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DICER1 mutated thyroid nodules are commonly seen in pediatric populations often, as part of DICER1 syndrome. We seek to evaluate DICER1 mutated thyroid nodules in adult populations to assess whether there exists distinctive clinical, cytologic, histologic, and molecular characteristics that underline our institutional cohort.Retrospective analysis was performed on all fine-needle aspiration (FNA) specimens with a corresponding ThyroSeq panel, to select a cohort of cases with DICER1 mutations. Clinical, radiologic, and cytology materials were reviewed, and histology was reviewed for corresponding resection cases were available. ThyroSeq panel was further scrutinized for additional molecular alterations and variant allele frequency.DICER1 mutated thyroid nodules (n = 8), more commonly occurred in younger adults (P = 0.01) with larger (P = 0.01) nodules and only in female patients in our cohort. FNA commonly demonstrates cellular specimens with banal cytomorphologic cues including regular nuclei, inconspicuous nucleoli, smooth nuclear membranes, and abundant colloid. On retrospective review by 2 cytopathologists, the lesions were frequently diagnosed as Bethesda II (5 of 8) by both reviewers. Histology, when available, showed that all nodules were categorized as follicular adenomas (5 of 5), often demonstrating macrofollicles with papillary excrescences demonstrating bland nuclei (4 of 5). DICER1 mutational profile revealed a variant allele frequency ofgt;40% in 25% of cases (2 of 8) andgt;30% in an additional 4 cases, highlighting a possible germline association.DICER1 mutated nodules may be under-reported due to banal cytomorphologic features and may be associated with an underlying germline alteration.

Programmed cell death ligand 1 (PD-L1) on tumor cells is a significant prognostic biomarker for a number of malignancies, although less is known about the significance of PD-L1 positive immune cells in colon carcinoma. The purpose of this study is to evaluate the role of PD-L1 in a large cohort of colon carcinomas to identify patterns of PD-L1 expression in the tumor microenvironment and its correlation with other key immune subsets to better understand the impact of these immune cells. We assessed 1218 colon carcinomas on representative tissue microarray sections, gathered relevant clinicopathologic information, and performed immunohistochemical staining for mismatch repair proteins, CD8, CD163, LAG3, PD-L1, FoxP3, and BRAF V600E. We then performed automated quantification; manual quantification was used for PD-L1 tumor cells and immune cells. Dual PD-L1/PU.1 immunostain was also performed. The majority of PD-L1 positive cells expressed PU.1 thus representing tumor-associated macrophages. Based on the median number of PD-L1 positive immune cells (7.6/mm

Fine-needle aspiration biopsy (FNAB) is a cost-effective and safe office procedure performed to evaluate thyroid nodules. We report a case of a 33-year-old woman who presented with pain and swelling of the thyroid after undergoing an FNAB for a right thyroid nodule at an outside hospital. The patient received a course of antibiotics without complete resolution of her symptoms and ultimately, underwent a right thyroid lobectomy. Pathology of the excised thyroid tissue showed chronic lymphohistiocytic inflammation with giant cell reaction and hemorrhage consistent with a foreign-body reaction. The patient's symptoms completely resolved after the surgery. Though uncertain what foreign body was introduced into the thyroid tissue during the FNAB, we surmise that an accidental introduction of ultrasound gel may have caused this rare and unexpected complication of a procedure with usually few and manageable complications.

Serrated adenocarcinoma (SAC), a recognised WHO variant of colonic adenocarcinoma, is the purported end-product of serrated neoplasia. However, the diagnosis of SAC is infrequently rendered, and little is known about its prognosis, immune microenvironment and molecular alterations.We assessed 903 consecutive colon carcinomas and recognised tumours with ≥ 5% (n = 77) serrated and ≥ 50% serrated patterns (n = 13). We assessed precursor polyps and synchronous polyps. We recorded demographic/clinical parameters, histological features and mismatch repair (MMR) status. We performed immunohistochemistry and quantification on tissue microarray for HLA class I/II proteins, B2MG, CD8, CD163, LAG3, FoxP3, PD-L1 and BRAF V600E.We identified ≥ 5% epithelial serration prevalence in 8.5% of cases and ≥ 50% epithelial serration prevalence in 1.4% of cases. Precursor lesions were present in 21.4% of cases; these were mostly tubular adenomas with two traditional serrated adenomas identified. SAC with ≥ 5% serrations exhibited lower numbers of CD8-positive lymphocytes (P = 0.002) and lower B2MG expression (P = 0.048), although neither value was significant at ≥ 50% serration threshold. There was no difference in HLA class I/II, or PD-L1 expression on tumour cells and no difference in PD-L1, LAG3, FoxP3 and CD163 expression on immune cells. There was no association with MMR status, or BRAFV600E relative to conventional adenocarcinoma. There was improved disease-specific survival on univariate (but not multivariate) analysis between carcinomas with serrated pattern and non-mucinous conventional colonic carcinomas at ≥ 5% epithelial serrations (P = 0.04).SAC category shows a limited impact on survival, and this phenotype may harbour a unique immunological milieu.

Background: Novel molecular tests (MTs), such as ThyroSeq, may improve the management of thyroid nodules with indeterminate cytologic diagnoses; however, the impact of these tests on cost and outco...

Background Maternal stress is potentially a modifiable risk factor for spontaneous preterm birth (sPTB). However, epidemiologic findings on the maternal stress-sPTB relationship have been inconsistent. Methods To investigate whether the maternal stress-sPTB associations may be modified by genetic susceptibility, we performed genome-wide gene × stress interaction analyses in 1490 African-American women from the Boston Birth cohort who delivered term (n = 1033) or preterm (n = 457) infants. Genotyping was performed using Illumina HumanOmni 2.5 array. Replication was performed using data from the NICHD genomic and Proteomic Network (GPN) for PTB research. Results rs35331017, a T-allele insertion/deletion polymorphism in the protein-tyrosine phosphatase receptor Type D (PTPRD) gene, was the top hit that interacted significantly with maternal lifetime stress on risk of sPTB (PG × E = 4.7 × 10-8). We revealed a dose-responsive association between degree of stress and risk of sPTB in mothers carrying the insertion/insertion genotype, but an inverse association was observed in mothers carrying the heterozygous or deletion/deletion genotypes. This interaction was replicated in African-American (PG × E = 0.088) and Caucasian mothers (PG × E = 0.023) from the GPN study. Conclusion We demonstrated a significant maternal PTPRD × stress interaction on sPTB risk. This finding, if further confirmed, may provide new insight into individual susceptibility to stress-induced sPTB. Impact This was the first preterm study to demonstrate a significant genome-wide gene-stress interaction in African Americans, specifically, PTPRD gene variants can interact with maternal perceived stress to affect risk of spontaneous preterm birth.The PTPRD × maternal stress interaction was demonstrated in African Americans and replicated in both African Americans and Caucasians from the GPN study.Our findings highlight the importance of considering genetic susceptibility in assessing the role of maternal stress on spontaneous preterm birth.

Background: It has been advocated to apply individualized strategies to evaluate thyroid nodules due to the growing awareness that the pathogenesis of thyroid cancer is not uniform. Molecular marke...

Clear cell renal cell carcinomas (ccRCCs) represent ∼75% of RCC cases and account for most RCC-associated deaths. Inter- and intratumoral heterogeneity (ITH) results in varying prognosis and treatment outcomes. To obtain the most comprehensive profile of ccRCC, we perform integrative histopathologic, proteogenomic, and metabolomic analyses on 305 ccRCC tumor segments and 166 paired adjacent normal tissues from 213 cases. Combining histologic and molecular profiles reveals ITH in 90% of ccRCCs, with 50% demonstrating immune signature heterogeneity. High tumor grade, along with BAP1 mutation, genome instability, increased hypermethylation, and a specific protein glycosylation signature define a high-risk disease subset, where UCHL1 expression displays prognostic value. Single-nuclei RNA sequencing of the adverse sarcomatoid and rhabdoid phenotypes uncover gene signatures and potential insights into tumor evolution. In vitro cell line studies confirm the potential of inhibiting identified phosphoproteome targets. This study molecularly stratifies aggressive histopathologic subtypes that may inform more effective treatment strategies.

Summary Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive cancer with poor patient survival. Toward understanding the underlying molecular alterations that drive PDAC oncogenesis, we conducted comprehensive proteogenomic analysis of 140 pancreatic cancers, 67 normal adjacent tissues, and 9 normal pancreatic ductal tissues. Proteomic, phosphoproteomic, and glycoproteomic analyses were used to characterize proteins and their modifications. In addition, whole-genome sequencing, whole-exome sequencing, methylation, RNA sequencing (RNA-seq), and microRNA sequencing (miRNA-seq) were performed on the same tissues to facilitate an integrated proteogenomic analysis and determine the impact of genomic alterations on protein expression, signaling pathways, and post-translational modifications. To ensure robust downstream analyses, tumor neoplastic cellularity was assessed via multiple orthogonal strategies using molecular features and verified via pathological estimation of tumor cellularity based on histological review. This integrated proteogenomic characterization of PDAC will serve as a valuable resource for the community, paving the way for early detection and identification of novel therapeutic targets.

Glioblastoma (GBM) is the most aggressive nervous system cancer. Understanding its molecular pathogenesis is crucial to improving diagnosis and treatment. Integrated analysis of genomic, proteomic, post-translational modification and metabolomic data on 99 treatment-naive GBMs provides insights to GBM biology. We identify key phosphorylation events (e.g., phosphorylated PTPN11 and PLCG1) as potential switches mediating oncogenic pathway activation, as well as potential targets for EGFR-, TP53-, and RB1-altered tumors. Immune subtypes with distinct immune cell types are discovered using bulk omics methodologies, validated by snRNA-seq, and correlated with specific expression and histone acetylation patterns. Histone H2B acetylation in classical-like and immune-low GBM is driven largely by BRDs, CREBBP, and EP300. Integrated metabolomic and proteomic data identify specific lipid distributions across subtypes and distinct global metabolic changes in IDH-mutated tumors. This work highlights biological relationships that could contribute to stratification of GBM patients for more effective treatment. Wang et al. perform integrated proteogenomic analysis of adult glioblastoma (GBM), including metabolomics, lipidomics, and single nuclei RNA-Seq, revealing insights into the immune landscape of GBM, cell-specific nature of EMT signatures, histone acetylation in classical GBM, and the existence of signaling hubs which could provide therapeutic vulnerabilities.

Fine-needle biopsy (FNB) predicts benign or malignant thyroid nodules. For indeterminate (ITN) FNBs, commercial molecular tests may improve the diagnostic accuracy and reduce the number of operations. These tests have had limited independent implementation studies in routine clinical practice. This is a prospective observational study. At Boston Medical Center, the 1,316 consecutive FNBs were classified to one of the six categories in the Bethesda classification system. Those ITN samples were submitted for ThyroSeqV.2 next generation sequencing panel analysis. The performance of ThyroSeqV.2 to predict “neoplasm requiring surgery” (NRS) was evaluated. ThyroSeqV.2 assay was performed in 398 FNBs on 384 cytologically ITN nodules (308 Bethesda III, 47 Bethesda IV and 29 Bethesda V). The first evaluable ThyroSeq result for each nodule was used for final analysis. Seventy-seven (72.0%) of 107 patients with a high risk molecular test underwent thyroid surgery resulting in 41 NRS (53.2%) and 36 benign nodules (46.8%). Of the 249 patients with a low risk or negative molecular analysis, 51 (20.5%) had surgery revealing 47 benign nodules (92.2%) and 4 NRS (7.8%). Based on surgical outcome of 128 ITN with evaluable ThyroSeq results, this molecular test had a sensitivity of 91% (95% CI: 79%-98%), specificity of 56% (45%-67%), positive predictive value (PPV) of 53% (42%-65%), negative predictive value (NPV) of 92% (81%-98%), and an overall accuracy of 69% (55%-85%) with a prevalence of NRS of 35% (27%-44%). ThyroSeqV.2 in this clinical use study in ITN nodules provided a similar NPV but a lower PPV than expected compared to published studies due to the detection of an array of mutations in benign nodules. The NPV of 92.0% for ITN cytology confirmed its utility as a “rule-out” test to exclude NRS.

Background: A subset of encapsulated/circumscribed follicular variant of papillary thyroid carcinoma (FVPTC) was reclassified as noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) in 2016 to reduce overtreatment of a low-risk tumor. Study objectives were to describe the epidemiology and long-term outcomes of NIFTP in a high-volume, urban, tertiary referral center. Methods: Among patients enrolled in the Boston Medical Center (BMC) Thyroid Cancer Registry, 110 cases of FVPTC underwent index thyroid surgery at BMC between 2000 and 2016. Historically, BMC pathologists assess all malignant nodules using sections ≤0.3 cm with evaluation of the entire nodule and capsule. After review of pathology reports to identify potential NIFTPs, slides were rereviewed using criteria established by the NIFTP Working Group in 2016 and 2018. We evaluated interobserver reliability using Cohen's Kappa coefficient. Results: Among 110 FVPTCs, 15 (13%) met NIFTP criteria; 11 women and 4 men, age range 31–64 (mean 47.5) years. Mean tumor diameter was 1.7 cm (compared with 2.2 cm for FVPTC). Among NIFTP cases, there were no lymph node metastases, distant metastases, or tumor recurrences. All NIFTP cases were American Thyroid Association (ATA) low risk compared with only 68% of FVPTC (p = 0.011). Among FVPTCs, 14% had positive lymph nodes at index operation. Four patients (4%) had distant metastases. Mean follow-up time was 46 and 69 months for FVPTC and NIFTP, respectively. Among FVPTCs with an excellent response to therapy (2015 ATA guidelines), there were no recurrences. Just over half (n = 8) of patients with NIFTP received postoperative radioactive iodine (RAI) therapy. Concordance between pathologists was high for ruling out NIFTP (75%), but only 36% for ruling in NIFTP. Overall, for NIFTP designation, Cohen's Kappa was 0.39, which is considered fair. Conclusions: Although this is a relatively small cohort, all NIFTP specimens underwent updated pathology review consistent with current guidelines; mean follow-up was nearly 6 years. NIFTP represents a small fraction of the total papillary neoplasia diagnosed at this tertiary referral center (2.3%). None of the NIFTP cohort experienced an adverse oncologic event, and there were no regional or distant metastases. Over 50% of patients with NIFTP received RAI. Thus, the NIFTP reclassification may substantially reduce the number of patients who require adjuvant therapies, such as completion surgery or RAI.

Paragangliomas, neuroendocrine tumors of neural crest origin, commonly occur in the adrenal medulla where they are called pheochromocytoma. Primary cardiac paragangliomas are uncommon whereby they arise in the left atrium and, less frequently, right atrium. We present a 43-year-old female with a cardiac paraganglioma presenting with ischemic and positional chest pains. CT scanning showed an infiltrative 15×10cm unresectable tumor with intense peripheral enhancement and central hypoattenuation located above the right atrium. The clinical impression was that of a high-grade sarcoma. Histopathological examination revealed tumor cell nests in a distinctive ‘Zellballen’ pattern with positive synaptophysin, chromogranin and GATA-3 staining confirming the diagnosis of paraganglioma. Immunohistochemical studies revealed that the tumor lacked the expression of SDHB and therefore indicating a SDHB gene mutation. The tumor was nonfunctioning, and therefore the absence of the classic adrenergic manifestations contributed to the late diagnosis of the condition. In conclusion, whereas preoperative diagnosis is challenging with nonfunctional paragangliomas, it is recommended that paragangliomas be considered in the differential diagnosis of cardiac neoplasms. Keywords: Paraganglioma, Cardiac, Neuroendocrine, Thoracic

Preterm birth (PTB) contributes significantly to infant mortality and morbidity with lifelong impact. Few robust genetic factors of PTB have been identified. Such ‘missing heritability' may be partly due to gene × environment interactions (G × E), which is largely unexplored. Here we conduct genome-wide G × E analyses of PTB in 1,733 African-American women (698 mothers of PTB; 1,035 of term birth) from the Boston Birth Cohort. We show that maternal COL24A1 variants have a significant genome-wide interaction with maternal pre-pregnancy overweight/obesity on PTB risk, with rs11161721 (PG × E=1.8 × 10−8; empirical PG × E=1.2 × 10−8) as the top hit. This interaction is replicated in African-American mothers (PG × E=0.01) from an independent cohort and in meta-analysis (PG × E=3.6 × 10−9), but is not replicated in Caucasians. In adipose tissue, rs11161721 is significantly associated with altered COL24A1 expression. Our findings may provide new insight into the aetiology of PTB and improve our ability to predict and prevent PTB., Preterm birth (PTB) has high prevalence and PTB infants have greater risk for mortality. Here, Hong and colleagues perform a genome-wide gene × environment interaction analysis and find that maternal COL24A1 variants have a significant interaction with maternal pre-pregnancy obesity in increasing PTB risk.

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.

The associations of maternal conditions, before or during pregnancy, with placental lesions have not been adequately studied in populations.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.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.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.

We present a proteogenomic study of 108 human papilloma virus (HPV)-negative head and neck squamous cell carcinomas (HNSCCs). Proteomic analysis systematically catalogs HNSCC-associated proteins and phosphosites, prioritizes copy number drivers, and highlights an oncogenic role for RNA processing genes. Proteomic investigation of mutual exclusivity between FAT1 truncating mutations and 11q13.3 amplifications reveals dysregulated actin dynamics as a common functional consequence. Phosphoproteomics characterizes two modes of EGFR activation, suggesting a new strategy to stratify HNSCCs based on EGFR ligand abundance for effective treatment with inhibitory EGFR monoclonal antibodies. Widespread deletion of immune modulatory genes accounts for low immune infiltration in immune-cold tumors, whereas concordant upregulation of multiple immune checkpoint proteins may underlie resistance to anti-programmed cell death protein 1 monotherapy in immune-hot tumors. Multi-omic analysis identifies three molecular subtypes with high potential for treatment with CDK inhibitors, anti-EGFR antibody therapy, and immunotherapy, respectively. Altogether, proteogenomics provides a systematic framework to inform HNSCC biology and treatment.

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.

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.

We undertook a comprehensive proteogenomic characterization of 95 prospectively collected endometrial carcinomas, comprising 83 endometrioid and 12 serous tumors. This analysis revealed possible new consequences of perturbations to the p53 and Wnt/β-catenin pathways, identified a potential role for circRNAs in the epithelial-mesenchymal transition, and provided new information about proteomic markers of clinical and genomic tumor subgroups, including relationships to known druggable pathways. An extensive genome-wide acetylation survey yielded insights into regulatory mechanisms linking Wnt signaling and histone acetylation. We also characterized aspects of the tumor immune landscape, including immunogenic alterations, neoantigens, common cancer/testis antigens, and the immune microenvironment, all of which can inform immunotherapy decisions. Collectively, our multi-omic analyses provide a valuable resource for researchers and clinicians, identify new molecular associations of potential mechanistic significance in the development of endometrial cancers, and suggest novel approaches for identifying potential therapeutic targets.

BACKGROUND The purpose of this study was to reevaluate the clinical and pathologic features and outcomes in patients with Crohn's 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 Crohn's 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 Crohn's 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 Crohn's 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.

Elevated pre-pregnancy body mass index (BMI), excessive gestational weight gain (GWG), and gestational diabetes (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 birthweight-for-gestational age, and whether the relationships differ by preterm status. We examined 1035 mother-infant pairs at birth from the Boston Birth Cohort. Data were collected by questionnaire and clinical measures. Placentas were weighed without membranes or umbilical cords. We performed sequential models excluding and including placental weight, stratified by preterm status. We found that 21% of mothers were obese, 42% had excessive GWG, and 5% had GDM. 41% were preterm. Among term births, after adjustment for sex, gestational age, maternal age, race, parity, education, smoking and stress during pregnancy, birthweight-for-gestational age z-score was 0.55 (0.30, 0.80) units higher for pre-pregnancy obesity vs. normal weight. It was 0.34 (0.13, 0.55) higher for excessive vs. adequate GWG, 0.67 (0.24, 1.10) for GDM vs. no DM, with additional adjustment for pre-pregnancy BMI. Adding placental weight to the models attenuated the estimates for pre-pregnancy obesity by 20%, excessive GWG by 32%, and GDM by 21%. Among preterm infants, GDM was associated with 0.67 (0.34, 1.00) higher birthweight-for-gestational age z-score, but pre-pregnancy obesity and excessive GWG were not. Attenuation by placental weight was 36% for GDM. These results suggest that placental weight partially mediates the effects of pre-pregnancy obesity, GDM and excessive GWG on fetal growth among term infants.

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.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.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 (P0.001). 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.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.

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.

Preterm delivery (PTD

To evaluate the impact of clinical and histopathologic correlates related to maternal and fetal inflammatory responses (MIR and FIR) on degree of preterm birth.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 (or=33 weeks, 29-32 weeks, and29 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.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 at29 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.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.

There is evidence that some cancers in patients with inflammatory bowel disease (IBD) develop via the serrated pathway of carcinogenesis. This study examined the clinicopathological features and outcome of 115 IBD patients (65 with ulcerative colitis, 50 with Crohn disease), all with at least 1 serrated polyp at endoscopy or colon resection, including the presence of synchronous and metachronous conventional neoplastic lesions (dysplasia or adenocarcinoma), over an average follow-up period of 56.4 months. Conventional neoplasia was categorized as flat dysplasia (low or high grade), sporadic adenoma, adenoma-like dysplasia-associated lesion or mass, or adenocarcinoma. Overall, 97% of patients had at least 1 hyperplastic polyp (HP), 6% had a sessile serrated adenoma/polyp, and none had a traditional serrated adenoma. Eight patients (7%) had a synchronous conventional neoplastic lesion; only 1 had flat dysplasia (1%) and 2 had adenocarcinoma (2%). Thirteen patients developed a metachronous conventional neoplastic lesion, with 8 developing their conventional neoplasm within an area of previous or concurrent colitis; only 1 patient developed flat dysplasia (1%), and none developed adenocarcinoma. A higher proportion of patients with both an HP and a synchronous conventional neoplastic lesion at index developed a metachronous conventional neoplastic lesion, compared with those with an index HP only (25% versus 7%). These results suggest that IBD patients (both ulcerative colitis and Crohn disease patients) with HP have a very low risk of developing a conventional neoplastic lesion (flat dysplasia or adenocarcinoma) that would warrant surgical resection.

PKC-delta is a serine/threonine kinase that mediates diverse signal transduction pathways. We previously demonstrated that overexpression of PKC-delta slowed the G1 progression of Caco-2 colon cancer cells, accelerated apoptosis, and induced cellular differentiation. In this study, we further characterized the PKC-delta dependent signaling pathways involved in these tumor suppressor actions in Caco-2 cells overexpressing PKC-delta using a Zn2+ inducible expression vector. Consistent with a G1 arrest, increased expression of PKC-delta caused rapid and significant downregulation of cyclin D1 and cyclin E proteins (50% decreases, P0.05), while mRNA levels remained unchanged. The PKC agonist, phorbol 12-myristate 13-acetate (TPA, 100 nM, 4 h), induced two-fold higher protein and mRNA levels of p21(Waf1), a cyclin-dependent kinase (cdk) inhibitor in PKC-delta transfectants compared with empty vector (EV) transfected cells, whereas the PKC-delta specific inhibitor rottlerin (3 microM) or knockdown of this isoenzyme with specific siRNA oligonucleotides blocked p21(Waf1) expression. Concomitantly, compared to EV control cells, PKC-delta upregulation decreased cyclin D1 and cyclin E proteins co-immunoprecipitating with cdk6 and cdk2, respectively. In addition, overexpression of PKC-delta increased binding of cdk inhibitor p27(Kip1) to cdk4. These alterations in cyclin-cdks and their inhibitors are predicted to decrease G1 cyclin kinase activity. As an independent confirmation of the direct role PKC-delta plays in cell growth and cell cycle regulation, we knocked down PKC-delta using specific siRNA oligonucleotides. PKC-delta specific siRNA oligonucleotides, but not irrelevant control oligonucleotides, inhibited PKC-delta protein by more than 80% in Caco-2 cells. Moreover, PKC-delta knockdown enhanced cell proliferation ( approximately 1.4-2-fold, P0.05) and concomitantly increased cyclin D1 and cyclin E expression ( approximately 1.7-fold, P0.05). This was a specific effect, as nontargeted PKC-zeta was not changed by PKC-delta siRNA oligonucleotides. Consistent with accelerated apoptosis in PKC-delta transfectants, compared to EV cells, PKC-delta upregulation increased proapoptotic regulator Bax two-fold at mRNA and protein levels, while antiapoptotic Bcl-2 protein was decreased by 50% at a post-transcriptional level. PKC-delta specific siRNA oligonucleotides inhibited Bax protein expression by more than 50%, indicating that PKC-delta regulates apoptosis through Bax. Taken together, these results elucidate two critical mechanisms regulated by PKC-delta that inhibit cell cycle progression and enhance apoptosis in colon cancer cells. We postulate these antiproliferative pathways mediate an important tumor suppressor function for PKC-delta in colonic carcinogenesis.

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

Inflammatory bowel disease (IBD) is a spectrum of disorders that leads to inflammation of the intestinal mucosa, classified clinically as ulcerative colitis (UC) or Crohn’s disease (CD). UC involves the large intestine and causes inflammation in a continuous pattern from the rectum to the cecum. CD, however, can involve the large or small intestines, generally spares the rectum, and can lead to fistulas, abscesses, and/or strictures. In the United States, it is estimated that between 1 million and 1.5 million people have IBD.1–3 There is no gold standard for classifying IBD as UC or CD, although this is crucial for prognostic and therapeutic reasons. In the majority of cases, UC can be distinguished from CD using clinical features, laboratory testing, routine white light endoscopy with associated biopsy histopathology, and radiological imaging. However, in approximately 10% to 15% of patients with disease limited to the colon, a definitive diagnosis can be difficult.4 IBD restricted to the colon that cannot be further classified as CD or UC is termed as IBD unclassified (IBD-U).5 Laboratory markers, such as fecal markers and serological antibody testing, may be used to aid in the diagnosis of IBD,6,7 and, in cases of IBD-U, to help and distinguish between IBD subtypes and identify high-risk individuals, which may have treatment implications.8,9 Although serological biomarkers alone are not useful in diagnosing IBD,10,11 they may have an adjunctive role in cases of IBD-U and in stratifying those at high-risk for disease-related complications. Optical spectroscopy has been suggested as a promising tool for the management of IBD.12–14 Fluorescence spectroscopy has been reported to differentiate normal colon from IBD ex vivo in murine models15 and to increase the detection of invisible flat intraepithelial neoplasia.16 Recently, Raman spectroscopy has been proposed as an optical biomarker for distinguishing CD from UC in vitro in ex vivo tissue samples from patients with IBD.17 Elastic scattering spectroscopy (ESS) and related reflectance spectroscopies have shown promise in vivo in the gastrointestinal tract for detecting neoplasia in the colon,18–22 dysplasia in the esophagus,21,23–27 and colitis and dysplasia in patients with IBD.18,19 ESS has also been used to distinguish pathologies in other epithelially lined hollow organs, such as the urinary bladder,28 and in cystic and solid tissues, including breast and associated lymph nodes,29,30 pancreas,31 and thyroid.32,33 ESS, mediated by application-specific fiberoptic probes with specialized optical geometries, is sensitive to the absorption spectra of major chromophores (e.g., oxy-/deoxy-hemoglobin) and, more importantly, to the scattering spectra related to micromorphological features of tissues that are in contact with the tip of the probe. ESS spectra derive from the wavelength-dependent optical scattering efficiency (and the effects of changes in the scattering angular probability) caused by optical index gradients because of cellular and subcellular structures. Thus, unlike Raman and fluorescence spectroscopy, ESS provides largely microstructural, not biochemical, information. As such, ESS is sensitive to structural features such as nuclear size, crowding, chromaticity, and chromatin granularity, as well as to mitochondrial and organellar size and density. Such features are, to varying degrees, components of a histopathological assessment. ESS, however, is a real-time, point-source measurement that senses these types of morphological changes semiquantitatively without actually rendering a microscopic image, per se. In addition, because of its inherent simplicity and miniaturizability, ESS is extremely low cost, clinically robust, and impacts procedure flow minimally, especially when integrated into standard endoscopic biopsy tools.21 In this article, we investigate whether ESS has utility as an in vivo real-time endoscopic reporter of disease activity and an optical biomarker for distinguishing CD from UC.

AL amyloidosis patients ineligible for dose-intensive melphalan (200 mg/m2) were enrolled on a phase II trial to be treated with two cycles of intermediate-dose melphalan (IDM 100 mg/m2) and mobilized blood stem cells (BSC). For mobilization patients were randomized to either GM-CSF 250 μg/m2 for 3 d followed by G-CSF 10 μg/kg for 3 d (GM+G), or G-CSF 10 μg/kg for 6 d (G-alone), with leukaphereses on days 5, 6 and 7. To minimize morbidity, we planned to support each cycle with 3.5 × 106 CD34+ cells/kg and had a collection target of 7 × 106 CD34+ cells/kg. Those who did not achieve the target were treated with one cycle of IDM. 30 patients, a median of 62 years old and 7 months from diagnosis, were enrolled. Both mobilization regimens were generally well tolerated, and similar in terms of CD34+ cells and CFU-GM collected, but only 6/28 patients achieved the collection target (GM+G four, G-alone two). Despite a 19% incidence of grade 4 toxicities, IDM therapy was well tolerated. At a median follow-up of 24 months (19–36) 57% of patients had survived, 17% with durable complete haematological responses and 40% with improved or stable amyloid organ involvement, including 3/9 patients with predominant cardiac amyloid who are alive 2–3 years after treatment. The 100 d mortality was 20%. In conclusion, no definitive differences were identified between the mobilization regimens and IDM was an active regimen in AL for selected patients.

Background We hypothesized that the method of breast cancer margin assessment may be associated with different rates of positive margins and residual carcinoma. Methods A total of 178 breast cancer specimens were divided into 2 groups (A and B) based on the margin assessment method used. Rates of positive margins, re-excision, and residual carcinoma at re-excision were compared and analyzed statistically. Results At least 1 margin was positive in 64.7% in group A and in 65.2% in group B. At directed re-excision 54% in group A and 51% in group B had residual carcinoma. The lateral margin was positive in 44% in group A compared with 26% in group B ( P = .06). The posterior margin was positive in 19% in group A and in 51% in group B ( P = .001). Conclusions Two different breast cancer specimen margin assessment methods had comparable rates of positive margins and residual carcinoma at re-excision. Different patterns of specific margin positivity suggest that the method of margin assessment may alter results.

One of the most prevalent products of oxygen radical injury in DNA is 8-hydroxyguanosine. Cells must be able to withstand damage by oxygen radicals and possess specific repair mechanisms that correct this oxidative lesion. However, when these defenses are oversaturated, such as under conditions of high oxidative stress, or when repair is inefficient, the miscoding potential of this lesion can result in mutations in the mammalian genome. In addition to causing genetic changes, active oxygen species can lead to epigenetic alterations in DNA methylation, without changing the DNA base sequence. Such changes in DNA methylation patterns can strongly affect the regulation of expression of many genes. Although DNA methylation patterns have been found to be altered during carcinogenesis, little is known about the mechanism(s) that produce this loss of epigenetic controls of gene expression in tumors. Replacement of guanine with the oxygen radical adduct 8-hydroxyguanine profoundly alters methylation of adjacent cytosines, suggesting a role for oxidative injury in the formation of aberrant DNA methylation patterns during carcinogenesis. In this paper, we review both the genetic and epigenetic mechanisms of oxidative DNA damage and its association with the carcinogenic process, with special emphasis on the influence of free radical injury on DNA methylation.

Preoperative chemoradiotherapy (preopCRT) for locally advanced rectal cancer is associated with grade 3 or higher acute gastrointestinal (GI) toxicity. This study was conducted to determine whether intensity-modulated radiation therapy (IMRT) significantly reduces acute GI toxicity, compared to 3-dimensional conformal RT (3D-CRT) in preopCRT for rectal cancer.A retrospective analysis was conducted of 48 patients treated between January 2002 and August 2010 with preopCRT for rectal cancer. 3D-CRT or IMRT was administered at a planned dose of 45-50.4 Gy to patients positioned prone on a bowel-displacement device. Data regarding patient and tumor characteristics, treatment, acute toxicity, and tumor response were collected. Comparisons of acute toxicity and treatment response between 3D-CRT and IMRT were performed with the Chi-square or Fisher's exact test.There were no significant differences in radiation dose, median age, race, gender, stage, type of concurrent chemotherapy, pathologic complete response (pCR), or type of surgery (lower anterior or abdominal perineal resection) between 3D-CRT and IMRT. There was a significant reduction in grade 2 or higher GI toxicity (3D-CRT, 60.7%; IMRT, 30%; P = .036) and grade 2 or higher diarrhea (3D-CRT, 42.8%; IMRT, 10%; P = .014). Two patients who underwent 3D-CRT required a treatment break (grade 3 diarrhea and grade 3 dehydration). Radiation duration was significantly less (IMRT, 35 days; 3D-CRT, 39 days; P ≤ .0001). pCR rates were 16.7% for 3D-CRT and 21.4% for IMRT (nonsignificant [NS]); pCR+microscopic residual rates were 57.1% for IMRT and 27.8% for 3D-CRT (P = .093).Maximal bowel displacement with IMRT yields favorable acute GI toxicity and pathologic downstaging profiles, as compared to 3D-CRT in preoperative CRT for rectal cancer and warrants further prospective investigation.

Patients with long-term ulcerative colitis are at risk for developing colorectal cancer.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.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% (p0.001) in high-grade dysplasia and by 60% (p0.001) in carcinoma when compared to the quiescent colitis group.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.

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.We examined 1,035 mother-infant pairs at birth from the Boston Birth Cohort. Data were collected by questionnaire and clinical measures. Placentas were weighed without membranes or umbilical cords. We performed sequential models excluding and including placental weight, stratified by preterm status.We found that 21% of mothers were obese, 42% had excessive GWG, and 5% had GDM. Forty-one percent were preterm. Among term births, after adjustment for sex, gestational age, maternal age, race, parity, education, smoking, and stress during pregnancy, birth weight-for-gestational age z-score was 0.55 (0.30, 0.80) units higher for pre-pregnancy obesity vs. normal weight. It was 0.34 (0.13, 0.55) higher for excessive vs. adequate GWG, 0.67 (0.24, 1.10) for GDM vs. no DM, with additional adjustment for pre-pregnancy BMI. Adding placental weight to the models attenuated the estimates for pre-pregnancy obesity by 20%, excessive GWG by 32%, and GDM by 21%. Among preterm infants, GDM was associated with 0.67 (0.34, 1.00) higher birth weight-for-gestational age z-score, but pre-pregnancy obesity and excessive GWG were not. Attenuation by placental weight was 36% for GDM.These results suggest that placental weight partially mediates the effects of pre-pregnancy obesity, GDM, and excessive GWG on fetal growth among term infants.

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.

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.

BACKGROUND The proinflammatory cytokine tumor necrosis factor-alpha (TNF-alpha) plays a key role in the pathogenesis of Crohn's disease (CD) and ulcerative colitis (UC). Recently, a new transcription factor termed LITAF (lipopolysaccharide-induced TNF-alpha factor) was shown to mediate TNF-alpha expression in human macrophages by direct binding to specific sequences in the promoter region of the TNF-alpha 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-alpha 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-alpha 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-alpha. These data provide strong evidence of a role for LITAF in the pathophysiological regulation of the TNF-alpha gene and underscore the potential value of anti-LITAF strategies in the clinical management of these diseases.