Search

Purpose: Crohn's disease is a type of inflammatory bowel disease affecting estimated 4 million people worldwide. Therapy stratification of Crohn's disease (CD) is mainly based on the inflammatory activity being assessed by endoscopic biopsy and clinical criteria. Cross-sectional imaging allows for the assessment of structural characteristics of the entire gastrointestinal tract including small bowel loops and may provide potential non-invasive image-based biomarkers for the inflammatory activity of CD. The aim of this study was to explore the predictive value of Computed Tomography-based morphologic patterns for inflammatory activity in CD., Material and Methods: 42 patients diagnosed with CD were included in a retrospective study (13 male, 29 female, median age 32 years). Abdominal CT imaging was carried out on symptomatic patients at a single institution 0-10 days prior to endoscopic biopsy or surgery using a protocol optimized for the characterization of structural bowel alterations. Image data were initially reviewed independently by three radiologists and discrepancies were settled in consensus with a focus on mesenteric fat stranding and combing, mesenteric adenopathy, mesenteric abscess, intraperitoneal free fluid, fistula, skip lesions, highest wall thickness and the localization of the affected bowel. The extent of inflammatory activity in the bowel wall was determined subsequently by histological analysis., Results: All intestinal and extraintestinal CT findings except the mesenteric comb sign showed a tendency towards higher extent or prevalence in patients with high histological inflammatory activity score, especially median bowel wall thickness (6.0 mm vs. 3.5 mm), mesenteric abscesses (32% vs. 0%) and mesenteric adenopathy (94% vs. 45%). Spearman rank order correlation coefficient indicated a significant correlation of bowel wall thickness (r = 0.40, p < 0.05), mesenteric adenopathy (r = 0.54, p < 0.05), mesenteric abscess (r = 0.33, p < 0.05) and mesenteric fat stranding (r = 0.33, p < 0.05) with the histological inflammatory activity score., Conclusion: CT-based biomarkers including wall thickness, mesenteric fat stranding, mesenteric lymphadenopathy and mesenteric abscess positively correlated with the histological inflammatory activity score and therefore provided additional information for therapy stratification in symptomatic patients with CD, particularly as most of these biomarkers are hidden from endoscopy.

Knowledge of the exact cell content of frozen tissue samples is of growing importance in genomic research. We developed a microaliquoting technique to measure and optimize the cell composition of frozen tumor specimens for molecular studies. Frozen samples of 31 mesothelioma cases were cut in alternating thin and thick sections. Thin sections were stained and evaluated visually. Thick sections, i.e., microaliquots, were annotated using bordering stained sections. A range of cellular heterogeneity was observed among and within samples. Precise annotation of samples was obtained by integration and compared to conventional single face and "front and back"’ section estimates of cell content. Front and back estimates were more highly correlated with block annotation by microaliquoting than were single face estimates. Both methods yielded discrepant estimates, however, and for some studies may not adequately account for the heterogeneity of mesothelioma or other malignancies with variable cellular composition. High yield and quality RNA was extracted from precision annotated, tumor-enriched subsamples prepared by combining individual microaliquots with the highest tumor cellularity estimates. Microaliquoting provides accurate cell content annotation and permits genomic analysis of enriched subpopulations of cells without fixation or amplification.

Inhibitor of apoptosis proteins (IAPs) comprise a family of structurally similar proteins, five of which are widely studied in the context of cancer: IAP-1/MIHC/cIAP2, IAP-2/MIHB/cIAP1, livin/ML-IAP/KIAP, survivin, and XIAP/MIHA/hILP. IAPs are overexpressed by most neoplasms, promote tumour cell survival after a wide variety of apoptotic stimuli, and frequently have gene and/or protein expression patterns associated with a relatively poor prognosis. However, many IAPs are also expressed by normal tissues, can facilitate apoptotic cell death, and have expression patterns associated with a relatively favourable prognosis in some cases. The result is that the precise role(s) of IAPs in human tumours is not exactly known. It has been previously reported that IAP-1 is overexpressed in malignant pleural mesothelioma (MPM) and is responsible for a large degree of the resistance of cultured MPM cells to cisplatin. Given the high homology of IAP family members, it is likely that other IAPs will be important in MPM. In the present study, the gene and protein expression patterns of IAP-1, IAP-2, survivin, livin, and XIAP have been determined in MPM cell lines (n=9) and a large number of MPM tumours using high-density oligonucleotide microarrays (n=40) and an MPM tissue array (n=66). Human tumours were linked to clinical data and it was found that IAP-1 and survivin mRNA expression patterns were associated with a relatively shorter patient survival, while those of XIAP and livin were associated with a relatively longer patient survival. Abundant protein for all IAPs was also detected in MPM tumours, where they were expressed primarily in the cytoplasm. Only IAP-1 and livin protein was expressed in the nucleus of MPM tumours. These results provide the rationale for additional study of this gene family in MPM and cancer in general., (Copyright (c) 2007 Pathological Society of Great Britain and Ireland.)

Objective: The purpose of this study was to analyze the correlation between pneumatosis or portomesenteric venous gas, or both, the severity of mural involvement, and the clinical outcome in patients with small- or large-bowel ischemia., Materials and Methods: CT scans of 23 consecutive patients presenting with pneumatosis or portomesenteric venous gas caused by bowel ischemia were reviewed. The presence and extent of both CT findings were compared with the clinical outcome in all patients and with the severity and extent of ischemic bowel wall damage as determined by surgery (15 patients), autopsy (three patients), or follow-up (five patients)., Results: Seven patients showed isolated pneumatosis, and 16 patients showed portomesenteric venous gas with or without pneumatosis (11 and five patients, respectively). Pneumatosis and portomesenteric venous gas were associated with transmural bowel infarction in 14 (78%) of 18 patients and 13 (81%) of 16 patients, respectively. Nine patients (56%) with portomesenteric venous gas died. Of seven patients with infarction limited to one bowel segment (jejunum, ileum, or colon), only one patient (14%) died, whereas of the 10 patients with infarction of two or three bowel segments, eight patients (80%) died., Conclusion: CT findings of pneumatosis intestinalis and portomesenteric venous gas due to bowel ischemia do not generally allow prediction of transmural bowel infarction, because they may be observed in patients with only partial ischemic bowel wall damage. The clinical outcome of patients with bowel ischemia with these CT findings seems to depend mainly on the severity and extent of their underlying disease.

p63 is a p53-related DNA-binding protein that helps regulate differentiation and proliferation in epithelial progenitor cells. Its expression has never been evaluated in the human gastrointestinal tract. The aim of this study was to evaluate the expression of p63 in the esophagus and related metaplastic and neoplastic disorders to gain insight into the pathogenesis of these processes. Of particular interest was the expression of p63 in Barrett esophagus (BE) and in BE-associated multilayered epithelium. Multilayered epithelium has been postulated to represent an early precursor to the development of BE primarily because it shares morphologic and immunophenotypic features of both squamous and columnar epithelium, and has been shown prospectively to be highly associated with BE. Routinely processed mucosal biopsy or resection specimens that contained normal esophageal squamous epithelium (n = 20), squamous dysplasia (n = 4), squamous cell carcinoma (n = 7), BE (n = 10), BE-associated multilayered epithelium (n = 13), esophageal mucosal gland ducts (n = 10), BE-associated dysplasia (n = 12), and BE-associated adenocarcinoma (n = 7) were immunostained for p63 to determine the extent and location of staining. p63 staining was compared with the staining patterns observed for p53, Ki 67 (proliferation marker), and cytokeratins (CKs) 13 (squamous marker), 14 (basal squamous marker), 8/18 (columnar marker), and 19 (basal/columnar marker). Expression of p63 messenger RNA (mRNA) isoforms was also analyzed by reverse-transcription polymerase chain reaction of freshly isolated tissues. In the normal esophagus, p63 was expressed in the basal and suprabasal layers of the squamous epithelium and in basal cells that line the mucosal gland ducts but was negative in all other epithelia of the gastrointestinal tract, including the stomach, small intestine, and colon. Similarly, p63 was not expressed in BE, but it, was present in the basal layer of multilayered epithelium in 9 of 13 cases (69%). p63-positive cells in multilayered epithelium and in the mucosal gland duct epithelium were positive for CK8/18 (100%) and CK13 (67% and 30%, respectively) and negative for CK14 (0%), in contrast to p63-positive cells in squamous epithelium, which were positive for CK14 and CK13 (100%) but negative for CK8/18. In neoplastic tissues, p63 was diffusely expressed in all cases of esophageal squamous cell dysplasia and carcinoma but was negative in all cases of esophageal and colorectal adenocarcinoma. The DeltaN isoform of p63 mRNA predominated in all benign and neoplastic squamous tissues examined. p63 may represent a marker of 2 distinct epithelial progenitor cells (basal squamous epithelium and gland duct epithelium) in the esophagus. P63 is upregulated in squamous neoplastic conditions and in this manner may play a role in squamous carcinogenesis. These data also indicate that multilayered epithelium is phenotypically similar to, and may share a lineage relationship with, mucosal gland duct epithelium., (Copyright 2001 by W.B. Saunders Company)

A wide variety of infectious, inflammatory, and other disorders affect the gastric mucosa in pediatric patients. The most common cause of gastritis in children is Helicobacter pylori infection, which is also responsible for the majority of duodenal ulcers. Acute erosive gastritis is most commonly the result of metabolic stress or drug or corrosive injury. Other major causes of gastritis include celiac disease, allergic disorders, and Crohn's disease. The distinctive clinical, endoscopic, and histologic features of these disorders are discussed.

A distinctive type of multilayered epithelium (ME) has been described at the neo-squamocolumnar junction and within columnar mucosa in patients with Barrett's esophagus (BE). This epithelium has morphologic and ultrastructural features of both squamous and columnar epithelium. Multilayered epithelium may represent an early or intermediate stage of columnar metaplasia; therefore, we performed this study to determine the morphologic and biologic characteristics of this epithelium and to gain insight into its derivation. Esophageal mucosal biopsies containing ME from 17 patients with BE were evaluated morphologically, stained with a variety of mucin histochemical stains; and also immunostained with antibodies against cytokeratins (CK) 13 (squamous epithelium marker); 14 (basal squamous epithelium marker) 7, 8/18, 19, and 20 (columnar epithelium markers), MIB-1 (proliferation marker); villin (intestinal brush border protein); and TGFalpha, EGFR, pS2, and hSP (enteric proliferation/differentiation regulatory peptides). The results were compared with normal esophageal squamous epithelium, normal gastric cardia epithelium, specialized-type intestinal epithelium (BE), and esophageal mucosal and submucosal gland duct epithelium. Multilayered epithelium expressed a pattern of mucin production (neutral mucin, sialomucin, and sulfomucin in 88%, 100%, and 71% of cases, respectively) and cytokeratin expression (CK 13 and 19 in the basal "squamoid" cells, CK 7, 8/18, 19, and 20 in the superficial "columnar" cells) similar to that of columnar epithelium in BE, and showed a high capacity for cellular proliferation (Ki-67-positive in 88% of cases) and differentiation (TGFalpha, EGFR, pS2 and villin-positive in 100%, 100%, 93%, and 66% of cases, respectively). The mucosal gland duct epithelium showed a similar phenotypic pattern and, in one case, was seen to give rise to ME at the surface of the mucosa. These data provide evidence in support of the hypothesis that ME represents an early or intermediate stage in the development of esophageal columnar metaplasia (BE). The mucosal gland duct epithelium may contain progenitor cells that can give rise to ME.

von Hippel-Lindau (VHL) disease is a pleomorphic familial tumor syndrome that is characterized by the development of highly vascularized tumors. Homozygous disruption of the VHL gene in mice results in embryonic lethality. To investigate VHL function in the adult we have generated a conditional VHL null allele (2-lox allele) and null allele (1-lox allele) by Cre-mediated recombination in embryonic stem cells. We show here that mice heterozygous for the 1-lox allele develop cavernous hemangiomas of the liver, a rare manifestation of the human disease. Histologically these tumors were associated with hepatocellular steatosis and focal proliferations of small vessels. To study the cellular origin of these lesions we inactivated VHL tissue-specifically in hepatocytes. Deletion of VHL in the liver resulted in severe steatosis, many blood-filled vascular cavities, and foci of increased vascularization within the hepatic parenchyma. These histopathological changes were similar to those seen in livers from mice heterozygous for the 1-lox allele. Hypoxia-inducible mRNAs encoding vascular endothelial growth factor, glucose transporter 1, and erythropoietin were up-regulated. We thus provide evidence that targeted inactivation of mouse VHL can model clinical features of the human disease and underline the importance of the VHL gene product in the regulation of hypoxia-responsive genes in vivo.

The authors describe the case of a 36-year-old man who presented with bitemporal hemianopsia and a serum prolactin concentration of 1440 ng/ml. Magnetic resonance imaging of the pituitary revealed a presumed macroadenoma with suprasellar and temporal lobe extension. Although the patient's prolactin level was lowered to 55 ng/ml by bromocriptine therapy, no tumor shrinkage occurred. Fourteen months later, progression of visual field defects necessitated transsphenoidal resection, which was incomplete. Immunocytochemical analysis of the biopsy tissue was positive for prolactin and, in view of the clinical picture, more detailed analysis was not performed. External-beam radiotherapy was given 2 years later because of enlargement of residual tumor. Subsequently, despite a fall in the serum prolactin concentration to less than 20 ng/ml in response to the course of bromocriptine, the mass displayed further extension into the temporal lobe. Nine years after the patient's initial presentation, he underwent transfrontal craniotomy for sudden deterioration in visual acuity caused by hemorrhage into the mass. No adenohypophyseal tissue was identified in the resected tissue. The mass was composed of dysplastic neurons that were strongly immunoreactive for synaptophysin and neurofilament (indicating neural differentiation) and prolactin. Review of the original biopsy specimen indicated that the prolactin-positive cells had striking neuronal morphological characteristics. The final diagnosis in this case is prolactin-secreting gangliocytoma. Although exceedingly rare, this disease must be added to the differential diagnosis in cases of "prolactinoma" when bromocriptine therapy is followed by a marked decline in serum prolactin that is not accompanied by significant tumor shrinkage. Furthermore, in such instances, consideration should be given to "obtaining a biopsy sample prior to electing for radiotherapy.

Background: Lymph node metastasis is a well known feature of poor prognosis in patients with esophageal adenocarcinoma and squamous cell carcinoma. However, a significant proportion of apparently lymph node negative patients die early of metastatic disease. The aim of this study was to determine the prevalence and prognostic significance of occult lymph node metastasis in patients with esophageal adenocarcinoma and squamous cell carcinoma., Methods: Lymph node sections from esophagectomy specimens of 78 patients with lymph node negative esophageal carcinoma (49 patients with adenocarcinoma and 29 with squamous cell carcinoma) were cut serially, it toto, and immunostained with the cytokeratin antibody AE1/AE3 and evaluated for occult lymph node metastasis. The results were correlated with the clinical and pathologic features and with patient survival., Results: Fifteen of 49 patients (31%) with adenocarcinoma and 5 of 29 patients (17%) with squamous cell carcinoma had occult lymph node metastasis detected by cytokeratin staining. In the adenocarcinoma patients, the presence of occult lymph node metastasis showed a significant correlation with increasing depth of invasion, but was not associated significantly with any other clinical or pathologic feature. In the squamous cell carcinoma patients, the presence of occult lymph node metastasis did not correlate significantly with any clinical or pathologic parameter, except that patients with occult lymph node metastasis were more likely to have received preoperative chemotherapy or radiation therapy. Occult lymph node metastasis did not correlate with poorer survival rates in patients with either adenocarcinoma (Cox proportional hazards ratio: 1.42; P - 0.46) or squamous cell carcinoma (Cox proportional hazards ratio: 0.86; P = 0.90)., Conclusions: Occult lymph node metastasis is not an independent poor prognostic feature in esophageal adenocarcinoma or squamous cell carcinoma. Therefore, the authors do not recommend extensive lymph node sectioning with keratin immunostaining for prognostication of patients with these malignancies.

The genetic disease abetalipoproteinemia is characterized by a total absence of apolipoprotein B-containing lipoproteins from plasma. A presumed synthetic defect in apolipoprotein B synthesis was thought to be responsible for this disorder. The present study quantitates apoprotein B synthesis and apolipoprotein B messenger RNA levels in duodenal mucosa from normal patients and four patients with abetalipoproteinemia. After in vitro [3H]leucine incorporation, small intestinal biopsy specimens from three of four patients with abetalipoproteinemia synthesized immunoprecipitable apolipoprotein B of identical mobility (on sodium dodecyl sulfate gel electrophoresis) to normal apolipoprotein B. In abetalipoproteinemia, the apolipoprotein B content of intestinal mucosa by radioimmunoassay was 15% of normal mucosal values, whereas apolipoprotein B messenger RNA quantitation showed 3-20-fold increased levels compared with normal mucosa. In one patient, smaller-molecular-weight fragments of apolipoprotein B were immunoprecipitated from duodenal biopsy specimens. The synthesis rates and messenger RNA levels of two other chylomicron apoproteins (apolipoprotein A-I and apolipoprotein A-IV) were found to be reduced by 50%. These results show the synthesis of immunologically recognizable apolipoprotein B48 in abetalipoproteinemia. The significance of mucosal apolipoprotein B content in abetalipoproteinemia is discussed in terms of factors controlling apolipoprotein B synthesis in normal mucosa and in abetalipoproteinemia.