Histologic and molecular analyses of colonic perineurial-like proliferations in serrated polyps: perineurial-like stromal proliferations are seen in sessile serrated adenomas

Colonic perineuriomas are recently described benign mucosal polyps that are composed of a bland spindle cell proliferation surrounding crypts that often demonstrate hyperplastic/serrated epithelial changes. However, the origin of this unique stromal proliferation is still unclear, and the association with serrated polyps, including sessile serrated adenomas, has not been fully described. We evaluated the pathologic and molecular features of colonic polyps associated with perineurial-like proliferations in 2 retrospective cohorts: (1) a series of 198 consecutive sessile serrated adenomas and (2) 20 colonic polyps diagnosed as a perineurioma irrespective of the presence of serrated colonic crypts. Thirteen of 198 (6.5%) sessile serrated adenomas demonstrated a perineurial-like stromal proliferation, with most (12 of 13, 92%) involving the right (9 cases) and transverse colon (3 cases). In all 13 cases, the perineurial-like proliferation surrounded serrated colonic crypts and typically involved only a small area of the sessile serrated adenoma (average 9% of polyp size; range, 2% to 19%). All 11 polyps evaluated for epithelial membrane antigen (EMA) expression demonstrated stromal EMA staining limited to the perineurial-like proliferation. Twelve of 13 (92%) sessile serrated adenomas with perineurial-like proliferations demonstrated a pV600E BRAF mutation. Of the 20 colonic polyps diagnosed as a perineurioma, 18 (90%) demonstrated serrated crypts intimately associated with the perineurial-like proliferation. In 13 of 18 polyps with associated serrated crypts, all serrated crypts were invested with the perineurial proliferation. In 5 cases, serrated crypts were seen away from the perineurial proliferation. Of these 18 polyps, the majority (16 of 18, 89%) were microvesicular hyperplastic polyps involving the left colon. However, 2 (11%) polyps in the right colon demonstrated histologic features diagnostic of sessile serrated adenoma. All 18 polyps with serrated crypts demonstrated a pV600E BRAF mutation. In contrast, the 2 polyps not associated with serrated crypts were negative for a BRAF mutation. Our results show for the first time that perineurial-like stromal proliferations frequently occur in sessile serrated adenomas. The presence of focal perineurial-like stromal proliferations in sessile serrated adenomas and the common finding of serrated crypts in colonic perineuriomas are likely indicative of an epithelial-stromal interaction, possibly related to some factor elaborated by the serrated epithelium.     

Free secretory component as a standardization protein for nasopharyngeal specimens from children with upper respiratory tract infection

Free secretory component (FSC) has been recommended as a reliable protein for correction of the unknown dilution in tracheal aspirate samples from preterm infants. To investigate whether FSC would also provide a valid standardization protein for samples of nasopharyngeal secretions, this study determined the intersubject variation and the alteration over time in the concentrations of FSC in nasal secretions from 35 children (median age 14 months) who participated in an antibiotic efficacy trial. Nasopharyngeal aspirates were obtained at enrolment and after 2-3 d. FSC in the specimens was quantified by a direct enzyme immunoassay. The concentrations of FSC in the nasal secretions ranged from 0.08 to 189.6 μg ml^-1 (median 12.3 μg ml^-1); the ratio of the highest to the lowest concentrations was 2370, the difference between the 90th and 10th percentile concentrations was 189-fold and the difference between the 75th and 25th percentile values was 26. FSC concentrations were significantly lower in children aged ≤12 months (median 2.2 μg ml^-1) than in the older children (median 21.5 μg ml^-1; p = 0.035). Between the first and the follow-up specimens, 65% of the children had ≥2-fold difference in the levels of FSC in the secretions. Because an optimal standardization protein should show minimal variation between individuals and over time, FSC may not be a suitable protein for correction of the unknown dilution of nasopharyngeal specimens from children with upper respiratory tract infection.     

Helicobacter pylori infection, not gastroesophageal reflux, is the major cause of inflammation and intestinal metaplasia of gastric cardiac mucosa

OBJECTIVE: The etiology of inflammation below the normal Z-line is an area of intense debate. Some suggest this is the earliest change of chronic gastroesophageal reflux disease (GERD), whereas others indict Helicobacter pylori (H. pylori) as the main cause. The aim of this study was to evaluate the relationship among inflammation of gastric cardiac mucosa (carditis), H. pylori infection, and intestinal metaplasia in patients with GERD and Barrett's esophagus compared with age-matched controls. METHODS: Patients with GERD and Barrett's esophagus were compared with controls undergoing endoscopy for a variety of other conditions. Endoscopic biopsy specimens from the gastric cardia (obtained on retroflexed view), fundus, and antrum were evaluated for inflammation, H. pylori infection, and intestinal metaplasia. RESULTS: The prevalence of H. pylori infection did not significantly differ among the study populations: controls (42%), GERD (33%), and Barrett's esophagus (27%) (p = 0.20). However, the prevalence of carditis significantly decreased from the control group (30%) to those with GERD (23%) and Barrett's esophagus (11%) (p = 0.03). Overall, 42 of 51 (82%) patients with carditis had H. pylori; all had pangastritis. The prevalence of cardia intestinal metaplasia also significantly decreased from the control group (15%) to those with GERD (4%) and Barrett's esophagus (0%) (p = 0.003). Of 13 patients with cardia intestinal metaplasia, 12 had carditis, 10 had H. pylori infection, and seven had intestinal metaplasia elsewhere in the stomach. CONCLUSIONS: Inflammation of gastric cardiac mucosa decreases in prevalence from controls to patients with GERD and Barrett's esophagus and correlates strongly with H. pylori infection. Cardia intestinal metaplasia is associated with H. pylori-related cardiac inflammation and intestinal metaplasia elsewhere in the stomach.     

Fecal lactoferrin for diagnosis of symptomatic patients with ileal pouch-anal anastomosis

BACKGROUND & AIMS: Increased stool frequency, urgency, and abdominal pain in patients with ileal pouch-anal anastomosis (IPAA) may be due to inflammatory conditions, including pouchitis, cuffitis, or Crohn's disease or noninflammatory conditions such as irritable pouch syndrome. Distinction among these entities requires pouch endoscopy and biopsy. Noninvasive means of diagnosis are preferable. METHODS: Sixty consecutive subjects with IPAA for inflammatory bowel disease had measurements of fecal lactoferrin and alpha1-antitrypsin and underwent pouch endoscopy with biopsy, with calculation of the pouchitis disease activity index in a prospective cross-sectional study. RESULTS: Symptomatic patients with an inflammatory condition had significantly higher fecal lactoferrin concentrations (median, 176.0 microg/mL, interquartile range [IQR] 79.0-450.8) compared with those with a noninflammatory condition (median, 4.8 microg/mL; IQR, 1.2-11.0) or those who were asymptomatic (median, 7.8 microg/mL; IQR, 1.4-12.9), P < 0.001. At a cutoff level of 7 microg/mL, fecal lactoferrin could distinguish patients with irritable pouch syndrome from those with pouchitis, cuffitis, or Crohn's disease with a sensitivity of 100% and specificity of 85%. Fecal alpha1-antitrypsin was not able to distinguish symptomatic patients with and without an inflammatory condition. CONCLUSIONS: Fecal lactoferrin can serve as a sensitive and noninvasive initial screening test in an algorithm for evaluation of symptomatic patients with IPAA. If fecal lactoferrin levels are low (<7 microg/mL), IPS can be diagnosed. If fecal lactoferrin levels are high, pouch endoscopy with biopsy is warranted to distinguish among different causes of inflammation. Longitudinal studies are needed to define better the role of this test in the management of patients with IPAA.     

A critical review of the diagnosis and management of Barrett's esophagus: the AGA Chicago Workshop

BACKGROUND & AIMS: The diagnosis and management of Barrett's esophagus (BE) are controversial. We conducted a critical review of the literature in BE to provide guidance on clinically relevant issues. METHODS: A multidisciplinary group of 18 participants evaluated the strength and the grade of evidence for 42 statements pertaining to the diagnosis, screening, surveillance, and treatment of BE. Each member anonymously voted to accept or reject statements based on the strength of evidence and his own expert opinion. RESULTS: There was strong consensus on most statements for acceptance or rejection. Members rejected statements that screening for BE has been shown to improve mortality from adenocarcinoma or to be cost-effective. Contrary to published clinical guidelines, they did not feel that screening should be recommended for adults over age 50, regardless of age or duration of heartburn. Members were divided on whether surveillance prolongs survival, although the majority agreed that it detects curable neoplasia and can be cost-effective in selected patients. The majority did not feel that acid-reduction therapy reduces the risk of esophageal adenocarcinoma but did agree that nonsteroidal antiinflammatory drugs are associated with a cancer risk reduction and are of promising (but unproven) value. Participants rejected the notion that mucosal ablation with acid suppression prevents adenocarcinoma in BE but agreed that this may be an appropriate strategy in a subgroup of patients with high-grade dysplasia. CONCLUSIONS: Based on this review of BE, the opinions of workshop members on issues pertaining to screening and surveillance are at variance with published clinical guidelines.     

Optical coherence tomography of the esophagus and proximal stomach in health and disease

OBJECTIVE: Surveillance of Barrett's esophagus is problematic, as high-grade dysplasia cannot be recognized endoscopically. Endoscopic ultrasound lacks the resolution to detect high-grade dysplasia. Optical coherence tomography (OCT) employs infrared light reflectance to provide in vivo tissue images at resolution far superior to endoscopic ultrasound, nearly at the level of histology. We have developed a catheter-based system well suited for study of the GI tract. The purpose of this study was to test this catheter-based OCT system and characterize the OCT appearance of normal squamous mucosa, gastric cardia, Barrett's esophagus, and carcinoma. METHODS: The OCT catheter was passed through the operating channel of the endoscope and placed in contact with the esophageal mucosa. Image acquisition occurred in approximately 3 s. OCT images were correlated with biopsy and/or resection specimens. RESULTS: OCT was used to construct 477 images of the esophagus and stomach in 69 patients. There were unique, distinct OCT appearances of squamous mucosa, gastric cardia, Barrett's esophagus, and carcinoma. Further, these OCT images were accurately recognized by observers unaware of their site of origin. CONCLUSIONS: OCT provides a highly detailed view of the GI wall, with clear delineation of a multiple layered structure. It is able to distinguish squamous mucosa, gastric cardia, Barrett's esophagus, and cancer. This technique holds great potential as an adjunct to the surveillance of patients with Barrett's esophagus, ulcerative pancolitis, and other premalignant conditions.     

Clostridium Difficile-Associated Pouchitis

Pouchitis is the most common long-term sequela of ileal pouch-anal anastomosis (IPAA) following total proctocolectomy. No single pathogen is identified as being solely responsible for the pathogenesis of the disease. Here we describe a case of Clostridium difficile-associated pouchitis that was successfully treated with ciprofloxacin and tinidazole. Diagnosis and management of a patient with medically refractory pouchitis associated with Clostridium difficile infection is described. A 63-year-old male with underlying ulcerative colitis and IPAA presented with increased stool frequency and seepage for 2 months, which partially responded to oral metronidazole. While on the antibiotic therapy, pouch endoscopy was performed and showed severe pouchitis. Assays for Clostridium difficile toxins in stool specimens were positive. He was treated with a 4-week course of ciprofloxacin 500 mg BID and tinidazole 500 mg TID. His symptoms resolved within several days from the initiation of therapy. A repeat pouch endoscopy at week 5 showed a complete resolution of mucosal inflammation of the pouch, while tests for Clostridium difficile toxins became negative. Clostridium difficile-associated pouchitis is rare. However, Clostridium difficile infection should be excluded in patients with chronic refractory pouchitis.     

A landscape effect in tenosynovial giant-cell tumor from activation of CSF1 expression by a translocation in a minority of tumor cells

Tenosynovial giant-cell tumor (TGCT) and pigmented villonodular synovitis (PVNS) are related conditions with features of both reactive inflammatory disorders and clonal neoplastic proliferations. Chromosomal translocations involving chromosome 1p13 have been reported in both TGCT and PVNS. We confirm that translocations involving 1p13 are present in a majority of cases of TGCT and PVNS and show that CSF1 is the gene at the chromosome 1p13 breakpoint. In some cases of both TGCT and PVNS, CSF1 is fused to COL6A3 (2q35). The CSF1 translocations result in overexpression of CSF1. In cases of TGCT and PVNS carrying this translocation, it is present in a minority of the intratumoral cells, leading to CSF1 expression only in these cells, whereas the majority of cells express CSF1R but not CSF1, suggesting a tumor-landscaping effect with aberrant CSF1 expression in the neoplastic cells, leading to the abnormal accumulation of nonneoplastic cells that form a tumorous mass.     

Genetic factors affecting the consistency and magnitude of changes in plasma cholesterol in response to dietary challenge

We examined the role of common genetic variation in determining the consistency and magnitude of change in plasma total cholesterol (TC) levels in response to two separate changes from a high-saturated (SFA) to a low-saturated/high-polyunsaturated-fat (PUFA) diet, in a group of free-living healthy men and women. Consistent responders were defined as those whose mean difference in the change in TC was within one SD of the mean for all participants, and the remainder were defined as variable responders. DNA was obtained from 55 individuals and genotype determined at the apolipoprotein (apo) B locus (signal peptide, SP), apoCIII (C1100-T) and lipoprotein lipase (LPL) gene loci (HindIII). In the 38 consistent responders, the apoBSP24 allele was significantly more common than in the 17 individuals with a variable response (0.29 vs. 0.12; p < 0.05). No other polymorphism showed a significant frequency difference between groups. In the group as a whole, the correlation between the change in TC level in response to the first and second dietary change was 0.28 (p = 0.05), but those with one or more apoB SP24 alleles and those with the apoCIII genotype CC had a significantly higher correlation than those with other genotypes (0.46 (p = 0.05) vs. 0.12 (NS) and 0.31 (p = 0.05) vs. 0.02 (NS), respectively). In the group as a whole, mean response left TC 10% higher on the SFA than on the PUFA diet, and neither apoB nor apoCIII genotypes affected the magnitude of this response. However, individuals with the LPL HindIII genotype H+ H+ had a significantly smaller change in mean TC in response to diet than those with one or more H- allele (9.3% vs. 14.4%; p = 0.03). Thus variation at the apoB and apoCIII loci affects the consistency of response to change in dietary fat content, while variation at the LPL gene locus affects magnitude of response.      

In-hospital and mid-term adverse clinical outcomes of a direct stenting strategy versus stenting after predilatation for the treatment of coronary artery lesions

Background

Direct stenting without balloon dilatation may reduce procedural costs and duration, and hypothetically, the restenosis rate. This study was designed to compare the in-hospital and long-term outcomes of direct stenting (DS) versus stenting after pre-dilatation (PS) in our routine clinical practice.

Methods

The 1 603 patients treated with stenting for single coronary lesions were enrolled into a prospective registry. Patients with acute myocardial infarction (MI) within the preceding 48 hours, and those with highly calcified lesions, total occlusions, or a lesion in a saphenous graft were excluded. The baseline, angiographic and procedural data, inhospital outcomes and follow-up data were recorded in our database and analysed with appropriate statistical methods.

Results

Eight hundred and fifty-seven patients (53.5%) were treated with DS and 746 (46.5%) underwent PS. In the DS group, lesions were shorter in length, larger in diameter and had lower pre-procedural diameter stenosis. Type C and diffuse lesions and drug-eluting stents were found less often (p < 0.001). With univariate analysis, dissection and non-Q-wave MI occurred less frequently in this group (0.2 and 0.6% vs 3.9 and 2.1%, p < 0.001 and p = 0.01, respectively). However, the cumulative major adverse cardiac events (MACE) did not differ significantly (4.9 vs 4.6%, p = 0.79). With multivariate analysis, direct stenting reduced the risk of dissection (OR = 0.07, 95% CI: 0.01–0.33, but neither the cumulative endpoint of MACE (OR = 1.1, 95% CI = 0.58–2.11, p = 0.7) nor its constructing components were different between the groups.

Conclusions

Direct stenting in the real world has at least similar long-term outcomes in patients treated with stenting after pre-dilatation, and is associated with lower dissection rates.