Dissection of a metastatic gene expression signature into distinct components

BACKGROUND: Metastasis, the process whereby cancer cells spread, is in part caused by an incompletely understood interplay between cancer cells and the surrounding stroma. Gene expression studies typically analyze samples containing tumor cells and stroma. Samples with less than 50% tumor cells are generally excluded, thereby reducing the number of patients that can benefit from clinically relevant signatures. RESULTS: For a head-neck squamous cell carcinoma (HNSCC) primary tumor expression signature that predicts the presence of lymph node metastasis, we first show that reduced proportions of tumor cells results in decreased predictive accuracy. To determine the influence of stroma on the predictive signature and to investigate the interaction between tumor cells and the surrounding microenvironment, we used laser capture microdissection to divide the metastatic signature into six distinct components based on tumor versus stroma expression and on association with the metastatic phenotype. A strikingly skewed distribution of metastasis associated genes is revealed. CONCLUSION: Dissection of predictive signatures into different components has implications for design of expression signatures and for our understanding of the metastatic process. Compared to primary tumors that have not formed metastases, primary HNSCC tumors that have metastasized are characterized by predominant down-regulation of tumor cell specific genes and exclusive up-regulation of stromal cell specific genes. The skewed distribution agrees with poor signature performance on samples that contain less than 50% tumor cells. Methods for reducing tumor composition bias that lead to greater predictive accuracy and an increase in the types of samples that can be included are presented

Metastatic potential of an aneurysmal bone cyst

Aneurysmal bone cysts (ABCs) are benign bone tumors consisting of blood-filled cavities lined by connective tissue septa. Recently, the hypothesis that ABCs are lesions reactive to local hemodynamics has been challenged after the discovery of specific recurrent chromosomal abnormalities. Multiple cases of malignant transformation of ABC into (osteo)sarcoma have been described, as well as a number of cases of telangiectatic osteosarcoma which had been misdiagnosed as ABC. We herewith document a case of a pelvic ABC metastatic to the lung, liver, and kidneys. Diagnosis was confirmed by the presence of a break in the USP6 gene, which is pathognomonic for ABC, in a pulmonary metastasis of our patient. Sarcomatous transformation as an explanation for this behavior was ruled out by demonstrating diploid DNA content in both the pulmonary lesion and the primary tumor

Grading systems in head and neck dysplasia: their prognostic value, weaknesses and utility

Contains fulltext : 80594.pdf (publisher's version ) (Open Access)ABSTRACT: BACKGROUND: Grading of dysplasia, including head and neck lesions, continues to be a hotly debated subject. It is subjective and lacks intra- and inter-observer reproducibility due to the insufficiency of validated morphological criteria and the biological nature of dysplasia. Moreover, due to the absence of a consensus, several systems are currently employed. OBJECTIVES: The aims of this review are to:1) Highlight the significance of dysplasia and the importance of a valid method for assessing precursor lesions of the head and neck.2) Review the different histopathological classification systems for grading intraepithelial lesions of the head and neck.3) Discuss and review quality requirements for these grading systems. CONCLUSION: Regarding the different classification systems, data concerning the WHO classification system are the most available in current literature. There is no simple relationship or overlapping between the classification systems. Further studies should be done to see whether other systems have advantages above the current WHO system and to discover indications that could lead to an universal classification system for intraepithelial lesions of the head and neck

Androgen receptor-positive salivary duct carcinoma: a disease entity with promising new treatment options

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Tumor control of cervical lymph node metastases of unknown primary origin: the impact of the radiotherapy target volume

Purpose Debate on the extent of treatment of neck metastasis of cancer of unknown primary tumors (CUPs) is still ongoing. In two Dutch tertiary referral centers, the post-surgical radiation target volume changed from the bilateral neck including the pharyngeal axis to the unilateral neck only, in the course of the last decade. This study aims to investigate the outcome of patients with CUP before and after de-escalation of post-surgical radiotherapy. Methods Data of two Dutch tertiary referral centers were merged. Disease-free survival (DFS), overall survival (OS), and regional control rate (RCR) of 80 patients diagnosed with CUP (squamous cell and undifferentiated carcinomas) between 1990 and 2009 were retrospectively analyzed. Results Thirty patients received bilateral neck and pharyngeal axis radiotherapy and 42 patients ipsilateral radiotherapy only. In another eight patients, the postsurgical radiation target volume was expanded to the contralateral neck or to the pharyngeal axis, due to suspicious lesions on imaging. The 5-year DFS, OS and RCR were 60%, 51.2%, and 80%, respectively, in the total patient population. RCR did not differ in patients treated with ipsilateral as compared to bilateral radiotherapy nor did 5-year OS and DFS. No tumors occurred in the pharyngeal axis. Conclusion In this study, omitting elective treatment of the contralateral neck and pharyngeal axis did not lead to a decrease in locoregional control or survival rates when treating patients with CUP.</p

T Cell Apoptosis in Human Heart Allografts : Association with Lack of Co-Stimulation?

It is unclear whether the intracardial immune reactivity after heart transplantation influences the peripheral immunological status (activation or nonresponsiveness) of the patient. Co-stimulation and activation-induced cell death (AICD) or apoptosis play an important role in determining the balance between lymphocyte reactivity and nonreactivity. Therefore, we studied the expression of co-stimulatory molecules and the process of apoptosis in biopsies of human heart allografts, using immunohistochemistry. Although a normal expression of co-stimulatory molecules on antigen-presenting cells was observed, the expression of their counter-structures on T cells was absent. This may be due to chronic T cell activation, which can lead to the induction of apoptosis via the Fas/Fas ligand pathway. In the infiltrates, a considerable percentage of the lymphocytes, but not the macrophages, were apoptotic. Apoptosis was confirmed by DNA fragmentation analysis. Increased numbers of Bax-expressing versus decreased numbers of Bcl2-expressing lymphocytes in comparison with normal lymphoid tissue confirmed a imbalance in favor of apoptosis. Apoptosis was biased towards CD4(+) T cells (65.7% versus 26.6% in CD8(+) T cells). Fas was expressed on most of the infiltrating cells. Fas ligand expression was also observed, not only on most of the T cells but also on all macrophages. Because macrophages were often detected in close contact with T cells, they may play a role in T cell regulation via the Fas/Fas ligand pathway. This study indicates that, during rejection, not only is tissue damage induced by infiltrating T cells, but also the infiltrating lymphocytes themselves are actively down-regulated (eg, AICD) by one another and by macrophages in the infiltrate. This regulatory process may affect the immunological status of the patient after heart transplantation

beta-TCP Versus Autologous Bone for Repair of Alveolar Clefts in a Goat Model.

Item does not contain fulltextObjective : The aim of this study in goats was to test the hypothesis that a novel synthetic bone substitute beta tricalcium phosphate (beta-TCP) can work as well as autologous bone harvested from the iliac crest for grafting and repair of alveolar clefts. Design : Ten adult Dutch milk goats ( Capra hircus ) were used in a split-mouth study design. Main outcome measures : Volumetric histologic assessment of new bone formation and radiographic measurement of orthodontic movement of teeth in a formerly created alveolar cleft. Conclusions : The synthetic bone substitute beta-TCP was shown to result in bone healing similar to that of iliac crest bone. The surgical, orthodontic, and histologic results now warrant the testing of beta-TCP in the human cleft situation.1 november 201