The Hippo effector TAZ (WWTR1) transforms myoblasts and TAZ abundance is associated with reduced survival in embryonal rhabdomyosarcoma

Acknowledgements This study was funded by Sarcoma UK, Friends of Anchor and the Medical Research Council grant number 99477 awarded to HW and PSZ. This work was also supported, in part, by NHS funding to the NIHR Biomedical Research Centre at The Royal Marsden and the Institute of Cancer Research, and the Chris Lucas Trust, UK. We also thank the CCLG Tissue Bank for access to samples, and contributing CCLG centres, including members of the ECMC paediatric network. The CCLG Tissue Bank is funded by Cancer Research UK and CCLG. In addition we would like to thank Prof KunLiang Guan and Prof Malcolm Logan for kindly providing constructs

Dasatinib (BMS-35482) potentiates the activity of gemcitabine and docetaxel in uterine leiomyosarcoma cell lines.

BACKGROUND: To explore the activity of dasatinib alone and in combination with gemcitabine and docetaxel in uterine leiomyosarcoma (uLMS) cell lines, and determine if dasatinib inhibits the SRC pathway. METHODS: SK-UT-1 and SK-UT-1B uLMS cells were treated with gemcitabine, docetaxel and dasatinib individually and in combination. SRC and paxcillin protein expression were determined pre- and post-dasatinib treatment using Meso Scale Discovery (MSD) multi-array immunogenicity assay. Dose-response curves were constructed and the coefficient of drug interaction (CDI) and combination index (CI) for drug interaction calculated. RESULTS: Activated phosphorylated levels of SRC and paxillin were decreased after treatment with dasatinib in both cell lines (p < 0.001). The addition of a minimally active concentration of dasatinib (IC25) decreased the IC50 of each cytotoxic agent by 2-4 fold. The combination of gemcitabine-docetaxel yielded a synergistic effect in SK-UT-1 (CI = 0.59) and an antagonistic effect in SK-UT-1B (CI = 1.36). Dasatinib combined with gemcitabine or docetaxel revealed a synergistic anti-tumor effect (CDI < 1) in both cell lines. The triple drug combination and sequencing revealed conflicting results with a synergistic effect in SK-UT-1B and antagonistic in SK-UT-1. CONCLUSION: Dasatinib inhibits the SRC pathway and yields a synergistic effect with the two-drug combination with either gemcitabine or docetaxel. The value of adding dasatinib to gemcitabine and docetaxel in a triple drug combination is uncertain, but may be beneficial in select uLMS cell lines. Based on our pre-clinical data and known activity of gemcitabine and docetaxel, further evaluation of dasatinib in combination with these agents for the treatment of uLMS is warranted.

THE HERPESVIRUS NUCLEAR EGRESS COMPLEX COMPONENT, UL31, IS RECRUITED TO SITES OF DNA DAMAGE THROUGH POLY(ADP-RIBOSE) BINDING

The herpes simplex virus (HSV) UL31 gene encodes a conserved member of the herpesvirus nuclear egress complex that not only functions in the egress of DNA-containing capsids from the nucleus, but is also required for optimal viral genome expression, replication and packaging into capsids. Here, we report that the UL31 protein from HSV-2 and the orthologous protein, ORF69, from Kaposi's sarcoma-associated herpesvirus (KSHV) are recruited to sites of DNA damage. Recruitment of UL31 to sites of DNA damage occurred in HSV-2 infected cells, but did not require other viral proteins. The N-terminus of UL31 contains sequences resembling a poly(ADP-ribose) (PAR) binding motif. As protein poly-ADP ribosylation (PARylation) is a hallmark of the DNA damage response we examined the relationship between PARylation and UL31 recruitment to DNA damage. While the PAR polymerase (PARP)1/2 inhibitor, olaparib, prevented UL31 recruitment to damaged DNA, KU55933 inhibition of signaling through the ataxia telangiectasia mutated (ATM) DNA damage response pathway had no effect. These findings were further supported by experiments demonstrating direct and specific interaction between HSV-2 UL31 and PAR using purified components. Co-transfection with the viral kinase Us3, known to phosphorylate UL31, inhibited UL31 recruitment to DNA damage but also prevented the recruitment of other proteins recruited to DNA damage sites. The viral E3 ubiquitin ligase ICP0 was observed to co-localize with UL31 in transfected cells in a manner that is independent of the PAR-binding ability of UL31. However, inhibition of PARP1/2/3 did not reduce the ability of HSV-2 to replicate and we observed reduced PAR levels in the nuclei of infected cells. This study reveals a previously unrecognized function for UL31 orthologs and may suggest that the recognition of PAR by UL31 is coupled to the nuclear egress of herpesvirus capsids, influences viral DNA replication and packaging, or possibly modulates the DNA damage response mounted by virally infected cells.

p.(L576P) -KIT mutation in GIST: Favorable prognosis and sensitive to imatinib?

Exon 11 KIT mutations are found in a majority of gastrointestinal stromal tumors (GIST) and are usually predictive of response to imatinib, a KIT, PDGFRA and ABL inhibitor. Exon 11 mutations with poor sensitivity to imatinib and poor outcome can be observed on rare occasions, including p.(L576P). In silico and in vitro studies suggested a decreased binding affinity for imatinib in p.(L576P) KIT mutations, thereby offering an explanation for their poor outcome and poor response to standard therapy. These observations were further corroborated with anecdotal case reports of refractoriness or non-durable response to imatinib therapy. However, we describe the favorable response to imatinib and outcome in 5 p.(L576P)-KIT mutant GIST patients treated at a tertiary sarcoma referral center. The sensitivity of p.(L576P)-KIT mutations to imatinib, and the prognostic impact of this mutation need to be further evaluated in a larger cohort. Based on our observations, p.(L576P) mutated GISTs should be treated with standard first line imatinib therapy.

Masson’s tumor: a soft tissue tumor simulating a tendon cyst. Case report

Introduction. Intravascular papillary endothelial hyperplasia (Masson's hemangioma or Masson’s tumor) is a benign vascular disease with an exuberant endothelial proliferation in normal blood vessels. Although relatively uncommon, its correct diagnosis is important because it can clinically be like both benign lesions and malignant neoplasms. We present a case of intravascular proliferative endothelial hyperplasia simulating a tendon cyst both clinically and on ultrasound. Case report. A 74-year old Caucasian female presented with a 4-month history of soreness and swelling in the fourth finger of the right hand. Ultrasound showed an oval mass with fluid content, referred to a tendon cyst. A wide surgical excision was subsequently performed. The final histological diagnosis was Masson’s tumor. Discussion. The pathogenesis of intravascular papillary endothelial hyperplasia is still unclear but the exuberant endothelial cell proliferation might be stimulated by an autocrine loop of endothelial basic fibroblast growth factor (bFGF) secretion. There are three types of papillary endothelial hyperplasia: primary, or intravascular; secondary, or mixed; and extravascular. The main differential diagnosis is against pyogenic granuloma, Kaposi sarcoma, hemangioma, and angiosarcoma. Conclusions. Masson's tumor can be like both benign lesions and malignant neoplasms clinically and on ultrasound. For this reason, the right diagnosis can be made only by histology, which reveals a papillary growth composed of hyperplastic endothelial cells supported by delicate fibrous stalks entirely confined within the vascular lumen.

Carcinoma of unknown primary (CUP); some considerations about pathogenesis and diagnostic strategy, particularly focusing on CUPS pertaining to the Urology

he term "carcinoma of unknown primary" (CUP) defines a malignant condition in which a metastatic cancer is documented in absence of a detectable primary site. It occurs in about 2÷6 % of cancer patients, according to various literature reports. The primary tumor site results indefinable because of several either single or associated factors, even remaining occult at autopsy in 15÷25% of CUP patients. The metastatic spread pattern of CUP is quite unlike that expected for analogous known primary malignancy. For instance, the unknown prostate cancer often metastasizes to the lungs and liver while the its known analogous usually spreads to the bone. Whether certain genetic abnormalities might play a role in determining a CUP condition, it remains undefined. Most CUP are adenocarcinoma, squamous cell carcinoma, either undifferentiated or differentiated carcinoma, whereas less frequently may be sarcoma, melanoma or neuroendocrine tumor. As CUP diagnostic management is concerned, two opposite approach modalities may be adopted, one, named "shotgun modality", consisting in a multiplicity of examinations aimed at achieving the identification of the primary tumor and the other, a nihilistic modality, by adopting tout court a palliative therapy of the metastatic disease. A reasonable intermediate diagnostic strategy consists in undertaking some procedures with a specific target and low cost/benefit ratio. Selected imaging studies, serum tumor markers, immunohistochemical analyses and genetic- molecular examinations on biopsy material allow sometimes to reach the detection of primary malignancies that might be responsive to a potential treatments. Nevertheless, in spite of recent sophisticated -laboratory and imaging progress, CUP remains a strong challenge in clinical oncology.

Células madre mesenquimales orales: estado del arte en Odontología

Desde la organogénesis y hasta estadios adultos, las células madre mesenquimales participan activamente dando origen y manteniéndola homeostasis del organismo. En la cavidad oral han sido aisladas desde variadas estructuras del órgano dental tales como el ligamento periodontal, pulpa dental, tejido gingival, folículo dental y papila apical significando una prometedora fuente de células madre mesenquimales las que pueden ser caracterizadas de acuerdo a los criterios mínimos establecidos por "The International Society for Cellular Therapy" que son: a) La adherencia al plástico; b) La expresión de marcadores CD73, CD90, CD105 y la carencia de CD34, CD45, CD14, CD11, CD79, CD19 y HLA-DR (clase II); c) Capacidad multipotencial de diferenciación hacia linaje osteogénico, condrogénico y adipogénico. El objetivo de esta revisión consiste en realizar un levantamiento de la situación actual de este tema efectuando una revisión comprensiva de la literatura en los campos de; identificación a través demarcadores de superficie, aislamiento por medio de mecanismos de digestión enzimática o explante, almacenamiento atendiendo a la necesidad de suprimir el uso de suero fetal bovino como medio de cultivo en un esfuerzo por avanzar hacia aplicaciones terapéuticas, banca o criopreservación destacando nuevas experiencia en este campo como lo es la criopreservación de piezas dentales completas gracias a la tecnología láser Nd:YAG. Y, finalmente, las aplicaciones clínicas que promete este grupo de células a través de la medicina regenerativa y la ingeniería tisular tanto en el campo de la odontología como la medicina general.

Mesenchymal chondrosarcoma: prognostic factors and outcome in 113 patients. A European Musculoskeletal Oncology Society study

BACKGROUND: Mesenchymal chondrosarcoma (MCS) is a distinct, very rare sarcoma with little evidence supporting treatment recommendations. PATIENTS AND METHODS: Specialist centres collaborated to report prognostic factors and outcome for 113 patients. RESULTS: Median age was 30 years (range: 11-80), male/female ratio 1.1. Primary sites were extremities (40%), trunk (47%) and head and neck (13%), 41 arising primarily in soft tissue. Seventeen patients had metastases at diagnosis. Mean follow-up was 14.9 years (range: 1-34), median overall survival (OS) 17 years (95% confidence interval (CI): 10.3-28.6). Ninety-five of 96 patients with localised disease underwent surgery, 54 additionally received combination chemotherapy. Sixty-five of 95 patients are alive and 45 progression-free (5 local recurrence, 34 distant metastases, 11 combined). Median progression-free survival (PFS) and OS were 7 (95% CI: 3.03-10.96) and 20 (95% CI: 12.63-27.36) years respectively. Chemotherapy administration in patients with localised disease was associated with reduced risk of recurrence (P=0.046; hazard ratio (HR)=0.482 95% CI: 0.213-0.996) and death (P=0.004; HR=0.445 95% CI: 0.256-0.774). Clear resection margins predicted less frequent local recurrence (2% versus 27%; P=0.002). Primary site and origin did not influence survival. The absence of metastases at diagnosis was associated with a significantly better outcome (P<0.0001). Data on radiotherapy indications, dose and fractionation were insufficiently complete, to allow comment of its impact on outcomes. Median OS for patients with metastases at presentation was 3 years (95% CI: 0-4.25). CONCLUSIONS: Prognosis in MCS varies considerably. Metastatic disease at diagnosis has the strongest impact on survival. Complete resection and adjuvant chemotherapy should be considered as standard of care for localised disease.

Hypoglyceamia in a Patient with a Solitary Fibrous Tumour

Objective: To illustrate an unusual mechanism causing hypoglycaemia. Material and methods: A 76-year-old man presented with episodes of agitation and confusion and was resuscitated with oral glucose gel when found to be hypoglycaemic. Results: A CT scan for an abdominal mass confirmed a solitary fibrous tumour (SFT). The sarcoma multidisciplinary team suggested conservative management. The patient's episodic hypoglycaemia was managed with diet modification including corn-based starch, scheduled snacks and dexamethasone. Glucose levels were within normal range at discharge from hospital. The patient was referred to the palliative care team for follow-up. Conclusion: SFTs causing non-islet cell tumour hypoglycaemia are difficult to treat. KEYWORDS

Dermatofibrosarcoma protuberans en pacientes pediátricos

Antecedentes y Objetivos. Presentamos 3 casos de dermatofibrosarcomaprotuberans (DFSP) en pacientes pediátricos para documentar la presentación clínica poco frecuente de esta patología. Pacientes y Método. Realizamos un análisis descriptivo retrospectivo de los 3 últimos casos de DFSP en nuestro centro durante los años 2010-2013. Resultados. Una niña de 12 años remitida desde otra institución por DFSP en parte distal del muslo, en la que ampliamos bordes quirúrgicos de resección en 3 cm y practicamos cobertura con dermis artificial e injerto autólogo; tras 1 año de observación sin recidiva, realizamos reconstrucción del defecto mediante injertos autólogos de grasa. Otra niña de 12 años diagnosticada de Síndrome de Hamartomatosis Múltiple asociado al gen PTEN, que presentó DFSP en labio mayor derecho y en mama derecha, recidivante en esta última localización. Por último, un DFSP congénito en una paciente remitida a los 3 meses de vida con tumoración gigante de pared abdominal. El diagnóstico orientativo inicial con resonancia magnética con gadolino, solo se confirmó finalmente por los hallazgos histopatológicos de la pieza de resección; ni la punción aspiración ni la biopsia cutánea lograron confirmar el diagnóstico. Conclusiones. El DFSP es un tipo de sarcoma raro de la piel del niño y del adulto, localmente agresivo y con una alta tasa de recidiva. La escisión local amplia puede provocar mutilaciones y desfigurar al paciente; por ello la cirugía micrográfica de Mohs permite reducir los márgenes quirúrgicos.

Uterine sarcomas: clinical presentation and MRI features

Uterine sarcomas are a rare heterogeneous group of tumors of mesenchymal origin, accounting for approximately 8% of uterine malignancies. They comprise leiomyosarcoma, endometrial stromal sarcoma, undifferentiated endometrial sarcoma, and adenosarcoma. Compared with the more common endometrial carcinomas, uterine sarcomas behave more aggressively and are associated with a poorer prognosis. Due to their distinct clinical and biological behavior, the International Federation of Gynecology and Obstetrics introduced a new staging system for uterine sarcomas in 2009, categorizing uterine carcinosarcoma as a variant of endometrial carcinoma, rather than a pure sarcoma. Magnetic resonance imaging (MRI) has a developing role in the assessment of these malignancies. Features such as tumor localization, irregular or nodular margins, necrosis, rapid growth, intense contrast enhancement, and restriction at diffusion-weighted imaging can suggest the diagnosis and help differentiate from more common leiomyomas and endometrial carcinoma. MRI is therefore extremely useful in preoperative detection and staging and, consequently, in determination of appropriate management. This pictorial review aims to discuss the clinical features of uterine sarcomas, as well as their most common appearances and distinct characteristics in MRI.

Efeitos ginecológicos do "tamoxifeno": contributo da radiologia

O “Tamoxifeno” (TAM) é a terapêutica anti-estrogénica de escolha nas doentes com cancro da mama. Os efeitos proliferativos do TAM em idade pós-menopausa têm sido associados a hiperplasia, pólipos, carcinoma e sarcoma do endométrio. As doentes tratadas com TAM têm também maior incidência de leiomiomas, adenomiose e endometriose, assim como maior risco de quistos do ovário. O método de primeira linha na vigilância das mulheres sob TAM é a ecografia transvaginal (US-TV). O endométrio apresenta-se frequentemente espessado e com áreas quísticas, aspectos passíveis de melhor caracterização por histerossonografia e ressonância magnética. Nas imagens ponderadas em T2, um endométrio espessado e heterogéneo com captação de aspecto reticulado e a opacificação da interface endométrio-miométrio associam-se a lesões de pior prognóstico (pólipos, hiperplasia atípica e neoplasia). O conhecimento dos efeitos ginecológicos do TAM e da sua tradução radiológica promove o diagnóstico precoce e adequado encaminhamento destas doentes.

Inmunoterapia autóloga con células dendríticas en modelos caninos con tumor venéreo transmisible

La inmunoterapia autóloga utiliza células del mismo cuerpo para estimular y restaurar las defensas naturales del sistema inmunológico. Algunas de las células que han sido utilizado en años recientes son: linfocitos infiltrantes de tumor, linfocitos T citotóxicos, células asesinas activadas por linfocinas y células dendríticas (CD). Las CD son células especializadas y su función es el capturar, procesar y presentar antígenos a los linfocitos para iniciar una respuesta inmune. El tumor venéreo transmisible (TVT), también conocido como sarcoma infeccioso o tumor de Sticker, es un cáncer transmisible en perros que afecta mayormente los genitales externos y se transmite durante el coito. En este trabajo se implementó por primera vez un modelo de TVT en el órgano genital (vagina) de los pacientes y se les administró la inmunoterapia autóloga con CD específicas contra el tumor. Para estudiar esta terapia se utilizaron tres grupos experimentales: el tumor sin tratamiento, el tumor tratado con sangre completa autóloga, y el tumor tratado con CD autólogas específicas para el TVT. Por último se evaluó la capacidad inmunológica del extracto tumoral total (ETT) del tumor como método de prevención in vivo. Para el tratamiento autólogo con las CD, se esperó que el tumor midiese 3cm, se realizó un cultivo primario de las células de TVT y se les extrajo el 4% de su peso corporal de sangre a los pacientes para realizar una diferenciación de los monocitos a CD. Para evaluar el efecto de la inmunoterapia autóloga con CD se observaron los efectos secundarios, el tamaño tumoral, las poblaciones de linfocitos, los niveles de IFN-γ en sangre y los linfocitos infiltrantes de tumor por histopatología. Los monocitos se diferenciaron a CD y se les realizó un análisis fenotípico mediante citometría de flujo. Los monocitos mostraron una expresión de CD14+ de 80.1%, CD80+ de 15.6%, CD83+ de 0.4% y un DLA II de1.8%. En las CD se obtuvo una expresión de 8.7% para CD14+, 80.3% para CD80+, 76.4% para CD83+ y 86.5% para DLA II y 62% en la prueba de fagocitosis. La terapia no mostró ningún efecto secundario en nuestro grupo experimental y hubo una regresión tumoral del 100% para la semana doce. Se encontró un aumento de expresión celular en sangre de CD4+ de 29%, de CD8+ de 34% y de IFN-γ de 120 pg/mL. Nuestros resultados demuestran que la inmunoterapia autóloga con CD específicas inducen una regresión del TVT en caninos.