RET proto-oncogene and thyroid cancer

TheRET proto-oncogene has not only conclusively been identified as responsible for the three subtypes of the inherited cancer syndrome multiple endocrine neoplasia type 2 (MEN-2) but also shown to be involved in the molecular evolution of sporadic medullary and papillary thyroid carcinoma as well as Hirschsprung's disease. A variety of recent studies have elucidated the pathophysiological mechanisms leading to neoplastic disease and we now understand that dominant activating germline mutations lead to MEN-2A, MEN-2B, and familial MTC; somatic mutations to sporadic medullary thyroid carcinoma;RET rearrangements to papillary thyroid carcinoma; and inactivating alterations to Hirschsprung's disease. The clinical significance, however, ofRET alterations especially in sporadic thyroid tumors is still controversial and therapeutic concepts in MEN-2 gene carriers only start to emerge. This article is a short summary of the recent findings on the structure and physiology of theRET proto-oncogene and its role in familial and sporadic thyroid cance

CARD In Situ hybridization: Sights and signals

During the last decade, several strategies have been developed to improve the detection sensitivity ofin situ hybridization (ISH) by amplification of either target nucleic acid sequences prior to ISH (e.g.,in situ PCR), or the detection signals after the hybridization procedures (signal amplification). Here we outline the principles of tyramide signal amplification using the catalyzed reporter deposition (CARD) technique, summarize applications as well as possible limitations of CARD ISH, and discuss some future directions ofin situ nucleic acid detection using this amplification strateg

Molecular profiles of gastroenteropancreatic endocrine tumors

Neuroendocrine tumors of the gastroenteropancreatic system are defined by their endocrine phenotype and share many histopathological and clinical features. However, the fact that the hormone production of tumors depends on their site of origin, that the tumors differ in their biology, and that the association with familial syndromes is nonrandom suggests heterogeneity. It is therefore conceivable that the gastroenteropancreatic neuroendocrine tumors also differ in their molecular profile. This review summarizes and discusses the available data in this fiel

Human insulinoma: Clinical, cellular, and molecular aspects

Insulinoma is the most frequently encountered functioning endocrine pancreatic tumor in humans. In this overview we summarize morphological and clinical features of insulinomas, report about the proinsulin-insulin conversion in normal and neoplastic B-cells, discuss the new classification, the criteria of malignancy, and the clonal composition of endocrine pancreatic tumors, and outline recent findings on the molecular pathology of these tumor

Immunostaining for the tumour suppressor gene p16 product is a useful marker to differentiate melanoma metastasis from lymph-node nevus

Upon the introduction of extensive sampling protocols of sentinel node biopsies, pathologists are increasingly confronted with small melanoma metastases. Using conventional histology, it proves sometimes difficult or impossible to differentiate small melanoma metastases from lymph-node nevi. Loss of the tumour suppressor gene p16 has been shown to be associated with tumour progression of melanoma. We investigated nevus and melanoma cells for the presence of the product of the gene p16, using immunohistochemistry. All nevus cells, independent of their location (nodal or skin) displayed an extensive nuclear and cytoplasmic staining for p16. In contrast, all cells of melanoma metastases, except one skin metastasis, lacked nuclear staining for p16. These findings indicate that p16 is a reliable marker to distinguish lymph-node nevi from melanoma metastasi

Paraneoplastic Necrotizing Myopathy with a Mild Inflammatory Component: A Case Report and Review of the Literature

Inflammatory myopathies such as dermatomyositis and polymyositis are well-recognized paraneoplastic syndromes. Little is known, however, about necrotizing myopathies in association with cancer. We here describe a case of paraneoplastic necrotizing myopathy with a mild inflammatory infiltrate in a patient with adenocarcinoma. After the rapid development of a severe, disabling muscle weakness, the patient experienced near complete recovery within 4 months under oral prednisone treatment. In the context of the presented case, we will review current knowledge about paraneoplastic necrotizing myopathies

Accuracy of multidetector-row CT for restaging after neoadjuvant treatment in patients with oesophageal cancer

Objectives: To assess the diagnostic accuracy of 64-multidetector CT (MDCT) for restaging of patients with oesophageal cancer undergoing neoadjuvant therapy. Methods: Results of pathological staging were correlated with those from 64-MDCT before and after neoadjuvant treatment in 35 patients using the American Joint Committee on Cancer/TNM classification (7th edition). CT response was determined using the Response Evaluation Criteria in Solid Tumours (RECIST) method, modified for one-dimensional tumour diameter measurement. Results: 64-MDCT predicted T stage correctly in 34% (12/35), overstaged in 49% (17/35) and understaged in 17% (6/35). Sensitivity/specificity values were as follows: T0, 20%/92%; T1-T2, 31%/59%; T3, 60%/64%; T4, 100%/4%. Negative predictive values for T3/T4 were 80%/100%. MDCT accurately predicted complete histopathological response in 20% (accuracy 74%) and overstaged in 80%. Tumour regression grade was predicted correctly in only 8% (2/25) and underestimated in 68% (17/25). Accurate N stage was noted in 69% (24/35). Conclusion: Although MDCT tends to be able to exclude advanced tumour stages (T3, T4) with a higher likelihood, the diagnostic accuracy of high resolution MDCT for restaging oesophageal cancer and assessing the response to neoadjuvant therapy has not improved in comparison to older-generation CT. Therefore, the future assessment of oesophageal tumour response should focus on combined morphologic and metabolic imaging. Key Points : • Multidetector CT (MDCT) has been beneficial for the evaluation of many tumours. • However diagnostic accuracy for restaging oesophageal cancer has not improved with MDCT. • MDCT tends to be able to exclude advanced tumour stages (T3/T4). • MDCT has a low accuracy for determining lymph node metastasis. • Oesophageal tumour response should be assessed by combined morphological and metabolic imagin

Differential loss of chromosome 11q in familial and sporadic parasympathetic paragangliomas detected by comparative genomic hybridization

Parasympathetic paragangliomas (PGLs) represent neuroendocrine tumors arising from chief cells in branchiomeric and intravagal paraganglia, which share several histological features with their sympathetic counterpart sympathoadrenal paragangliomas. In recent years, genetic analyses of the familial form of PGL have attracted considerable interest. However, the majority of paragangliomas occurs sporadically and it remains to be determined whether the pathogenesis of sporadic paraganglioma resembles that of the familial form. Furthermore, data on comparative genetic aberrations are scarce. To provide fundamental cytogenetic data on sporadic and hereditary PGLs, we performed comparative genomic hybridization using directly fluorochrome-conjugated DNA extracted from 12 frozen and 4 paraffin-embedded tumors. The comparative genomic hybridization data were extended by loss of heterozygosity analysis of chromosome 11q. DNA copy number changes were found in 10 (63%) of 16 tumors. The most frequent chromosomal imbalance involved loss of chromosome 11. Six of seven familial tumors and two of nine sporadic tumors showed loss of 11q (86% versus 22%, P = 0.012). Deletions of 11p and 5p were found in two of nine sporadic tumors. We conclude that overall DNA copy number changes are infrequent in PGLs compared to sympathetic paragangliomas and that loss of chromosome 11 may be an important event in their tumorigenesis, particularly in familial paragangliomas

Losses of chromosomes 1p and 3q are early genetic events in the development of sporadic pheochromocytomas

Despite several loss of heterozygosity studies, a comprehensive genomic survey of pheochromocytomas is still lacking. To identify DNA copy number changes which might be important in tumor development and progression and which may have diagnostic utility, we evaluated genetic aberrations in 29 sporadic adrenal and extra-adrenal pheochromocytomas (19 clinically benign tumors and 10 malignant lesions). Comparative genomic hybridization was performed using directly fluorochrome-conjugated DNA extracted from frozen (16) and paraffin-embedded (13) tumor tissues. The most frequently observed changes were losses of chromosomes 1p11-p32 (86%), 3q (52%), 6q (34%), 3p, 17p (31% each), 11q (28%), and gains of chromosomes 9q (38%) and 17q (31%). No amplification was identified and no difference between adrenal and extra-adrenal tumors was detected. Progression to malignant tumors was strongly associated with deletions of chromosome 6q (60% versus 21% in clinically benign lesions, P = 0.0368) and 17p (50% versus 21%). Fluorescence in situ hybridization confirmed the comparative genomic hybridization data of chromosomes 1p, 3q, and 6q, and revealed aneuploidy in some tumors. Our results suggest that the development of pheochromocytomas is associated with specific genomic aberrations, such as losses of 1p, 3q, and 6q and gains of 9q and 17q. In particular, tumor suppressor genes on chromosomes 1p and 3q may be involved in early tumorigenesis, and deletions of chromosomes 6q and 17p in progression to malignancy

An optimised assay for quantitative, high-throughput analysis of polysialyltransferase activity

YesThe polysialyltransferases are biologically important glycosyltransferase enzymes responsible for the biosynthesis of polysialic acid, a carbohydrate polymer that plays a critical role in the progression of several diseases, notably cancer. Having improved the chemical synthesis and purification of the fluorescently-labelled DMB-DP3 acceptor, we report optimisation and validation of a highly sensitive cell-free high-throughput HPLC-based assay for assessment of human polysialyltransferase activity