Analysis of KIT (CD117) expression in gallbladder carcinomas by tissue microarray.

AIMS: KIT (CD117) is a transmembrane tyrosinase-kinase receptor which has been related to cell proliferation, differentiation, adhesion and control of apoptosis. If present, KIT may provide a suitable target for tumour therapy. In this study, we report the presence of KIT in primary and metastatic gallbladder carcinomas. METHODS: Formalin-fixed and paraffin-embedded specimens of 57 primary gallbladder carcinomas and 18 corresponding metastases were stained using a tissue microarray technique and two different antibodies. RESULTS: Only three tumours stained for KIT. With a polyclonal antibody only one well differentiated papillary adenocarcinoma was immunoreactive. With a monoclonal antibody two additional poorly differentiated tubular adenocarcinoma showed weak and focal immunostaining. CONCLUSIONS: KIT immunoreactivity is infrequent in gallbladder carcinoma. Thus, routine screening of tumour tissues for KIT by immunohistochemistry appears to be cost-ineffective and cannot be recommended. Moreover, the lack of substantial KIT immunoreactivity in both primary and metastatic gallbladder carcinoma tissues does not provide a rationale to investigate imatinib mesylate therapy in clinical trials including patients with advanced disease.     

Biotransformation of the trapidil (rocornal) derivative AR 12463 in the rat

After p.o. administration of 5-piperidino-7-[N-pentyl-N-(beta- hydroxyethyl)]amino-s-triazolo[1,5-a]pyrimidine (1; AR 12463) more than 15 metabolites were isolated from urine and feces of male Wistar rats. Only small amounts of unchanged 1 were observed. The structure of 12 metabolites was elucidated or proposed on the basis of UV-, 13C NMR- and mass spectra. Main metabolites are 5-piperidin-4'-olyl-7-[N-pentyl-N-(beta- hydroxyethyl)]amino-s-triazolo[1,5-a]pyrimidine and 5-piperidin-4'-olyl-7-[N-pent-4-olyl-N-(beta-hydroxyet hyl)]amino-s- triazolo[1,5-a]pyrimidine. The other metabolites are mainly hydroxy- or ketopentyl derivatives and piperidinoles or piperidinones, respectively. Conjugates of most of the metabolites were identified, but the ratio phase-I/II metabolites was about 3:1. In contrast to trapidil, 5-methyl-7-diethylamino-s- triazolo[1,5-a]pyrimidine, no hydroxy derivatives of the bicyclic system were observed. The major part of unchanged 1 and metabolites is excreted via kidneys.     

Microalbuminuria in children and adolescents with and without Type-I diabetes mellitus (IDDM)

In 73 healthy (group I) and 32 children and juveniles with insulin dependent diabetes mellitus (IDDM, group II) urinary albumin excretion is determined by radioimmunoassay (RIA). In both groups albumin excretion is observed in every urine sample when measured by RIA (mean +/- SD: group I: 7-19 h: 5.17 +/- 5.28 mg, 19-7 h: 3.86 +/- 4.00 mg, 24 h: 9.03 +/- 8.60 mg; group II: 7-19 h: 6.68 +/- 6.86 mg, 19-7 h: 3.46 +/- 2.82 mg, 24 h: 10.13 +/- 9.25 mg). No significant difference is detected between the values of the two groups. However in diabetic patients a significant difference is observed between diurnal and nocturnal urinary albumin excretion. Microalbuminuria is defined as an albumin excretion above 30 mg/d and is present in 6.9% of the values in group I and in 3.1% in group II. The physiological limits of microalbuminuria in children and juveniles compared to adults and several methods of urine sampling are discussed.     

Histopathological diagnosis of Barrett's mucosa and associated neoplasias. Results of a consensus conference of the Working Group for "Gastroenterological Pathology of the German Society for Pathology" on 22 September 2001

There are a number of difficulties regarding the diagnosis of Barrett's mucosa and the varying grades of neoplasia that may be associated with it. It was therefore the aim of a consensus conference of the "Working Group for Gastroenterological Pathology within the German Society of Pathology" to achieve standardization regarding the following issues: definition and diagnostic criteria for Barrett's mucosa and its discrimination from intestinal metaplasia of the cardia, diagnostic criteria for intraepithelial neoplasia, number of biopsies necessary to establish the diagnosis, significance of additional immunohistochemical and/or molecular biological methods as well as importance of a second opinion in the diagnosis of intraepithelial neoplasia.     

Diagnostic reproducibility of tumour budding in colorectal cancer: a multicentre,multinational study using virtual microscopy

Puppa G, Senore C, Sheahan K, Vieth M, Lugli A, Zlobec I, Pecori S, Wang L M, Langner C, Mitomi H, Nakamura T, Watanabe M, Ueno H, Chasle J, Conley S A, Herlin P, Lauwers G Y & Risio M
(2012) Histopathology  61, 562–575 Diagnostic reproducibility of tumour budding in colorectal cancer: a multicentre, multinational study using virtual microscopy Aims: Despite the established prognostic relevance of tumour budding in colorectal cancer, the reproducibility of the methods reported for its assessment has not yet been determined, limiting its use and reporting in routine pathology practice. Methods and results: A morphometric system within telepathology was devised to evaluate the reproducibility of the various methods published for the assessment of tumour budding in colorectal cancer. Five methods were selected to evaluate the diagnostic reproducibility among 10 investigators, using haematoxylin and eosin (H&E) and AE1‐3 cytokeratin‐immunostained, whole‐slide digital scans from 50 pT1–pT4 colorectal cancers. The overall interobserver agreement was fair for all methods, and increased to moderate for pT1 cancers. The intraobserver agreement was also fair for all methods and moderate for pT1 cancers. Agreement was dependent on the participants’ experience with tumour budding reporting and performance time. Cytokeratin immunohistochemistry detected a higher percentage of tumour budding‐positive cases with all methods compared to H&E‐stained slides, but did not influence agreement levels. Conclusions: An overall fair level of diagnostic agreement for tumour budding in colorectal cancer was demonstrated, which was significantly higher in early cancer and among experienced gastrointestinal pathologists. Cytokeratin immunostaining facilitated detection of budding cancer cells, but did not result in improved interobserver agreement.     

Heightened Hippocampal β-Adrenergic Receptor Function Drives Synaptic Potentiation and Supports Learning and Memory in the TgF344-AD Rat Model during Prodromal Alzheimer's Disease

The central noradrenergic (NA) system is critical for the maintenance of attention, behavioral flexibility, spatial navigation, and learning and memory, those cognitive functions lost first in early Alzheimer''s disease (AD). In fact, the locus coeruleus (LC), the sole source of norepinephrine (NE) for >90% of the brain, is the first site of pathologic tau accumulation in human AD with axon loss throughout forebrain, including hippocampus. The dentate gyrus is heavily innervated by LC–NA axons, where released NE acts on β-adrenergic receptors (ARs) at excitatory synapses from entorhinal cortex to facilitate long-term synaptic plasticity and memory formation. These synapses experience dysfunction in early AD before cognitive impairment. In the TgF344-AD rat model of AD, degeneration of LC–NA axons in hippocampus recapitulates human AD, providing a preclinical model to investigate synaptic and behavioral consequences. Using immunohistochemistry, Western blot analysis, and brain slice electrophysiology in 6- to 9-month-old wild-type and TgF344-AD rats, we discovered that the loss of LC–NA axons coincides with the heightened β-AR function at medial perforant path–dentate granule cell synapses that is responsible for the increase in LTP magnitude at these synapses. Furthermore, novel object recognition is facilitated in TgF344-AD rats that requires β-ARs, and pharmacological blockade of β-ARs unmasks a deficit in extinction learning only in TgF344-AD rats, indicating a greater reliance on β-ARs in both behaviors. Thus, a compensatory increase in β-AR function during prodromal AD in TgF344-AD rats heightens synaptic plasticity and preserves some forms of learning and memory.SIGNIFICANCE STATEMENT The locus coeruleus (LC), a brain region located in the brainstem which is responsible for attention and arousal, is damaged first by Alzheimer''s disease (AD) pathology. The LC sends axons to hippocampus where released norepinephrine (NE) modulates synaptic function required for learning and memory. How degeneration of LC axons and loss of NE in hippocampus in early AD impacts synaptic function and learning and memory is not well understood despite the importance of LC in cognitive function. We used a transgenic AD rat model with LC axon degeneration mimicking human AD and found that heightened function of β-adrenergic receptors in the dentate gyrus increased synaptic plasticity and preserved learning and memory in early stages of the disease.     

Pancreatic acinar cells—a normal finding at the gastroesophageal junction? Data from a prospective Central European multicenter study

Pancreatic acinar cells are a well-recognized finding at the gastroesophageal junction, but their histogenesis and biological significance are unclear. From the prospective Central European multicenter histoGERD trial, we recruited 1,071 individuals undergoing gastroscopy for various non-selected reasons. Biopsy material was systematically sampled from the gastroesophageal junction and from the stomach. The study aimed to assess the prevalence of pancreatic acinar cells and to relate their presence to various histologic and clinical features. Overall, pancreatic acinar cells were observed in 184 (17.2 %) participants. Individuals diagnosed with pancreatic acinar cells were slightly younger than those without (median 50 vs. 53 years; p?=?0.009). There was no association with patients’ symptoms and/or complaints or with an endoscopic diagnosis of esophagitis or Barrett’s esophagus. Regarding histology, pancreatic acinar cells were not associated with features of the squamous epithelium indicating reflux disease, such as basal cell hyperplasia, papillary elongation, dilation of intercellular spaces, and inflammatory cell number, but were associated with the presence of cardiac mucosa (p?<?0.001), oxyntocardiac mucosa (p?<?0.001), and intestinal metaplasia (p?=?0.038), respectively. No association with Helicobacter pylori infection or diagnosis of gastritis was noted. In conclusion, pancreatic acinar cells are a common finding at the gastroesophageal junction, and no association with either reflux disease (histologically or endoscopically) or diagnosis of gastritis was observed. These data suggest a congenital rather than an acquired (metaplastic) origin of pancreatic acinar cells at the gastroesophageal junction. This questions the term “pancreatic acinar metaplasia” which is currently widely used for their diagnosis.