Any disagreement will be resolved through discussion with a third review team member

Any disagreement will be resolved through discussion with a third review team member. Controlled Trials (CENTRAL), Database of Abstracts of Reviews of Effects). There will be no restriction concerning language and publication date. The qualitative and quantitative synthesis of the systematic review will be conducted with randomized controlled trials (RCT), prospective and retrospective comparative cohort studies, and case-control studies. Case series will be collected in a separate database and only used for descriptive purposes. == Results == This study is ongoing and presents a protocol of six systematic reviews to elucidate the role of histopathological and biochemical markers, biopsies of the primary tumor and the metastases as well as morphological and functional imaging modalities for the diagnosis and prediction of neuroendocrine liver metastases. == Conclusions == These systematic reviews will assess the value and accuracy of several diagnostic modalities in patients with NET liver metastases, and will provide a basis for the development of clinical practice guidelines. == Trial Registration == The systematic reviews have been prospectively registered with the International Prospective Register of Systematic Reviews (PROSPERO): CRD42012002644; http://www.metaxis.com/prospero/full_doc.asp?RecordID=2644 (Archived by WebCite at http://www.webcitation.org/6LzCLd5sF), CRD42012002647; http://www.metaxis.com/prospero/full_doc.asp?RecordID=2647 (Archived by WebCite at http://www.webcitation.org/6LzCRnZnO), CRD42012002648; http://www.metaxis.com/prospero/full_doc.asp?RecordID=2648 (Archived by WebCite at http://www.webcitation.org/6LzCVeuVR), CRD42012002649; http://www.metaxis.com/prospero/full_doc.asp?RecordID=2649 (Archived by WebCite at http://www.webcitation.org/6LzCZzZWU), CRD42012002650; http://www.metaxis.com/prospero/full_doc.asp?RecordID=2650 (Archived by WebCite at Mouse monoclonal to AFP http://www.webcitation.org/6LzDPhGb8), CRD42012002651; http://www.crd.york.ac.uk/PROSPERO/display_record.asp?ID=CRD42012002651#.UrMglPRDuVo (Archived by WebCite at http://www.webcitation.org/6LzClCNff). Keywords:neuroendocrine tumors (NET), liver metastases, Ki67, mitotic count, genetic signatures, tumor cells, biochemical markers, morphological imaging, functional imaging, systematic review == Introduction == == Background == == Neuroendocrine Tumors == Neuroendocrine tumors (NETs) arise from the diffuse neuroendocrine system and therefore appear widespread over the whole body, especially in the gastrointestinal tract and the bronchopulmonary system MRT68921 dihydrochloride [1,2]. NETs secreting hormones lead to a symptomatic disease. Nonsecreting NETs may occur initially asymptomatic or with delayed symptoms due to progressive increase in tumor mass MRT68921 dihydrochloride [3,4]. Therefore, differences in functional behavior are the basis of a classification system categorizing functioning and nonfunctioning NETs [4]. Other reported classification systems are based on embryological origin or histopathological findings. In 2010 2010, The World Health Organization (WHO) presented a new classification on the basis of tumor grading using histopathological criteria such as Ki67 index, mitotic count, and presence or absence of necrosis [5]. NETs is a relatively rare disease with an incidence of 1-3 per 100,000 [6,7]. The large range of reported incidence might be due to the fact that NETs often present initially asymptomatic and are often found accidentally or in autopsies [4]. Predominantly, NETs emerge sporadically (>90%) and are traditionally assigned to multiple endocrine neoplasia type 1 (MEN1), neurofibromatosis-type 1 (NF1), and Von-Hippel-Lindau syndrome [1,4]. The clinical picture of NETs spans over different effects of excessive hormone secretion such as hypergastrinemia in Zollinger-Ellison Syndrome (ZES) with hyperchlorhydria, hyperinsulinemia in insulinoma, flushing MRT68921 dihydrochloride and diarrhoea in the serotoninergic carcinoid syndrome. In the case of nonsecreting NETs, symptoms present due to the adverse effects of the growing primary tumor or metastases [8]. == Biochemical Markers == Hormones secreted from NETs can be used as specific markers for NETs. Moreover, NETs express, store, and secrete characteristic neuronal proteins such as acid glycoprotein chromogranin A (a component of the membrane neurosecretory granula), neuron-specific-enolase (NSE), and synaptophysin [3,9]. These proteins derived from neuronal structures could serve as markers and are even positive in nonfunctioning NETs [1,3]. Since more than one half of NETs are nonsecreting, these proteins play a crucial role [4]. Assessment of different biochemical markers depends on various parameters, such as threshold cut-off level, detecting method of urine, serum or plasma as well as location of the primary tumor or metastases and extension of the disease. Due to the large variety and number of evaluation parameters, it is difficult to compare the studies [10,11]. == Histopathological Prognostic Markers == Ki67 is a monoclonal antibody, which was introduced in 1984 by Gerdes et al [11]. It detects a growth rate depending on the nuclear antigen Ki67 which is only expressed during active cell cycle phases (S, G2, and M-phase). Ki67 is completely absent during the resting phase G0. Therefore, cell proliferation is assessed by the immunohistologic presence of Ki67 positive cells per area in stained tissue blocks [11]. For various human neoplasms such as breast, lung, and solid cancers, Ki67 proliferation index has been successfully established as a predictive marker [12,13]. The higher the cell proliferation, the greater is the.