Growth factor modulation of hepatic inflammation: a novel approach to the management of total parenteral nutrition-associated liver disease.

PURPOSE: Dependence on total parenteral nutrition in intestinal failure or short bowel syndrome patients can lead to many complications. The most significant complication is progressive liver injury leading to liver failure. This study assesses the potential of hepatocyte growth factor (HGF) in modulating the hepatic response in a rat cholestatic liver injury model. METHODS: Female Sprague-Dawley rats were divided into 3 groups: control (n = 5), chronic liver injury (alpha-naphtylisocyocyanate [ANIT] every 3.5 days at 75 mg/kg; n = 5), and chronic liver injury plus HGF (ANIT + HGF at 250 microg kg(-1) d(-1); n = 5). The rats initially underwent massive (80%) small bowel resections. Seven days later, they were given intraperitoneal injections of saline (control) or ANIT and implantation of an osmotic minipump for continuous intravenous saline or HGF. Intraperitoneal saline or ANIT injections were subsequently administered every 3.5 days to create a chronic cholestatic model. After 14 days, the animals were euthanized, and liver biopsies were obtained. The liver biopsies were evaluated by histology, immunofluorescence staining for interleukin-6 and tumor necrosis factor alpha, and assessment of apoptosis by terminal dUTP-transferase-mediated nick end labeling (TUNEL) technique. RESULTS: In this chronic liver injury model, HGF did not effect the grade of inflammation. However, HGF did induce retention of the ductal structures and avoided ductal proliferation, damage, and evidence of primary sclerosing cholangitis (P < .05). Hepatocyte growth factor induced less interleukin-6 (P < .011) and tumor necrosis factor alpha (P < .01) expression. Apoptotic activity was also significantly less in the HGF group (P < .01). CONCLUSION: Hepatocyte growth factor preserved the hepatic ductal system, modulated the hepatic inflammatory response, and reduced the apoptotic index in this chronic cholestatic liver injury model. It may diminish or prevent liver damage in patients with total parenteral nutrition-induced liver injury.

Helicobacter pylori-negative gastritis in erosive esophagitis, nonerosive reflux disease or functional dyspepsia patients.

BACKGROUND: Although Helicobacter pylori infection is believed to be the main cause of chronic gastritis, a US clinical trial investigating the long-term effects of lansoprazole as maintenance therapy for erosive esophagitis revealed a surprisingly high prevalence (over 90%) and severity of chronic gastritis in H. pylori-negative subjects. GOALS: This study aims to compare prevalence and severity of chronic gastritis of the body and antrum in H. pylori-negative subjects with erosive esophagitis, nonerosive reflux disease, or functional dyspepsia from several trials. STUDY: Pretreatment gastric histology was compared in 1595 H. pylori-negative subjects with erosive esophagitis (>or= grade 2; n=196), nonerosive reflux disease (n=688), or functional dyspepsia (n=711) who participated in US Takeda-sponsored lansoprazole trials. RESULTS: Pretreatment histology data from US clinical studies showed that 67.5% and 75.0% of H. pylori-negative adult subjects with erosive esophagitis had moderate or severe body and antral chronic gastritis, respectively. Chronic gastritis was also observed in H. pylori-negative subjects with nonerosive reflux disease or functional dyspepsia, although prevalence was significantly less (P<0.001) than in erosive esophagitis. CONCLUSIONS: Chronic gastritis in H. pylori-negative subjects is more common than previously appreciated. These results highlight the need for better characterization of gastric mucosal histology in these gastrointestinal disorders.

Long-term quality of life improvement in subjects with healed erosive esophagitis: treatment with lansoprazole.

BACKGROUND: Gastroesophageal reflux disease (GERD) is a chronic symptomatic condition and may be associated with erosive esophagitis (EE). Considerable data on the long-term maintenance of healing of EE are available, but data on long-term GERD symptom prevention and patient quality of life (QOL) are limited. AIMS: To investigate QOL in subjects with healed EE who received 12 months of double-blind maintenance treatment with lansoprazole or ranitidine, followed by long-term open-label lansoprazole therapy to prevent recurrence of EE. METHODS: Subjects with healed EE received 12 months of double-blind maintenance treatment with lansoprazole 15 mg once daily or ranitidine 150 mg twice daily, followed by dose-titrated, open-label lansoprazole therapy for up to 82 months. RESULTS: During double-blind treatment (n = 206), lansoprazole-treated patients showed significantly (P

Growth factor manipulation of intestinal angiogenesis: a possible new paradigm in the management of inflammatory bowel disease.

BACKGROUND: Using the transgenic HLA-B27 rat model of inflammatory bowel disease (IBD), we have previously demonstrated hepatocyte growth factor's (HGF) potential to ameliorate diarrhea and decrease bowel injury. This study was designed to assess the effect of HGF on the neovascularization and inflammation in IBD. MATERIALS AND METHODS: Female transgenic HLA-B27 rats were divided into two groups: group 1, saline (control, n = 6); group 2, HGF (150 mug/kg/d, n = 9). Treatments were delivered into the jugular vein via a 14-d subcutaneously placed osmotic mini-pump. Intestinal microvascular density (MVD), histologic inflammatory score, inflammatory cell infiltration, and cytokine expression (tumor necrosis factor-alpha {TNF-alpha}, interferon-gamma {IFN-gamma}, and interleuken-2 {IL-2}) were assessed. Analysis of variance (ANOVA) was used to determine statistical significance. RESULTS: Administration of HGF resulted in variable but significant alterations in ileal and colonic histology compared with control animals. Compared with group 1, inflammatory cell infiltration was significantly reduced in group 2 (7.7 +/- 1.2 versus 13.3 +/- 2.1 SEM, P < 0.05). Enzyme linked immunosorbent assays (ELISA) demonstrated significantly less expression of ileal IFN-gamma, ileal IL-2 and colonic IL-2 in group 2 (P < 0.05) (Fig. 1). Of importance is that Group 2 exhibited significantly greater MVD in the ileum and colon, both P < 0.05 (Figs. 2 and 3). CONCLUSION: HGF stimulates neovascularization while modulating the intestinal inflammatory response. This is the first demonstration in which a growth factor (HGF) stimulates nonpathologic angiogenesis in an animal model of IBD. HGF administration may be beneficial in the clinical management of IBD.

Neuroendocrine adenoma of the middle ear (NAME).

Neuroendocrine adenoma of the middle ear (NAME) is a rare tumor. We report a case of NAME, the clinical and pathologic findings of which illustrate the biologic behavior of adenomatous tumors of the middle ear and their relationship with rare carcinoid tumors of the middle ear. A 29-year-old man presented with a history of recurrent otitis media, right conductive hearing loss, and aural fullness. The tumor was removed in its entirety. Otolaryngologists should be familiar with this unusual but important entity.

Long-term efficacy of lansoprazole in preventing relapse of erosive reflux esophagitis.

In a phase III study of lansoprazole treatment, patients with healed or unhealed erosive esophagitis entered a titrated open-label treatment period and received lansoprazole for

Lansoprazole for long-term maintenance therapy of erosive esophagitis: double-blind comparison with ranitidine.

In a study evaluating the efficacy and safety of lansoprazole to prevent the relapse of erosive esophagitis (EE), 206 of 241 patients (85%) healed after open-label treatment with lansoprazole 30 mg once daily for 8 weeks and received double-blind maintenance treatment with lansoprazole 15 mg once daily or ranitidine 150 mg twice daily for up to 1 year. At 1 year, 67% of lansoprazole-treated and 13% of ranitidine-treated patients remained healed (P<0.001). Lansoprazole-treated patients experienced significantly greater symptom relief (P<0.001), and, if asymptomatic at entry into the maintenance phase, remained asymptomatic for significantly longer than ranitidine-treated patients (P<0.001). Symptom status correlated with healing (P=0.001), supporting the symptom-directed management of EE. Both treatments were well tolerated and no unexpected events occurred. Daily therapy with lansoprazole to prevent the relapse of EE is effective, well tolerated, and superior to ranitidine in the maintenance of healing and symptom relief.

Increased sensitivity of anal cytology in evaluation of internal compared with external lesions.

OBJECTIVE: To investigate the impact of keratin on the accuracy of internal and external anal brush sampling of known lesions. STUDY DESIGN: A group of 46 human immunodeficiency virus (HIV)-seropositive patients underwent external and internal anal brush sampling before biopsy of known lesions. RESULTS; A total of 92 ThinPrep (46 external, 46 internal) an 211 biopsies were examined. The sensitivity and specificity for internal lesions positive and negative for anal squa mous intraepithelial lesion (ASIL) was 91.1% and 42.8%, respectively; and for external lesions was 79.4% and 100%, respectively. Low cellularity on cytology and markedly thickened keratin on biopsy were significantly more common in external compared with internal lesions (p < 0.0001). CONCLUSION: We conclude that hyperkeratosis interferes with adequate sampling and accurate grading of external anal lesions by brush sampling.

Prostatic basal cells in the peripheral and transitional zones: zonal variation in morphology and in immunophenotype.

BACKGROUND: Benign prostatic hyperplasia and prostatic adenocarcinoma exhibit prominent zonal predilections. Basal cells from the transitional zone and from the peripheral zone are postulated to have different underlying biological properties. We studied basal cells in both prostatic zones. METHODS: Tissue microarrays (TMA) were prepared from 65 whole-mounted prostatectomy specimens with prostatic adenocarcinoma. The transitional zone and peripheral zone were sampled from each prostate. TMA sections were stained with a basal cell cocktail (CK 34betaE12 + p63). The immunostaining pattern and the morphology of basal cells were recorded. RESULTS: Triangular-shaped basal cells were highlighted by CK 34betaE12 cytoplasmic and p63 nuclear staining. These basal cells had their long axis oriented perpendicular to the basement membrane and their apex toward the lumen interdigited between secretory luminal cells. This morphology was seen in the majority of peripheral zone benign prostatic glands (92.0%) but only a minority of transitional zone benign prostatic glands (18.0%). Basal cells of the transitional zone showed weak or absent CK 34betaE12 staining in 65.9% of glands while maintaining p63. All glands with high-grade prostatic intraepithelial neoplasia (HGPIN) contained the triangular basal cells. In addition, basal cell clusters were identified in 8.7% of peripheral zone glands and 5.2% of HGPIN glands. CONCLUSIONS: Our results indicate that the basal cell morphology and the basal cell immunophenotype have a zonal variation. The finding of a unique morphology of basal cells and the presence of basal cell clusters in the peripheral zone suggests that the peripheral zone might be the stem/progenitor cell-rich area in the human prostates.

Gastric biopsies: increasing the yield.

Gastric biopsies can provide useful information beyond the identification of inflammation or Helicobacter organisms. The key to maximizing the diagnostic yield is providing sufficient context, adequate sampling, and good communication. Clinical information including medical history, surgical procedures, endoscopic impression, and imaging findings aids in detection and classification of findings. Adequate biopsies entail good sampling technique, proper labeling, and submission. Histologic evaluation can be enhanced by special stains, ancillary studies, and working knowledge of the diversity of diagnoses. Difficult cases are best managed by a combined clinicopathologic approach.

Large-scale computations on histology images reveal grade-differentiating parameters for breast cancer.

BACKGROUND: Tumor classification is inexact and largely dependent on the qualitative pathological examination of the images of the tumor tissue slides. In this study, our aim was to develop an automated computational method to classify Hematoxylin and Eosin (H&E) stained tissue sections based on cancer tissue texture features. METHODS: Image processing of histology slide images was used to detect and identify adipose tissue, extracellular matrix, morphologically distinct cell nuclei types, and the tubular architecture. The texture parameters derived from image analysis were then applied to classify images in a supervised classification scheme using histologic grade of a testing set as guidance. RESULTS: The histologic grade assigned by pathologists to invasive breast carcinoma images strongly correlated with both the presence and extent of cell nuclei with dispersed chromatin and the architecture, specifically the extent of presence of tubular cross sections. The two parameters that differentiated tumor grade found in this study were (1) the number density of cell nuclei with dispersed chromatin and (2) the number density of tubular cross sections identified through image processing as white blobs that were surrounded by a continuous string of cell nuclei. Classification based on subdivisions of a whole slide image containing a high concentration of cancer cell nuclei consistently agreed with the grade classification of the entire slide. CONCLUSION: The automated image analysis and classification presented in this study demonstrate the feasibility of developing clinically relevant classification of histology images based on micro- texture. This method provides pathologists an invaluable quantitative tool for evaluation of the components of the Nottingham system for breast tumor grading and avoid intra-observer variability thus increasing the consistency of the decision-making process.

Orbital lymphoma with concomitant sarcoid-like granulomas.

A 41-year-old man presented with chronic eyelid swelling, conjunctival injection, and decreased ocular motility in all gaze directions. MRI showed bilateral enlarged extraocular muscles, including the tendons. Laboratory tests revealed elevated levels of angiotensin-converting enzyme. An orbital biopsy showed collections of monotonous small lymphocytes, and granulomatous inflammation that included multinucleated giant cells, predominantly Langhans type. Flow cytometric analysis of tissue demonstrated a light chain-restricted clonal population of B cells, a finding that confirmed the morphologic impression of lymphoma. This case demonstrates that elevated angiotensin-converting enzyme and granulomatous inflammation can occur in lymphoma. Careful histopathologic examination and flow cytometric analysis are essential to avoid an erroneous diagnosis that could lead to inappropriate management.

Rab11a immunohistochemical analysis does not distinguish indefinite, low-, and high-grade dysplasia in Barrett esophagus.

Our aim was to determine whether p53 and Rab11a immunoreactivity enhance diagnostic assessment of esophageal dysplasia. Histologic sections from 68 cases of Barrett esophagus obtained as part of a 12-institution study were stained with antibodies to p53 and Rab11a, randomized, and coded. The mucosal surface layer and deeper glands were scored blindly on a semiquantitative scale. The correlations between p53 and Rab11a scoring with the consensus diagnosis of dysplasia were analyzed. The histologic scale was as follows: no dysplasia, indefinite, low-grade dysplasia, high-grade dysplasia, intramucosal carcinoma, and invasive carcinoma. Rab11a staining was most prominent in epithelia negative for dysplasia but with regenerative features. There was an inverse relationship between Rab11a staining and findings of surface dysplasia (P < .02, chi(2)). However, statistical significance largely reflected loss of Rab11a immunoreactivity in intramucosal and invasive carcinoma, which was not a diagnostic dilemma. There was a strong positive correlation of p53 immunoreactivity with an increasing degree of epithelial dysplasia and carcinoma (P < .03, chi(2)). Rab11a immunoreactivity did not enhance the diagnostic assessment of dysplasia in Barrett esophagus. The previously reported positive correlation of p53 immunoreactivity with the presence of dysplasia in Barrett esophagus was confirmed.

Gastrointestinal neurofibromatosis: an unusual cause of gastric outlet obstruction.

Neurofibromatosis type-1 (NF-1), also known as von Recklinghausen disease, is a common autosomal dominant condition occurring in approximately 1/3000 births. NF-1 is known to be associated with gastrointestinal neoplasms in 2-25 per cent of patients. We report the first case of gastric outlet obstruction with perforation caused by neurofibroma in a patient with NF-1. The literature is reviewed, examining 61 previously reported cases of noncarcinoid gastrointestinal (GI) neoplasms in patients with NF-1 for symptoms, location, and types of neoplasms. Neoplasms were located most often in the small intestine (72%). Neurofibromas, found in 52 per cent of patients, were the most frequently diagnosed benign neoplasms followed by leiomyomas (13%), ganglioneurofibromas (9.8%), and gastrointestinal stomal tumor (GIST) (6.5%). Adenocarcinoma was present in 23 per cent of patients. Patients with NF-1 and GI symptoms are at risk for gastrointestinal neoplasms from which symptomatic patients are likely to experience significant morbidity.

Malignant pericardial effusion--an uncommon complication of multiple myeloma: case report.

Multiple myeloma is a condition usually associated with lesions of the skeleton. However, under rare circumstances, the malignant plasma cells may infiltrate the pericardium, resulting in an effusion. If left untreated, the abnormal accumulation of pericardial fluid will result in cardiac tamponade, requiring drainage. The following report describes a multiple myeloma patient who developed secondary pericardial and pleural effusions, which were surgically drained via a pleuropericardial window.

Malignant fibrous histiocytoma of the head and neck after radiation for squamous cell carcinoma.

A 60-year-old man presented with malignant fibrous histiocytoma of the oropharynx. The mass extended into the nasopharynx and larynx and caused severe upper airway obstruction that required emergency tracheotomy. Ten years earlier, he had undergone a right partial glossectomy and segmental mandibulectomy for squamous cell carcinoma of the right tongue base,followed by 50 Gy of radiation delivered over 33 sessions. The tumor was so aggressive that changes in its volume were visually distinguishable during physical examination over a 2-week hospital stay. Histologic evaluation revealed 7 mitotic figures per high-power field. Although radiation-induced malignant fibrous histiocytoma is rare in the head and neck, the recent medical literature indicates that its incidence is rising. This rise has been attributed to the increased effectiveness of head and neck cancer therapy, which results in prolonging patients' survival and, hence, their risk of subsequent disease. Because malignant fibrous histiocytoma is a late complication of radiation therapy, appearing on average 10 years following treatment, it is important that physicians who treat head and neck cancer monitor these patients over the long term and remain alert for its appearance, even despite the apparent "cure" of their original neoplasm.

Carcinoembryonic antigen elevation due to bowel sequestration with mucocele formation following colonic resection.

Carcinoembryonic antigen (CEA) is recommended as a serologic marker to monitor colorectal carcinoma recurrence. Elevations of CEA due to causes other than carcinoma exist and may lead to a misdiagnosis of recurrent carcinoma. We report a case of bowel sequestration with mucocele formation at the site of previous colo-colic anastomosis causing a mild elevation in CEA. The patient exhibited increasing CEA levels 6 years after resection of a sigmoid colon carcinoma with end-to-end anastomosis. Subsequently, computed tomographic and positron emission tomographic scans documented the presence of a cystic mass showing increased uptake at the anastomotic site. At exploratory laparotomy a mass lesion with mucus-filled protrusions was resected. Pathologic examination documented the presence of sequestration of a segment of the bowel wall with a mucocele and no overlying defect at the mucosal anastomotic site by demonstrating the presence of all bowel layers. After resection of the lesion, the CEA level normalized.

Pancreatic acinar cell metaplasia in autoimmune gastritis.

OBJECTIVE: To determine the frequency and significance of pancreatic acinar cells in the gastric oxyntic mucosa. DESIGN: One hundred gastric oxyntic mucosal biopsy specimens from patients with chronic active gastritis (n = 30), multifocal atrophic gastritis (n = 15), autoimmune gastritis (n = 18), and normal gastric oxyntic mucosa (n = 37) were evaluated for the presence of pancreatic acinar cells. Formalin-fixed, paraffin-embedded tissues were stained with hematoxylin-eosin, and those positive for pancreatic acinar cells were immunostained with antibodies against trypsin and pancreatic amylase. RESULTS: Eleven (11%) of 100 oxyntic mucosal tissue samples contained pancreatic acinar cells. These samples came from 9 of the 18 (50%) specimens of autoimmune gastritis, 1 of the 15 (6.6%) specimens of multifocal atrophic gastritis, and 1 of the 37 (2.7%) specimens of normal oxyntic mucosa. None of the samples with chronic active gastritis contained pancreatic acinar cells. CONCLUSIONS: Pancreatic acinar cells were found in the oxyntic mucosa of patients with autoimmune gastritis significantly more frequently (P <.001) than in individuals with multifocal atrophic gastritis, normal oxyntic mucosa, or chronic active gastritis. Our study supports a metaplastic origin for pancreatic acinar cells in the oxyntic mucosa. Furthermore, detection of pancreatic acinar cells in the oxyntic mucosa of patients with gastritis strongly suggests an autoimmune pathogenesis.

Effect of H. pylori status on gastric ulcer healing in patients continuing nonsteroidal anti-inflammatory therapy and receiving treatment with lansoprazole or ranitidine.

OBJECTIVES: The purpose of this research was to determine the impact of pretreatment Helicobacter pylori infection on gastric ulcer healing rates in patients receiving nonsteroidal anti-inflammatory drugs (NSAIDs) and antisecretory medications. METHODS: This was a pooled, prospective analysis of two identical double blind, multicenter, parallel group studies. Six hundred ninety-two patients receiving NSAIDs and with endoscopy-documented gastric ulcers were enrolled from 90 North American sites in primary care and referral centers. Patients were randomized to receive ranitidine (150 mg b.i.d.) or lansoprazole (15 mg or 30 mg once daily) for 8 wk. Ulcer healing was assessed by endoscopy at 4 and 8 wk in an intent-to-treat population. H. pylori status was determined at baseline by histology. RESULTS: Across all three treatment groups, gastric ulcers were more likely to heal and heal faster if the individual was infected with H. pylori. Healing rates at 8 wk were statistically significantly greater among H. pylori positive patients (n = 181) than among negative patients (n = 497) (70% vs 61%, respectively; p < 0.05), especially among those with large ulcers (> 10 mm) and in younger patients (< 60 yr old). Simple healing rates (regardless of H. pylori status) were significantly better in the 15- and 30-mg lansoprazole groups than in the ranitidine group after 4 wk (46%, 54%, and 32%, respectively; p < or = 0.01) and 8 wk (66%, 74%, and 50%, respectively; p < 0.001). CONCLUSIONS: In patients receiving NSAIDs, gastric ulcer healing with an antisecretory agent is significantly enhanced in the presence of H. pylori infection.

The type of sodium-coupled solute modulates small bowel mucosal injury, transport function, and ATP after ischemia/reperfusion injury in rats.

BACKGROUND & AIMS: Gastrointestinal function may be impaired after severe injury, hampering tolerance to enteral nutrition. The purpose of this study was to determine how different sodium-coupled solutes modulate gut function after ischemia/reperfusion (I/R) in a rodent model. METHODS: At laparotomy, rats had jejunal sacs filled with (glucose + alanine), glucose, glutamine, alanine, or mannitol (osmotic control), followed by superior mesenteric artery clamping for 60 minutes and 30 minutes of reperfusion. After reperfusion, sacs were harvested for morphologic examination, adenosine triphosphate (ATP) assay, or mounted in an Ussing chamber. RESULTS: Small intestinal epithelial absorptive capacity, as assessed by changes in short-circuit current in response to glucose, after gut I/R, was decreased by alanine or (glucose + alanine) but not glucose or glutamine alone and correlated with changes in tissue ATP. Gut I/R caused a significant morphologic injury that was worsened by alanine or (glucose + alanine) but lessened by glucose or glutamine alone. CONCLUSIONS: During gut I/R, alanine can enhance gut injury, deplete energy (ATP), and impair gut absorption, whereas glucose or glutamine is protective against injury and can maintain absorptive capacity and ATP. These results suggest that solutes (such as alanine), which further stress an already metabolically stressed bowel, should be cautiously administered to critically ill patients whereas those solutes that contribute to energy production (such as glucose and glutamine) may be safely continued.