Neonatal co-infection with helicobacter species markedly accelerates the development of inflammation-associated colonic neoplasia in IL-10(-/-) mice.

BACKGROUND: Inflammatory bowel disease (IBD) is hypothesized to represent an aberrant immune response against enteric bacteria that occurs in a genetically susceptible host. Humans and mice with IBD are at markedly increased risk for colonic neoplasia. However, the long lead time required before development of inflammation-associated colon neoplasia in commonly used murine models of IBD slows the development of effective chemopreventative therapies. MATERIALS AND METHODS: Neonatal coinfection with Helicobacter typhlonius and Helicobacter rodentium was used to trigger the onset of IBD in mice deficient in the immunoregulatory cytokine interleukin (IL)-10. The severity of colon inflammation and incidence of neoplasia was determined histologically. RESULTS: IL-10(-/-) mice demonstrated early onset, severe colon inflammation following neonatal infection with H. typhlonius and H. rodentium. The incidence of inflammation-associated colon neoplasia was approximately 95% at a mean age of 21 +/- 2 weeks. Mutation of endoglin, an accessory receptor for TGF-beta, did not affect the severity of IBD or the incidence of neoplasia in this model. CONCLUSIONS: The rapid onset of severe colon inflammation and multiple neoplastic lesions in the colons of IL-10(-/-) mice neonatally coinfected with H. typhlonius and H. rodentium makes this model well-suited for investigating the mechanisms involved in inflammation-associated colon cancer as well as its chemoprevention.

Functional evaluation of the grafted wall with porcine-derived small intestinal submucosa (SIS) to a stomach defect in rats.

BACKGROUND: Small intestinal submucosa (SIS) represents a novel bio-scaffolding material that may be used to repair hollow-organ defects. However, it is unclear whether neurophysiologic responses return to SIS-grafted areas in the gut. We evaluated the functional recovery of a stomach defect grafted with the porcine-derived SIS. METHODS: Twelve rats had a full-thickness defect created in the stomach. SIS was secured to the gastric wall. After 6 months, muscle strips were harvested from within the grafted area to perform both a histologic and a functional study. Additional full-thickness muscle strips were harvested from the posterior in the same stomach as controls. A dose response curve was obtained with carbachol (CCH) or sodium nitroprusside (SNP). Activation of intrinsic nerves was achieved by electrical field stimulation (EFS). RESULTS: The response to CCH and amplitude in EFS showed tonic contraction in both controls and SIS strips in a concentration-dependent and frequency-dependent manner. The magnitude after each stimulation was significantly lower in SIS strips compared with controls (P < .01). However, the contraction ratio of EFS to ED(50) of CCH was not significantly different between the groups. Additionally, SNP produced relaxation in both strips in a concentration-dependent manner. Histologic findings revealed that an insufficient amount of smooth-muscle cells existed in the muscularis propria, whereas compensated growth was observed in the submucosa with nerve regeneration. CONCLUSIONS: This study demonstrates that SIS provides a template for nerve migration to the graft in the rodent stomach. Innervations showed a similar distribution to that observed in the controls. The clinical implications of such findings warrant additional investigation.

In situ detection of nuclear atypia in Barrett's esophagus by using angle-resolved low-coherence interferometry.

BACKGROUND: Monitoring of patients with Barrett's esophagus (BE) for dysplasia, currently done by systematic biopsy, can be improved through increasing the proportion of at-risk tissue examined. OBJECTIVE: Optical biopsy techniques, which do not remove the tissue but interrogate the tissue with light, offer a potential method to improve the monitoring of BE. Frequency-domain angle resolved low-coherence interferometry (fa/LCI) is an optical spectroscopic technique applied through an endoscopic fiber bundle and measures the depth-resolved nuclear morphology of tissue, a key biomarker for identifying dysplasia. The aim of the study was to assess the diagnostic capability of fa/LCI for differentiating healthy and dysplastic tissue in patients with BE. METHODS: Depth-resolved angular scattering data are acquired by using fa/LCI from tissue excised from 3 patients who had esophagogastrectomy. The data are processed to determine the average nuclear size and density as a function of depth beneath the tissue surface. These data are compared with the pathologic classification of the tissue. MAIN OUTCOME MEASUREMENTS: Average of depth-resolved nuclear diameter and nuclear density measurements in tissue samples. RESULTS: Upon comparison to pathologic diagnosis, the fa/LCI data results report the nuclear atypia characteristic of dysplasia in the epithelial tissue. Examination of the average nuclear morphology over the superficial 150 mum results in complete separation between healthy columnar and BE dysplastic tissues. LIMITATIONS: Lack of in vivo data; lack of nondysplastic BE data because of limited sample size. CONCLUSIONS: In complicated tissue structures, such as BE, depth-resolved nuclear morphology measurements provided an excellent means to identify dysplasia. The preliminary results demonstrate the great potential for the in vivo application of fa/LCI as a targeting mechanism for physical biopsy in patients with BE.

Glycogen storage disease type III-hepatocellular carcinoma a long-term complication?

BACKGROUND/AIMS: Glycogen storage disease III (GSD III) is caused by a deficiency of glycogen-debranching enzyme which causes an incomplete glycogenolysis resulting in glycogen accumulation with abnormal structure (short outer chains resembling limit dextrin) in liver and muscle. Hepatic involvement is considered mild, self-limiting and improves with age. With increased survival, a few cases of liver cirrhosis and hepatocellular carcinoma (HCC) have been reported. METHODS: A systematic review of 45 cases of GSD III at our center (20 months to 67 years of age) was reviewed for HCC, 2 patients were identified. A literature review of HCC in GSD III was performed and findings compared to our patients. CONCLUSIONS: GSD III patients are at risk for developing HCC. Cirrhosis was present in all cases and appears to be responsible for HCC transformation There are no reliable biomarkers to monitor for HCC in GSD III. Systematic evaluation of liver disease needs be continued in all patients, despite lack of symptoms. Development of guidelines to allow for systematic review and microarray studies are needed to better delineate the etiology of the hepatocellular carcinoma in patients with GSD III.

The Kraske procedure: a critical analysis of a surgical approach for mid-rectal lesions.

BACKGROUND AND OBJECTIVES: To analyze the Kraske procedure as an approach to mid-rectal disease. METHODS: Twenty-two patients underwent a Kraske procedure at either Duke University Medical Center, the Durham Veterans Administration Medical Center, or the Durham Regional Hospital between 1992 and 1997. The clinical and pathologic characteristics of these patients were retrospectively analyzed and compared with previous published series. RESULTS: Of the 22 patients, 13 underwent resection of an adenocarcinoma and 9 underwent resection of a villous adenoma. Post-operative complications included four fecal fistulas (two of which required a temporary diverting colostomy), two wound infections, two cases of urinary retention, and one case of transient fecal incontinence. CONCLUSIONS: The Kraske procedure minimizes exposure of mid-rectal lesions without the morbidity of a major laparotomy. However, it does carry a moderate complication rate and thus should be utilized selectively in managing patients with mid-rectal tumors not amenable to other treatment options.

Acoustic radiation force impulse (ARFI) imaging of the gastrointestinal tract.

The evaluation of lesions in the gastrointestinal (GI) tract using ultrasound can suffer from poor contrast between healthy and diseased tissue. Acoustic Radiation Force Impulse (ARFI) imaging provides information about the mechanical properties of tissue using brief, high-intensity, focused ultrasound to generate radiation force and ultrasonic correlation-based methods to track the resulting tissue displacement. Using conventional linear arrays, ARFI imaging has shown improved contrast over B-mode images when applied to solid masses in the breast and liver. The purpose of this work is to (1) investigate the potential for ARFI imaging to provide improvements over conventional B-mode imaging of GI lesions and (2) demonstrate that ARFI imaging can be performed with an endocavity probe. ARFI images of an adenocarcinoma of the gastroesophageal (GE) junction, status-post chemotherapy and radiation treatment, demonstrate better contrast between healthy and fibrotic/malignant tissue than standard B-mode images. ARFI images of healthy gastric, esophageal, and colonic tissue specimens differentiate normal anatomic tissue layers (i.e., mucosal, muscularis and adventitial layers), as confirmed by histologic evaluation. ARFI imaging of ex vivo colon and small bowel tumors portray interesting contrast and structure that are not as well defined in B-mode images. An endocavity probe created ARFI images to a depth of over 2 cm in tissue-mimicking phantoms, with maximum displacements of 4 microm. These findings support the clinical feasibility of endocavity ARFI imaging to guide diagnosis and staging of disease processes in the GI tract.

Treatment with oral bromelain decreases colonic inflammation in the IL-10-deficient murine model of inflammatory bowel disease.

Bromelain is a mixture of proteinases derived from pineapple stem that is marketed in health food stores as a "digestive aid". Orally administered bromelain was anecdotally reported to induce clinical and endoscopic remission of ulcerative colitis in two patients whose disease was refractory to multi-agent conventional medical therapy. However, the potential efficacy of bromelain in colitis has not yet been tested rigorously in either animals or humans. In this study, the clinical and histologic severity of inflammatory bowel disease (IBD) was determined in IL-10-/- mice treated orally with bromelain in vivo. Daily treatment with oral bromelain beginning at age 5 weeks decreased the incidence and severity of spontaneous colitis in C57BL/6 IL-10-/- mice. Bromelain also significantly decreased the clinical and histologic severity of colonic inflammation when administered to piroxicam-exposed IL-10-/- mice with established colitis. Proteolytically active bromelain was required for anti-inflammatory effects in vivo. Adverse effects of dermatitis, hair loss, and weight loss due to mucositis were rare, dose related, and were not seen in wild-type mice treated orally with up to 1000 mg bromelain/kg/day for 18 weeks. Although the exact mechanisms by which exogenous proteinases affect bowel inflammation have not yet been determined, the results justify additional studies of this complementary biologically based approach to treatment of IBD.

Significance of histological response to preoperative chemoradiotherapy for pancreatic cancer.

BACKGROUND: Neoadjuvant (preoperative) chemoradiotherapy (CRT) for pancreatic cancer offers theoretical advantages over the standard approach of surgery followed by adjuvant CRT. We hypothesized that histological responses to CRT would be significant prognostic factors in patients undergoing neoadjuvant CRT followed by resection. METHODS: Since 1994, 193 patients with biopsy-proven pancreatic adenocarcinoma have completed neoadjuvant CRT, and 70 patients have undergone resection. Specimens were retrospectively examined by an individual pathologist for histological responses (tumor necrosis, tumor fibrosis, and residual tumor load) and immunohistochemical staining for p53 and epidermal growth factor receptor. Factors influencing overall survival were analyzed with the Kaplan-Meier (univariate) and Cox proportional hazards (multivariate) methods. RESULTS: The estimated overall survival (median +/- SE) in the entire group of patients undergoing resection was 23 +/- 4.2 months, with an estimated 3-year survival of 37% +/- 6.6% and a median follow-up of 28 months. Complete histological responses occurred in 6% of patients. Overexpression of p53 was more common in patients with large residual tumor loads. Tumor necrosis was an independent negative prognostic factor, as were positive lymph nodes, a large residual tumor load, and poor tumor differentiation. CONCLUSIONS: Histological response to neoadjuvant CRT--as measured by residual tumor load--may be useful as a surrogate marker for treatment efficacy. Characterization of the tumor cells that survive neoadjuvant CRT may help us to identify new or more appropriate targets for systemic therapy.

Heterotopic ossification in rectal cancer: Rare finding with a novel proposed mechanism.

The rare finding of heterotopic ossification in a case of primary rectal adenocarcinoma is described along with a review of the literature. Immunohistochemistry for a bone morphogenic protein (BMP-2) and fibroblast growth factor (FGF-2), both of which induce and stimulate bone formation, was performed and revealed overexpression of BMP-2 by the tumor cells, elucidating a possible mechanism which up to now had been based merely on speculation.

Evaluation of porcine-derived small intestine submucosa as a biodegradable graft for gastrointestinal healing.

High-risk anastomoses in the gut may benefit from the application of a synthetic reinforcement to prevent an enteric leak. Recently a porcine-derived small intestine submucosa (SIS) was tested as a bioscaffold in a number of organ systems. The aim of this study was to evaluate the effectiveness of SIS in stimulating healing in the stomach. Twelve rats underwent surgical removal of a full-thickness gastric defect (1 cm) and subsequent repair with a double-layer patch of porcine-derived SIS. The graft was secured with interrupted sutures placed within 1 mm of the edge of the graft. After 21 days, the animals were killed and their stomachs harvested for histologic examination. Cross sections were processed for paraffin embedding and 4-micron sections were stained with hematoxylin and eosin. All animals survived, gained weight, and demonstrated no signs of peritonitis over the 3-week postoperative period. On postmortem examination, the defect was completely closed in all animals by granulation tissue and early fibrosis. Although most of the luminal surface of the grafted areas remained ulcerated, early regeneration of normal gastric mucosa was seen at the periphery of the defect. SIS may act as an effective scaffolding agent for intestinal mucosa and may offer protection in high-risk anastomoses.

Clinical utility of positron emission tomography in the diagnosis and management of periampullary neoplasms.

BACKGROUND: This study examined the effect that 18-fluorodeoxyglucose positron emission tomography ((18)FDG-PET) imaging had on the clinical management of patients with suspected periampullary malignancy. METHODS: Fifty-four patients with suspected pancreatic neoplasms underwent both whole-body (18)FDG-PET and abdominal computed tomography (CT). Malignant or benign disease was confirmed pathologically in 47 patients. RESULTS: Of the 41 patients with malignancy, (18)FDG-PET failed to identify the primary tumor in 5 patients. (18)FDG-PET demonstrated increased uptake suggesting primary malignancy in 37 patients. Malignant pathology was confirmed in 36 cases. (18)FDG-PET identified malignant locoregional lymph node metastases in six of ten patients. All nodes identified before surgery by (18)FDG-PET were also seen on preoperative CT. Six patients who were thought to have resectable disease by CT were found to have distant metastasis at laparotomy. (18)FDG-PET did not detect metastasis in any of these cases. Before surgery, (18)FDG-PET identified distant metastases that were not detected by CT in one patient. CONCLUSIONS: Despite high sensitivity and specificity in diagnosing periampullary malignancy, (18)FDG-PET did not change clinical management in the vast majority of patients previously evaluated by CT. In addition, (18)FDG-PET missed >10% of periampullary malignancies and did not provide the anatomical detail necessary to define unresectabilty.