Preterm birth subtypes, placental pathology findings, and risk of neurodevelopmental disabilities during childhood.

INTRODUCTION: Preterm birth (PTB) and in-utero inflammation are recognized risk factors of neurodevelopmental disabilities (NDDs); however, their combined role in NDDs is unknown. We examined the independent and joint association of PTB and placental histological findings with the childhood risk of NDDs (overall and by subgroups including autism spectrum disorder (ASD) and ADHD). METHODS: We analyzed data from the Boston Birth Cohort, where mother-infant pairs were enrolled at birth and followed from birth onwards. Birth outcomes, placental pathology and NDDs were obtained from electronic medical records. Placental pathology was categorized using a standardized classification system proposed by the Amsterdam Placental Workshop Group. RESULTS: PTB (all, including spontaneous, medically indicated) was an independent risk factor for NDDs. Placental histological chorioamnionitis (CA) and PTB additively increased the odds of NDDs (aOR: 2.16, 95% CI: 1.37, 3.39), as well as ADHD (aOR: 2.75, 95% CI: 1.55, 4.90), other developmental disabilities (aOR: 1.96, 95% CI: 1.18, 3.25) and possibly ASD (aOR: 2.31, 95% CI: 0.99, 5.39). The above associations were more pronounced in spontaneous than medically indicated PTB. PTB alone in the absence of CA only had a moderate association with ASD and ADHD. Placental maternal vascular malperfusion alone or in combination with PTB was not associated with the risk of NDDs. DISCUSSION: Our study provided new insights on PTB and NDDs by further considering preterm subtypes and placental histology. We revealed that children of spontaneous PTB along with histological CA were at the highest risk for a spectrum of NDDs.

Maternal vascular malperfusion of the placental bed associated with hypertensive disorders in the Boston Birth Cohort.

INTRODUCTION: The associations of maternal conditions, before or during pregnancy, with placental lesions have not been adequately studied in populations. METHODS: In the Boston Birth Cohort, we evaluated associations between three maternal medical conditions (hypertensive disorders [HDs], gestational/pre-gestational diabetes and obesity), and placental histological findings, using a standardized classification system proposed by the Amsterdam Placental Workshop Group. Placental pathology diagnoses and clinical data from 3074 mothers with clinical indications who delivered singleton live births at the Boston Medical Center between October 1998 and November 2013 were evaluated. Associations between each maternal condition and maternal vascular malperfusion (MVM) of the placental bed and its standardized subgroups were examined using multivariate logistic and multinomial regressions. RESULTS: Women with HDs (chronic hypertension, eclampsia, preeclampsia, HELLP syndrome) had significantly increased odds of MVM lesions when compared to women with no HD (aOR 2.08 95% CI 1.74-2.50), after adjusting for demographics, substance use, diabetes and body mass index. No significant differences in frequencies or aORs were seen in women with and without diabetes, or across body mass index categories. Co-morbid condition patterns that included HDs were more likely to be associated with MVM than those without. DISCUSSION: Using a standardized classification system, we showed that MVM is strongly and specifically associated with maternal HDs, but not other maternal conditions. Additional studies are needed to confirm and validate our findings, and evaluate the role of maternal vascular lesions of the placental bed in relation to postnatal growth and development of the offspring and effect modifiers.

Candidate gene analysis in a case of congenital absence of the endometrium.

BACKGROUND: Primary amenorrhea usually result from a genetic or anatomic abnormality. We present the first reported patient with the absence of endometrium and lumen in a small bicornuate uterus in a patient with primary amenorrhea. CASE PRESENTATION: A 41-year-old woman presented for evaluation of primary amenorrhea and infertility. She did develop normal secondary sexual characteristics but never had menses. Physical examination, hormone analyses, and karyotype analysis were normal. Transvaginal ultrasonography revealed a small uterus with absent endometrial stripe. Ovaries were normal in size. Pathology from hysterectomy for abnormal Pap smears revealed a hypoplastic bicornuate uterus with absence of lumen and absent endometrium. DNA analyses for mutations in the coding sequences of three members of HOXA gene family was performed, but no variants in the coding sequence of these genes were found. These findings support the hypothesis that mutations in the coding sequence of HOXA10, HOXA11, and HOXA13 are not responsible for congenital endometrial absence with bicornuate hypoplastic uterus. CONCLUSIONS: Congenital absence of the endometrium is an uncommon etiology for primary amenorrhea, and nonvisualization of the endometrial stripe on ultrasound imaging in association with primary amenorrhea should raise suspicion of this rare disorder in this case.

Endoscopic histological assessment of colonic polyps by using elastic scattering spectroscopy.

BACKGROUND: Elastic-scattering spectroscopy (ESS) can assess in vivo and in real-time the scattering and absorption properties of tissue related to underlying pathologies. OBJECTIVES: To evaluate the potential of ESS for differentiating neoplastic from non-neoplastic polyps during colonoscopy. DESIGN: Pilot study, retrospective data analysis. SETTING: Academic practice. PATIENTS: A total of 83 patients undergoing screening/surveillance colonoscopy. INTERVENTIONS: ESS spectra of 218 polyps (133 non-neoplastic, 85 neoplastic) were acquired during colonoscopy. Spectral data were correlated with the classification of biopsy samples by 3 GI pathologists. High-dimensional methods were used to design diagnostic algorithms. MAIN OUTCOME MEASUREMENTS: Diagnostic performance of ESS. RESULTS: Analysis of spectra from polyps of all sizes (N = 218) resulted in a sensitivity of 91.5%, specificity of 92.2%, and accuracy of 91.9% with a high-confidence rate of 90.4%. Restricting analysis to polyps smaller than 1 cm (n = 179) resulted in a sensitivity of 87.0%, specificity of 92.1%, and accuracy of 90.6% with a high-confidence rate of 89.3%. Analysis of polyps 5 mm or smaller (n = 157) resulted in a sensitivity of 86.8%, specificity of 91.2%, and accuracy of 90.1% with a high-confidence rate of 89.8%. LIMITATIONS: Sample size, retrospective validation used to obtain performance estimates. CONCLUSION: Results indicate that ESS permits accurate, real-time classification of polyps as neoplastic or non-neoplastic. ESS is a simple, low cost, clinically robust method with minimal impact on procedure flow, especially when integrated into standard endoscopic biopsy tools. Performance on polyps 5 mm or smaller indicates that ESS may, in theory, achieve Preservation and Incorporation of Valuable Endoscopic Innovations performance thresholds. ESS may one day prove to be a useful tool used in endoscopic screening and surveillance of colorectal cancer.

Elastic scattering spectroscopy as an optical marker of inflammatory bowel disease activity and subtypes.

BACKGROUND: In 10% to 15% of individuals, inflammatory bowel disease (IBD) is difficult to classify as ulcerative colitis (UC) or Crohn's disease (CD). Previous work has demonstrated that probe-based elastic scattering spectroscopy (ESS) can produce spectra, informed by parameters like tissue ultrastructure and hemoglobin content, capable of differentiating pathologies. This study investigates whether ESS is an in vivo optical biomarker for the presence, activity, and type of IBD in the colon. METHODS: Pilot study, a retrospective data analysis. ESS spectra of endoscopically normal and inflamed colon were obtained from 48 patients with IBD and 46 non-IBD controls. Measurements from patients with IBD were categorized as CD or UC based on clinical diagnosis. Spectra were analyzed using high-dimensional methods. Leave-one-patient-out cross-validation was used to obtain diagnostic performance estimates. RESULTS: Patients with IBD were distinguishable from non-IBD controls with a sensitivity of 0.93 and specificity of 0.91 based on readings from endoscopically normal mucosa, and 0.94 and 0.93 from inflamed mucosa. In patients with IBD, histologically normal and inflamed colon were distinguishable with per-class accuracies of 0.83 and 0.89, respectively; histologically normal from inactive inflammation with accuracies of 0.73 and 0.89, respectively; and inactive from active colitis with accuracies of 0.87 and 0.84, respectively. The diagnosis of CD versus UC was made with per-class accuracies of 0.92 and 0.87 in normal and 0.87 and 0.85 in inflamed mucosa, respectively. CONCLUSIONS: ESS, a simple, low-cost clinically friendly optical biopsy modality, has the potential to enhance the endoscopic assessment of IBD and its activity in real time and may help to distinguish CD from UC.

Plasminogen activator inhibitor-1 is increased in colonic epithelial cells from patients with colitis-associated cancer.

BACKGROUND: Patients with long-term ulcerative colitis are at risk for developing colorectal cancer. METHODS: Archival formalin-fixed paraffin-embedded tissue from ulcerative colitis patients who underwent a colectomy for high-grade dysplasia or carcinoma was examined for changes in expression of plasminogen activator inhibitor-1 (PAI-1) as well as other mediators of inflammation-associated cancer. Epithelia from areas of colons that showed histologic evidence of carcinoma, high-grade dysplasia, and epithelia that were not dysplastic or malignant but did contain evidence of prior inflammation (quiescent colitis) was microdissected using laser capture microscopy. mRNA was extracted from the microdissected tissue and PCR array analysis was performed. To extend our findings, PAI-1 protein levels were determined using immunohistochemistry. RESULTS: The mRNA expression of PAI-1 is increased 6-fold (p=0.02) when comparing the carcinoma group to the quiescent colitis group; increases were also observed in NFKB2, REL, SRC, and VEGFA. The protein levels of PAI-1 are increased by 50% (p<0.001) in high-grade dysplasia and by 60% (p<0.001) in carcinoma when compared to the quiescent colitis group. CONCLUSIONS: The increase in PAI-1 in high-grade dysplasia and carcinoma suggests a functional role for PAI-1 in malignant transformation in colitis-associated cancer. PAI-1 could also prove a useful diagnostic marker to identify patients at risk for neoplasia and it may be a useful therapeutic target to treat colitis-associated cancer.

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 Crohn's disease. The purpose of this study was to evaluate the clinical and pathological features of patients with Crohn's 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 Crohn's disease were evaluated and compared with 45 Crohn's disease patients who presented initially with both ileal and colonic involvement. Clinically, patients with isolated colonic Crohn's 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 Crohn's disease at disease onset. Pathologically, patients with isolated colonic Crohn's 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 Crohn's disease showed a trend toward a lower number of major microscopic Crohn's disease features. A small proportion of patients from both Crohn's 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 Crohn's disease'. These patients were significantly younger than those with mural involvement. Overall, 44% of patients from both Crohn's disease groups developed at least one adverse outcome, and neither the number nor the type of major Crohn's disease features correlated with adverse outcome. Patients with isolated colonic involvement have distinctive clinical and pathological features. A small subgroup of Crohn's patients shows only mucosal involvement reminiscent of ulcerative colitis.

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.

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 χ(2)-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.