualmente ocurre a edades mayores. Es necesario vigilar la función renal en caso de glucogenosis, aún desde edades tempranas