Sandra Cerda

Variation in the detection of serrated polyps in an average risk colorectal cancer screening cohort.

OBJECTIVES:Serrated polyps are precursors in an alternative pathway to colon cancer. These polyps are frequently sessile or flat, located in the proximal colon, and may be overlooked during colonoscopy. Histological criteria to classify these polyps have only recently been described. This study assessed the variation of serrated polyp detection among endoscopists and pathologists in an average risk-screening cohort and trends in detection over time.METHODS:Endoscopy and pathology reports were reviewed from all average risk-screening colonoscopies at an urban academic medical center from 2006 through 2008. Polyps were classified as adenoma (tubular, tubulovillous, or villous), serrated polyp (hyperplastic polyp (HP), sessile serrated adenoma (SSA), or dysplastic serrated polyp (DSP)), adenocarcinoma, or other. Differences in polyp detection among endoscopists and pathologists were tested with χ2-tests. Potential predictors of polyp detection were modeled with Poisson regression.RESULTS:Included in the study were 4,335 polyps from 7,192 colonoscopies. Detection prevalence (patients with at least one polyp per 100 colonoscopies) was 22.2 for adenomas, 11.7 for HP, 0.6 for SSA, and 0.2 for DSP. Detection prevalence of proximal SSAs increased from 0.2 in 2006 to 4.4 in 2008 (P<0.001). Detection prevalences among endoscopists differed significantly for adenomas, HP, and SSA. Classification rates among pathologists differed significantly for HP and SSA, but not for adenoma or DSP. On multivariate analysis, endoscopist was a significant predictor of adenoma, HP, and SSA. Pathologist was a significant predictor of HP, SSA, and DSP, but not adenoma.CONCLUSIONS:This study describes the detection of colorectal polyps in an average risk-screening cohort at an urban academic medical center. Detection of proximal SSAs increased during the study period. Detection of adenoma, HP, and SSA differed significantly by endoscopist. Classification of HP and SSA differed significantly by pathologist. Endoscopy and pathology practices should consider educational interventions to improve serrated polyp detection and standardize classification.

An Assessment of Digital Image Analysis to Measure Fibrosis in Liver Biopsy Specimens of Patients With Chronic Hepatitis C

The aim was to assess the validity of a digitally computed fibrosis ratio as a measure of fibrosis stage in liver biopsy specimens. We scored 230 liver biopsy specimens from patients with chronic hepatitis C for fibrosis using modified Knodell criteria; fibrosis ratios were computed from digital images that encompassed the complete trichrome-stained section of each case. Although an overall correlation between fibrosis ratio and ordinal score was present, subset analysis showed that this correlation existed only among biopsy specimens with high scores (3-6, early bridging fibrosis to established cirrhosis). There was no correlation or difference between category means found among biopsy specimens with low scores (0-3, normal to early bridging fibrosis). Furthermore, concordance by both estimates in direction of fibrosis change among serial liver biopsy specimens was found in only 11 (30%) of 37 pairs compared. The findings suggest that a qualitative assessment of the computerized fibrosis pattern is necessary for the interpretation of computerized fibrosis ratio measurements, particularly in patients with early stage fibrosis.

A new transcription factor that regulates TNF-α gene expression, LITAF, is increased in intestinal tissues from patients with CD and UC

Background: The proinflammatory cytokine tumor necrosis factor‐&agr; (TNF‐&agr;) plays a key role in the pathogenesis of Crohns disease (CD) and ulcerative colitis (UC). Recently, a new transcription factor termed LITAF (lipopolysaccharide‐induced TNF‐&agr; factor) was shown to mediate TNF‐&agr; expression in human macrophages by direct binding to specific sequences in the promoter region of the TNF‐&agr; gene. Methods: In this report, we identified LITAF in resected ileal and colonic tissues from patients with CD and UC by immunohistochemistry, real‐time polymerase chain reaction, and Western blot analysis. LITAF expression in inflamed and noninflamed areas of the tissues was compared. Results: This is the first demonstration of LITAF, a newly discovered transcription factor that regulates TNF‐&agr; gene transcription in ileal and colonic tissues from patients with either CD or UC. LITAF immunostaining was localized to lamina propria macrophages and was markedly increased relative to tissues from controls without inflammatory bowel disease. In patients with CD, a 5‐fold increase in LITAF mRNA was measurable in noninflamed colonic tissues compared with controls without inflammatory bowel disease. LITAF mRNA in tissues from inflamed areas of the colon was increased by an additional 60% compared with noninflamed tissues. In patients with UC, LITAF mRNA levels in colonic tissues resected from noninflamed areas were elevated 15‐fold above nondisease controls, but they were not different in tissues resected from inflamed areas. Western blot analysis showed that in patients with CD, there was a marked increase in LITAF protein in inflamed areas compared with noninflamed areas. LITAF protein levels were not different between noninflamed and inflamed tissues obtained from patients with UC. TNF‐&agr; mRNA and protein levels paralleled LITAF. Similarly, in inflamed ileal tissues from patients with CD, LITAF is also localized to lamina propria macrophages. LITAF mRNA and LITAF protein were significantly increased in inflamed ileal tissues compared with noninflamed areas. Conclusions: LITAF is readily detectable in ileal and colonic tissues from patients with either CD or UC, is significantly elevated above controls, and is localized to macrophages, a major source of TNF‐&agr;. These data provide strong evidence of a role for LITAF in the pathophysiological regulation of the TNF‐&agr; gene and underscore the potential value of anti‐LITAF strategies in the clinical management of these diseases.

Quantitative analysis of allele imbalance supports atypical ductal hyperplasia lesions as direct breast cancer precursors

It remains unclear whether hyperplastic breast lesions, especially with atypia, are cancer precursors or markers of increased cancer risk. Quantified comparisons of genomic alterations in coexisting lesions could address this question. Therefore, we examined allele imbalance (AI), also known as loss of heterozygosity (LOH), at 20 microsatellite markers on nine chromosome arms, in DNA from 106 samples microdissected from 17 randomly selected cancer‐containing breast specimens: 13 simple (DH) and 45 atypical ductal hyperplastic (ADH) lesions, 30 in situ (DCIS) and 18 invasive ductal carcinomas (IDC). Data were analysed using regression models and generalized estimating equations. We found that AI increased as histology became more aberrant and varied with histology across the chromosome arms (p <0.0001). ADH had more AIs on 1q (p = 0.03) and 16q (p = 0.02) and fewer AIs on 17p (p = 0.06) and 17q (p <0.0001) than on other arms. In cancers, AIs remained high on 1q and 16q, and became frequent on 17p and 17q. Concordance between AIs in ADHs and cancers exceeded the 50% expected if the lesions were separate clones in 16/20 (80%) ADHs (p = 0.05), from 9/11 (82%) cases (p = 0.03), and involved 41/51 (80%) evaluable markers (p = 0.05). The occurrence of any AI in ADH predicted greater AI (p = 0.009) and possibly lower grade (p = 0.05) in coexisting cancers. Nevertheless, ADHs were not genetically identical to cancers or to each other. We found AIs discordant between ADHs and cancers (always on 1q and 16q), AIs unique to ADH (usually on 11q) and some genetic heterogeneity among coexisting ADHs. We conclude that ADH lesions are genetically advanced, with frequent alterations on 1q and 16q, and are often direct cancer precursors. Their global genetic characteristics predict features of cancers in the same breast. Nevertheless, the genetic heterogeneity detected suggests that hyperplasias and cancers may arise on a field at generalized increased cancer risk. Copyright

Placental Inflammatory Response Is Associated With Poor Neonatal Growth: Preterm Birth Cohort Study

OBJECTIVE: We sought to determine whether placental markers of intrauterine inflammation were associated with poor weight gain among premature infants in the neonatal period. METHODS: We reviewed 697 preterm births prospectively enrolled as part of an ongoing molecular epidemiological study. Placental markers and serial weight gain were analyzed for premature infants who were hospitalized for ≥21 days (N = 256). Placentas were examined for maternal inflammatory response (MIR), defined as subchorionitis, chorioamnionitis, deciduitis, or free membranitis, and fetal inflammatory response (FIR), defined as inflammation extending to the umbilical cord or chorionic plate. Multivariate linear regression and stratified analyses were performed. RESULTS: Decreases in weight gain at day 21 were associated with the presence of either MIR or FIR (β coefficient = −4.63 ± 1.41; P = .001). The association was stronger with FIR than MIR (P for trend = .0027) and persisted in the remaining hospitalized infants at day 28 (n = 223; β coefficient = −5.53 ± 1.85; P = .0028). Mean body weights were similar among the 3 groups by corrected age of 36 weeks or discharge, whichever came first. Associations between placental inflammation and poor growth persisted among infants with prenatal corticosteroid exposure and/or neonatal complications and remained marginally significant in the nonexposed groups. Among infants without intrauterine growth restriction, significant association persisted (n = 186; β coefficient = −5.68 ± 1.56; P = .0003). CONCLUSIONS: Placental inflammation is associated with poor neonatal growth. MIR and FIR may be useful markers for identifying infants at risk for postnatal growth failure.

Truncated neurokinin-1 receptor is increased in colonic epithelial cells from patients with colitis-associated cancer

Patients with chronic ulcerative colitis (UC) are at high risk for developing colorectal cancer. In this study, archival formalin-fixed paraffin-embedded colonic tissue from patients with UC who developed carcinoma (CA) or high-grade dysplasia (HGD) was examined for changes in expression of the proinflammatory and mitogenic neurokinin-1 receptor (NK-1R). Laser capture microscopy was used to microdissect epithelia from areas of colons that showed histologic evidence of CA, HGD, and epithelia that were not dysplastic or cancerous but did contain evidence of prior inflammation (quiescent colitis). mRNA was extracted from the dissected tissue, and PCR array analysis was performed on extracted mRNA. Two antibodies were necessary to separately estimate the protein levels of the truncated (tr-NK-1R) and full-length (fl-NK-1R) receptors by immunohistochemistry. mRNA expression of tr-NK-1R increased 14-fold (P = 0.02) when comparing the HGD and CA groups. In contrast, the fl-NK-1R transcript showed no significant differences among groups. The protein levels of the total NK-1R increased by 40% (P = 0.02) in HGD and 80% (P = 0.0007) in CA compared with quiescent colitis. There were no significant changes in protein levels of the fl-NK-1R. We conclude that the increase in total NK-1R protein in HGD and CA is attributable to an increase in tr-NK-1R, suggesting there may be a functional role for tr-NK-1R in malignant transformation in colitis-associated cancer. The tr-NK-1R could prove useful as a diagnostic marker to identify patients at risk for neoplasia and may serve as a useful therapeutic target in the treatment of colitis-associated cancer.

Impact of clinical and histologic correlates of maternal and fetal inflammatory response on gestational age in preterm births

Objective. To evaluate the impact of clinical and histopathologic correlates related to maternal and fetal inflammatory responses (MIR and FIR) on degree of preterm birth. Methods. Pathology reports and clinical data from 577 singleton preterm births (<37 weeks of gestation) that took place between 1998 and 2004 were analyzed according to decreasing gestational age (≥33 weeks, 29–32 weeks, and <29 weeks). MIR was defined by presence of subchorionitis, chorioamnionitis, deciduitis, or free membranitis; FIR was defined by presence of funisitis or chorionic plate vasculitis. The associations between MIR alone and MIR with FIR and gestational age subgroups were assessed using logistic regression. Results. The presence of FIR in addition to MIR was more strongly associated with degree of prematurity than the presence of MIR alone, especially for those born at <29 weeks (OR = 10.1 (95% CI 4.3–23.7) and OR = 5.3 (95% CI 2.3–12.5), respectively). These associations remained significant after adjusting for maternal race, clinical signs of chorioamnionitis, medically indicated birth, and intrapartum corticosteroid, tocolysis and antibiotic use, and after stratification by clinical signs of chorioamnionitis and medically indicated birth. Conclusions. The combined presence of MIR and FIR is associated with a higher risk of extreme preterm birth (<29 weeks) than MIR alone, suggesting a contributory role of FIR in the pathophysiology of preterm birth.

Clinical and pathological analysis of colonic Crohn's disease, including a subgroup with ulcerative colitis-like features.

Little is known regarding the clinical and, in particular, pathological manifestations of patients with isolated colonic Crohns disease. The purpose of this study was to evaluate the clinical and pathological features of patients with Crohns disease limited to the colon at initial presentation, and to determine whether there are any histological features that are predictive of outcome after surgery. The clinical features, outcome after surgery, and pathological features of colonic resection specimens of 73 patients who presented initially with isolated colonic Crohns disease were evaluated and compared with 45 Crohns disease patients who presented initially with both ileal and colonic involvement. Clinically, patients with isolated colonic Crohns disease presented at a significantly older age at the time of diagnosis, and had a significantly shorter duration of colitis before surgical resection, than did patients with ileocolonic Crohns disease at disease onset. Pathologically, patients with isolated colonic Crohns disease showed a significantly higher proportion of cases with subtotal, total, or left-sided colitis, and significantly fewer strictures/stenosis, pericolonic adhesions, pyloric metaplasia, and cases with proximal worse than distal colonic disease. Overall, patients with isolated colonic Crohns disease showed a trend toward a lower number of major microscopic Crohns disease features. A small proportion of patients from both Crohns disease groups (14% and 13%, respectively) showed inflammatory disease limited to the mucosa, without mural involvement, reminiscent of ulcerative colitis, and these were termed ‘ulcerative colitis-like Crohns disease’. These patients were significantly younger than those with mural involvement. Overall, 44% of patients from both Crohns disease groups developed at least one adverse outcome, and neither the number nor the type of major Crohns disease features correlated with adverse outcome. Patients with isolated colonic involvement have distinctive clinical and pathological features. A small subgroup of Crohns patients shows only mucosal involvement reminiscent of ulcerative colitis.

Placental weight mediates the effects of prenatal factors on fetal growth: the extent differs by preterm status.

Elevated pre‐pregnancy BMI, excessive gestational weight gain (GWG), and gestational diabetes mellitus (GDM) are known determinants of fetal growth. The role of placental weight is unclear. We aimed to examine the extent to which placental weight mediates the associations of pre‐pregnancy BMI, GWG, and GDM with birth weight‐for‐gestational age, and whether the relationships differ by preterm status.

Polypectomy is adequate treatment for adenoma-like dysplastic lesions (DALMs) in Crohn's disease.

Background:The purpose of this study was to reevaluate the clinical and pathologic features and outcomes in patients with Crohns disease with an adenoma-like dysplasia-associated lesion or mass (DALMs) to determine if polypectomy is adequate treatment. Methods:The clinical, endoscopic and pathologic features, and outcomes of 50 patients with Crohns disease, each with ≥1 adenoma-like DALM were evaluated. The median length of follow-up was 39 months (range: 0.5–156 months). Results:Of the 50 patients with Crohns disease (male to female ratio, 30:20; median age: 53 years; median duration of disease: 83 months), 11 had ileal disease, 26 had colonic disease, and 13 had both ileal and colonic disease. Approximately 43% of polyps occurred within areas of previous or concurrent colitis, whereas 57% occurred in areas not previously involved by colitis. Most polyps had tubular architecture and contained low-grade dysplasia. Of the patients who had polypectomy followed by surveillance, 45% developed new adenoma-like DALMs, but none developed flat dysplasia and only 1 had adenocarcinoma at the time of resection, which was within 3 months of polypectomy. There were no differences in the clinical or pathologic features or outcomes in patients who had adenoma-like DALMs within versus outside areas of previous or concurrent colitis, except that the former showed a higher risk of developing new polyps within areas of colitis and near the site of the original polyp compared with the latter. Conclusions:Patients with Crohns disease who develop an adenoma-like DALM, regardless of its location in relationship to previous or concurrent colitis, may be treated safely with polypectomy and continued surveillance.