TLR cross-talk specifically regulates cytokine production by B cells from chronic inflammatory disease patients.

Chronic systemic inflammation links periodontal disease and diabetes to increased incidence of serious comorbidities. Activation of TLRs, particularly TLR2 and TLR4, promotes chronic systemic inflammation. Human B cells have been generally thought to lack these TLRs. However, recent work showed that an increased percentage of circulating B cells from inflammatory disease patients express TLR2 and TLR4, and that TLR engagement on B cells resulted in unexpected changes in gene expression. New data show that B cells from inflammatory disease patients secrete multiple cytokines in response to different classes of TLR ligands. Furthermore, the B cell response to combinations of TLR ligands is cytokine- and ligand-specific. Some cytokines (IL-1beta and IL-10) are predominantly regulated by TLR4, but others (IL-8 and TNF-alpha) are predominantly regulated by TLR2, due in part to TLR-dictated changes in transcription factor/promoter association. TLR2 and TLR9 also regulate B cell TLR4 expression, demonstrating that TLR cross-talk controls B cell responses at multiple levels. Parallel examination of B cells from periodontal disease and diabetes patients suggested that outcomes of TLR cross-talk are influenced by disease pathology. We conclude that disease-associated alteration of B cell TLR responses specifically regulates cytokine production and may influence chronic inflammation.

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.

Do colorectal cancer patients understand that their family is at risk?

AIM: The aim of this study was to assess whether patients with colorectal cancer (CRC) are aware of the risk to family members and to test an educational intervention. METHODS: CRC patients were surveyed regarding their cancer, family history, understanding of familial risk of CRC, and knowledge of existing screening guidelines for their relatives. An educational intervention was mailed to them and 6 months later they were resurveyed. RESULTS: Of 253 CRC patients who agreed to participate, only 120 (47.4%) knew that their first-degree relatives were at increased risk for CRC. African-American (AA) race, educational background, income, and previous family history of CRC were significant predictive factors on univariate analysis, but only AA race remained significant on multivariate analysis. Two hundred two patients received the educational intervention and were resurveyed. The understanding of family risk did not improve with this intervention. CONCLUSION: Most CRC patients do not know about their family members' risk. Better educational tools are needed.

A selective small molecule inhibitor of c-Met, PHA665752, inhibits tumorigenicity and angiogenesis in mouse lung cancer xenografts.

The c-Met receptor tyrosine kinase is emerging as a novel target in many solid tumors, including lung cancer. PHA-665752 was identified as a small molecule, ATP competitive inhibitor of the catalytic activity of the c-Met kinase. Here, we show that treatment with PHA665752 reduced NCI-H69 (small cell lung cancer) and NCI-H441 (non-small cell lung cancer) tumorigenicity in mouse xenografts by 99% and 75%, respectively. Reduction in tumor size was also observed by magnetic resonance imaging of tumors in mice. PHA665752 inhibited c-Met phosphorylation at the autophosphorylation and c-Cbl binding sites in mouse xenografts derived from non-small cell lung cancer cell lines (NCI-H441 and A549) and small cell lung cancer cell line (NCI-H69). PHA665752 also inhibited angiogenesis by >85% in all the abovementioned cell lines and caused an angiogenic switch which resulted in a decreased production of vascular endothelial growth factor and an increase in the production of the angiogenesis inhibitor thrombospondin-1. These studies show the feasibility of selectively targeting c-Met with ATP competitive small molecule inhibitors and suggest that PHA665752 may provide a novel therapeutic approach to lung cancer.

Outcome after surveillance of low-grade and indefinite dysplasia in patients with ulcerative colitis.

BACKGROUND: The management of low-grade (LGD) and indefinite dysplasia (IND) in patients with ulcerative colitis (UC) remains controversial, as outcomes after a diagnosis of LGD or IND in previous studies vary widely. METHODS: All patients evaluated were from a single institution referral center who had a history of UC and a diagnosis of either LGD or IND between 1994 and 2008 as confirmed by 2 expert gastrointestinal (GI) pathologists. Data were collected by chart review of electronic and paper medical records. All patients who did not undergo a colectomy within 90 days of their dysplasia diagnosis were included in the final analysis. Hazard ratios for risk factors as well as incidence rates and Kaplan-Meier estimates were used to calculate the progression to high-grade dysplasia (HGD) or colorectal cancer (CRC). RESULTS: Thirty-five patients were included in the analysis, of whom 2 patients with IND and 2 patients with LGD developed HGD or CRC over a mean duration of 49.8 months. In total, the incident rate for advanced neoplasia for all patients was 2.7 cases of HGD or CRC per 100 person-years at risk. For flat and polypoid LGD the incident rate of advanced neoplasia was 4.3 and 1.5 cases per 100 person-years at risk, respectively. Patients with primary sclerosing cholangitis (PSC) had an incident rate of 10.5 cases per 100 years of patient follow-up. CONCLUSIONS: We report a low rate of progression to HGD or CRC in patients who underwent surveillance for LGD or IND; polypoid dysplasia showed less risk of progression than flat dysplasia.

Association of colorectal cancer and prostate cancer and impact of radiation therapy.

To quantify the risk of prostate cancer after colorectal cancer and the risk of colorectal cancer after prostate cancer and to examine the impact of radiation therapy on subsequent cancer risk, we conducted retrospective cohort studies using data from the Surveillance, Epidemiology and End Results program from 1973 to 2005. Standardized incidence ratios (SIR) and 95% confidence intervals (95% CI) were calculated, adjusting for age, ethnicity, and calendar year. The subsequent risk of developing a prostate cancer was significantly elevated in patients diagnosed with colon cancer before age 50 years (SIR, 1.38; 95% CI, 1.18-1.60). The risk of subsequent prostate cancer was decreased for men with rectal cancer who received radiation therapy (SIR, 0.57; 95% CI, 0.52-0.63). Interestingly, this beneficial effect of radiation therapy was only observed in the prostate-specific antigen (PSA) era (1988+). In addition, the prostate cancer cases developed in the radiation therapy group tended to have higher-grade, later-stage tumors, higher PSA levels, and worse survival than those developed in the nonradiation therapy group. In the cohort of prostate cancer patients, the risk of colon cancer was elevated in patients diagnosed with prostate cancer before age 50 years (SIR, 1.51; 95% CI, 1.03-2.20). In conclusion, a diagnosis of colon or prostate cancer in men of younger ages may be an indication for screening of prostate or colon cancer, respectively. The decreased prostate cancer risk in men who received radiation therapy for rectal cancer may be related to the use of PSA for prostate cancer screening or the cure of occult prostate cancer.

Hyperactivated B cells in human inflammatory bowel disease.

IBD is characterized by a chronic, dysregulated immune response to intestinal bacteria. Past work has focused on the role of T cells and myeloid cells in mediating chronic gastrointestinal and systemic inflammation. Here, we show that circulating and tissue B cells from CD patients demonstrate elevated basal levels of activation. CD patient B cells express surface TLR2, spontaneously secrete high levels of IL-8, and contain increased ex vivo levels of phosphorylated signaling proteins. CD clinical activity correlates directly with B cell expression of IL-8 and TLR2, suggesting a positive relationship between these B cell inflammatory mediators and disease pathogenesis. In contrast, B cells from UC patients express TLR2 but generally do not demonstrate spontaneous IL-8 secretion; however, significant IL-8 production is inducible via TLR2 stimulation. Furthermore, UC clinical activity correlates inversely with levels of circulating TLR2+ B cells, which is opposite to the association observed in CD. In conclusion, TLR2+ B cells are associated with clinical measures of disease activity and differentially associated with CD- and UC-specific patterns of inflammatory mediators, suggesting a formerly unappreciated role of B cells in the pathogenesis of IBD.

Are dysplasia and colorectal cancer endoscopically visible in patients with ulcerative colitis?

BACKGROUND: Dysplasia and colorectal cancer (CRC) in ulcerative colitis (UC) develop via pathways distinct from sporadic CRC and may occur in flat mucosa indistinct from surrounding tissue. Surveillance guidelines, therefore, have emphasized the ;roach of periodic endoscopic examinations and systematic random biopsies of involved mucosa. Given the imperfect nature of this random approach, recent work has focused on improved surveillance techniques and suggests that neoplasia is endoscopically visible in many patients. OBJECTIVE: To assess the endoscopic visibility of dysplasia and CRC in UC. DESIGN: This was a retrospective review that used the University of Chicago Inflammatory Bowel Disease Registry and the clinical administrative database. All cases of dysplasia or CRC in UC between November 1994 and October 2004 were identified. The approach to surveillance in these patients included both random biopsies at approximately 10-cm intervals throughout the involved colon and directed biopsies of polypoid lesions, masses, strictures, or irregular mucosa distinct from surrounding inflamed tissue. Findings on endoscopy were compared with pathologic findings from biopsy or surgical specimens. Visible dysplasia was defined as a lesion reported by the endoscopist that led to directed biopsy and that was confirmed by pathology. Invisible dysplasia was defined as dysplasia diagnosed on pathology but not described on endoscopy. Per-lesion and per-patient sensitivities were determined. SETTING: Tertiary referral center. PATIENTS: Database of patients with inflammatory bowel disease seen at the University of Chicago. MAIN OUTCOME MEASUREMENTS: Endoscopically visible neoplasia. RESULTS: In this database, there were 1339 surveillance examinations in 622 patients with UC. Forty-six patients were found to have dysplasia or CRC at a median age of 48 years and with median duration of disease of 20 years. Of these patients, 77% had pancolitis, 21% had left-sided colitis, and 2% had proctitis. These patients had 128 surveillance examinations (median 3 per patient; range, 1-9 per patient), and, in 51 examinations, 75 separate dysplastic or cancerous lesions were identified (mean, 1.6 lesions per patient; standard deviation, 1.3). Thirty-eight of 65 dysplastic lesions (58.5%) and 8 of 10 cancers (80.0%) were visible to the endoscopist as 23 polyps and masses, 1 stricture, and 22 irregular mucosa. The per-patient sensitivities for dysplasia and for cancer were 71.8% and 100%, respectively. The overall per-lesion and per-patient sensitivities were 61.3% and 76.1%, respectively. LIMITATIONS: Retrospective review of clinical databases and medical records. CONCLUSIONS: Dysplasia and cancer in UC are endoscopically visible in most patients and may be reliably identified during scheduled examinations. Future surveillance guidelines should incorporate this information.