Factors Associated with Adenoma Detection Rate and Diagnosis of Polyps and Colorectal Cancer during Colonoscopy in France: Results of a Prospective,Nationwide Survey

Introduction

Colonoscopy can prevent deaths due to colorectal cancer (CRC) through early diagnosis or resection of colonic adenomas. We conducted a prospective, nationwide study on colonoscopy practice in France.

Methods

An online questionnaire was administered to 2,600 French gastroenterologists. Data from all consecutive colonoscopies performed during one week were collected. A statistical extrapolation of the results to a whole year was performed, and factors potentially associated with the adenoma detection rate (ADR) or the diagnosis of polyps or cancer were assessed.

Results

A total of 342 gastroenterologists, representative of the overall population of French gastroenterologists, provided data on 3,266 colonoscopies, corresponding to 1,200,529 (95% CI: 1,125,936-1,275,122) procedures for the year 2011. The indication for colonoscopy was CRC screening and digestive symptoms in 49.6% and 38.9% of cases, respectively. Polypectomy was performed in 35.5% of cases. The ADR and prevalence of CRC were 17.7% and 2.9%, respectively. The main factors associated with a high ADR were male gender (p=0.0001), age over 50 (p=0.0001), personal or family history of CRC or colorectal polyps (p<0.0001 and p<0.0001, respectively), and positive fecal occult blood test (p=0.0005). The prevalence of CRC was three times higher in patients with their first colonoscopy (4.2% vs. 1.4%; p<0.0001).

Conclusions

For the first time in France, we report nationwide prospective data on colonoscopy practice, including histological results. We found an average ADR of 17.7%, and observed reduced CRC incidence in patients with previous colonoscopy.     

Linking of Primary Care Records to Census Data to Study the Association between Socioeconomic Status and Cancer Incidence in Southern Europe: A Nation-Wide Ecological Study

Background

Area-based measures of economic deprivation are seldom applied to large medical records databases to establish population-scale associations between deprivation and disease.

Objective

To study the association between deprivation and incidence of common cancer types in a Southern European region.

Methods

Retrospective ecological study using the SIDIAP (Information System for the Development of Research in Primary Care) database of longitudinal electronic medical records for a representative population of Catalonia (Spain) and the MEDEA index based on urban socioeconomic indicators in the Spanish census. Study outcomes were incident cervical, breast, colorectal, prostate, and lung cancer in 2009–2012. The completeness of SIDIAP cancer recording was evaluated through linkage of a geographic data subset to a hospital cancer registry. Associations between MEDEA quintiles and cancer incidence was evaluated using zero-inflated Poisson regression adjusted for sex, age, smoking, alcoholism, obesity, hypertension, and diabetes.

Results

SIDIAP sensitivity was 63% to 92% for the five cancers studied. There was direct association between deprivation and lung, colorectal, and cervical cancer: incidence rate ratios (IRR) 1.82 [1.64–2.01], IRR 1.60 [1.34–1.90], IRR 1.22 [1.07–1.38], respectively, comparing the most deprived to most affluent areas. In wealthy areas, prostate and breast cancers were more common: IRR 0.92 [0.80–1.00], IRR 0.91 [0.78–1.06]. Adjustment for confounders attenuated the association with lung cancer risk (fully adjusted IRR 1.16 [1.08–1.25]), reversed the direction of the association with colorectal cancer (IRR 0.90 [0.84–0.95]), and did not modify the associations with cervical (IRR 1.27 [1.11–1.45]), prostate (0.74 [0.69–0.80]), and breast (0.76 [0.71–0.81]) cancer.

Conclusions

Deprivation is associated differently with the occurrence of various cancer types. These results provide evidence that MEDEA is a useful, area-based deprivation index for analyses of the SIDIAP database. This information will be useful to improve screening programs, cancer prevention and management strategies, to reach patients more effectively, particularly in deprived urban areas.     

The Performance of Three-Sample Qualitative Immunochemical Fecal Test to Detect Colorectal Adenoma and Cancer in Gastrointestinal Outpatients: An Observational Study

Background

Repeated qualitative fecal immunochemical test (qlFIT) is a clinical strategy widely used to detect lower gastrointestinal lesions, but its diagnostic power has not been assessed in opportunistic screening for colorectal neoplasia.

Objective

This study aimed to determine the performance of three-sample qlFIT in screening for colorectal cancer and its precursors in high-risk participants.

Methods

513 gastrointestinal outpatients yielded three qlFITs before a standard colonoscopy. We evaluated the diagnostic value of one, two, and three positive qlFITs serving as the positivity threshold. The risk factors of colorectal neoplasia to yield positive qlFITs were also determined.

Results

52 patients were diagnosed with colorectal cancer and 70 with advanced adenomatous polyp. For colorectal cancer, the sensitivity and specificity of one positive qlFIT were 90.4% and 53.8%, of two were 80.8% and 75.1%, and of three were 53.9% and 88.5%, respectively. For advanced adenomatous polyp, the sensitivity and specificity of one positive qlFIT were 81.4% and 54.2%, of two were 50.0% and 72.5%, and of three were 28.6% and 86.2%. Left-sided location (OR 2.50, 95%CI 1.26–4.95) and advanced histology of tumors (OR 3.08, 95%CI 1.58–6.01) were independently associated with positive qlFITs.

Conclusions

Three-sample qlFIT is a reasonably good method to detect colorectal neoplasia in high-risk population. Tumors in the left side or with advanced pathological features are more likely to produce positive qlFITs.     

Patients' & Healthcare Professionals' Values Regarding True- & False-Positive Diagnosis when Colorectal Cancer Screening by CT Colonography: Discrete Choice Experiment

Purpose

To establish the relative weighting given by patients and healthcare professionals to gains in diagnostic sensitivity versus loss of specificity when using CT colonography (CTC) for colorectal cancer screening.

Materials and Methods

Following ethical approval and informed consent, 75 patients and 50 healthcare professionals undertook a discrete choice experiment in which they chose between “standard” CTC and “enhanced” CTC that raised diagnostic sensitivity 10% for either cancer or polyps in exchange for varying levels of specificity. We established the relative increase in false-positive diagnoses participants traded for an increase in true-positive diagnoses.

Results

Data from 122 participants were analysed. There were 30 (25%) non-traders for the cancer scenario and 20 (16%) for the polyp scenario. For cancer, the 10% gain in sensitivity was traded up to a median 45% (IQR 25 to >85) drop in specificity, equating to 2250 (IQR 1250 to >4250) additional false-positives per additional true-positive cancer, at 0.2% prevalence. For polyps, the figure was 15% (IQR 7.5 to 55), equating to 6 (IQR 3 to 22) additional false-positives per additional true-positive polyp, at 25% prevalence. Tipping points were significantly higher for patients than professionals for both cancer (85 vs 25, p<0.001) and polyps (55 vs 15, p<0.001). Patients were willing to pay significantly more for increased sensitivity for cancer (p = 0.021).

Conclusion

When screening for colorectal cancer, patients and professionals believe gains in true-positive diagnoses are worth much more than the negative consequences of a corresponding rise in false-positives. Evaluation of screening tests should account for this.     

Better Long-Term Survival in Young Patients with Non-Metastatic Colorectal Cancer after Surgery,an Analysis of 69,835 Patients in SEER Database

Objective

To compare the long-term survival of colorectal cancer (CRC) in young patients with elderly ones.

Methods

Using Surveillance, Epidemiology, and End Results (SEER) population-based data, we identified 69,835 patients with non-metastatic colorectal cancer diagnosed between January 1, 1988 and December 31, 2003 treated with surgery. Patients were divided into young (40 years and under) and elderly groups (over 40 years of age). Five-year cancer specific survival data were obtained. Kaplan-Meier methods were adopted and multivariable Cox regression models were built for the analysis of long-term survival outcomes and risk factors.

Results

Young patients showed significantly higher pathological grading (p<0.001), more cases of mucinous and signet-ring histological type (p<0.001), later AJCC stage (p<0.001), more lymph nodes (≥12 nodes) dissected (p<0.001) and higher metastatic lymph node ratio (p<0.001). The 5-year colorectal cancer specific survival rates were 78.6% in young group and 75.3% in elderly group, which had significant difference in both univariate and multivariate analysis (P<0.001). Further analysis showed this significant difference only existed in stage II and III patients.

Conclusions

Compared with elderly patients, young patients with colorectal cancer treated with surgery appear to have unique characteristics and a higher cancer specific survival rate although they presented with higher proportions of unfavorable biological behavior as well as advanced stage disease.     

Should Prior FIT Results Be Incorporated as an Additional Variable to Estimate Risk of Colorectal Neoplasia? A Prospective Study of 5,813 Screening Colonoscopies

Background

Recent studies showed that previous negative results from faecal immunochemical tests (FITs) for colorectal cancer (CRC) screening was associated with lower risk of advanced neoplasia (AN). We evaluated whether prior FIT results should be included to estimate the risk of AN in 2008–2012.

Methods

A community-based screening practice recruited 5,813 asymptomatic residents aged 50 to 70 years in Hong Kong for CRC screening. We included study participants who had (1). positive FIT with subsequent colonoscopy workup (FIT+ group; n = 356); (2). negative FIT in three consecutive years and received a colonoscopy (FIT- group; n = 857); (3). received colonoscopy without FIT (colonoscopy group; n = 473); and (4). received both colonoscopy and FIT at the same time (combined group; n = 4,127). One binary logistic regression model evaluated whether prior FIT results were associated with colonoscopy findings of AN.

Results

The proportion of participants having AN/CRC was 18.0% (FIT+), 5.5% (FIT-), 8.0% (colonoscopy group), and 4.3% (combined group), respectively. When compared with the colonoscopy group, those in the FIT- group were not significantly more or less likely to have AN/CRC (AOR  = 0.77, 95% C.I. = 0.51 to 1.18, p  = 0.230). Having one (AOR = 0.73, 95% C.I. 0.48–1.12, p = 0.151) or three consecutive negative FIT result (AOR = 0.98, 95% C.I. 0.60–1.62, p = 0.944) were not associated with lower risks of AN/CRC. Subjects in the FIT+ group was 3.32-fold (95% C.I. 2.07 to 5.32, p<0.001) more likely to have AN/CRC.

Conclusions

These findings indicated that subjects with negative FIT findings could be risk stratified similarly as those who had not previously received FIT.     

Concomitant Tumor Expression of EGFR and TATI/SPINK1 Associates with Better Prognosis in Colorectal Cancer

Background

Epidermal growth factor receptor (EGFR) activation plays a role in colorectal cancer (CRC) carcinogenesis, and anti-EGFR drugs are used in treatment of advanced CRC. One of the EGFR ligands is tumor-associated trypsinogen inhibitor TATI, also called serine protease inhibitor Kazal type1 (SPINK 1), which we recently showed to be an independent prognostic marker in CRC.

Methods

We studied the prognostic value of immunohistochemical expression of EGFR and concomitant expression of EGFR and TATI/SPINK1 in a series of 619 colorectal cancer patients.

Results

Of the samples, 92% were positive for EGFR. EGFR+/TATI+ was seen in 62.8%, EGFR+/TATI− in 29.5%, EGFR−/TATI+ in 4.9%, and EGFR−/TATI− in 2.7% of patients. EGFR expression correlated with WHO grade (p = 0.040). In univariate analysis, EGFR expression correlated with favourable survival (p = 0.006). EGFR+/TATI+ patients showed better survival than did those with other combinations (p<0.001). In multivariate analysis, EGFR+/TATI+ was an independent prognostic factor of favourable prognosis (p<0.001).

Conclusion

Concomitant positivity of EGFR and TATI/SPINK1 predicts favourable prognosis in CRC.     

Utilization of Surveillance after Polypectomy in the Medicare Population – A Cohort Study

Background

Surveillance in patients with previous polypectomy was underused in the Medicare population in 1994. This study investigates whether expansion of Medicare reimbursement for colonoscopy screening in high-risk individuals has reduced the inappropriate use of surveillance.

Methods

We used Kaplan-Meier analysis to estimate time to surveillance and polyp recurrence rates for Medicare beneficiaries with a colonoscopy with polypectomy between 1998 and 2003 who were followed through 2008 for receipt of surveillance colonoscopy. Generalized Estimating Equations were used to estimate risk factors for: 1) failing to undergo surveillance and 2) polyp recurrence among these individuals. Analyses were stratified into three 2-year cohorts based on baseline colonoscopy date.

Results

Medicare beneficiaries undergoing a colonoscopy with polypectomy in the 1998–1999 (n = 4,136), 2000–2001 (n = 3,538) and 2002–2003 (n = 4,655) cohorts had respective probabilities of 30%, 26% and 20% (p<0.001) of subsequent surveillance events within 3 years. At the same time, 58%, 52% and 45% (p<0.001) of beneficiaries received a surveillance event within 5 years. Polyp recurrence rates after 5 years were 36%, 30% and 26% (p<0.001) respectively. Older age (≥ 70 years), female gender, later cohort (2000–2001 & 2002–2003), and severe comorbidity were the most important risk factors for failure to undergo a surveillance event. Male gender and early cohort (1998–1999) were the most important risk factors for polyp recurrence.

Conclusions

Expansion of Medicare reimbursement for colonoscopy screening in high-risk individuals has not reduced underutilization of surveillance in the Medicare population. It is important to take action now to improve this situation, because polyp recurrence is substantial in this population.     

A Comparison of Positron Emission Tomography and Colonoscopy for the Detection of Advanced Colorectal Neoplasms in Subjects Undergoing a Health Check-Up

Background & Aims

There is no agreement as to whether F-18 fluorodeoxyglucose positron emission tomography and computed tomography (FDG PET/CT) screening for advanced colorectal neoplasms is meaningful. This retrospective study was undertaken to determine whether FDG PET/CT may be a valuable screening tool for the detection of advanced colorectal neoplasms.

Methods

A retrospective review of the records of 1,109 FDG PET/CT scans acquired from January 2007 to December 2011 was performed. Colonoscopy and FDG PET/CT imaging were performed within two days of each other. The results of colonoscopy were taken as the gold standard, either with or without the results of the histopathological examination. An advanced neoplasm was defined as the presence of a malignant tumor, an adenoma ≥1 cm, or histological evidence of high-grade dysplasia or significant villous components.

Results

A total of 36 subjects had advanced colorectal neoplasms detected by colonoscopy (totaling 38 neoplasms). Six of the 38 neoplasms were also detected by FDG PET/CT. The sensitivity, specificity, positive predictive value, negative predictive value, and overall accuracy of FDG PET/CT in the detection of advanced colorectal neoplasms were 15.8% (6/38), 99.1% (1063/1073), 37.5% (6/16), 97.1% (1063/1095), and 96.2% (1069/1111) respectively. The presence of lesions with an endoscopic size ≤1.5 cm (P<0.001) and low-grade dysplasia (P<0.001) were the main predictors of false-negative FDG PET/CT findings.

Conclusions

We conclude that FDG PET/CT screening of advanced colorectal neoplasms is unwarranted, especially in the presence of lesions with an endoscopic size ≤1.5 cm or low-grade dysplasia.     

The Knowledge of Colorectal Cancer Symptoms and Risk Factors among 10,078 Screening Participants: Are High Risk Individuals More Knowledgeable?

Objectives

We tested the a priori hypothesis that self-perceived and real presences of risks for colorectal cancer (CRC) are associated with better knowledge of the symptoms and risk factors for CRC, respectively.

Methods

One territory-wide invitation for free CRC screening between 2008 to 2012 recruited asymptomatic screening participants aged 50–70 years in Hong Kong. They completed survey items on self-perceived and real presences of risks for CRC (advanced age, male gender, positive family history and smoking) as predictors, and knowledge of CRC symptoms and risk factors as outcome measures, respectively. Their associations were evaluated by binary logistic regression analyses.

Results

From 10,078 eligible participants (average age 59 years), the mean knowledge scores for symptoms and risk factors were 3.23 and 4.06, respectively (both score range 0–9). Male gender (adjusted odds ratio [AOR] = 1.34, 95% C.I. 1.20–1.50, p<0.01), self-perception as not having any risks for CRC (AOR = 1.12, 95% C.I. 1.01–1.24, p = 0.033) or uncertainty about having risks (AOR = 1.94, 95% C.I. 1.55–2.43, p<0.001), smoking (AOR 1.38, 95% C.I. 1.11–1.72, p = 0.004), and the absence of family history (AOR 0.61 to 0.78 for those with positive family history, p<0.001) were associated with poorer knowledge scores (≤4) of CRC symptoms. These factors remained significant for knowledge of risk factors.

Conclusions

Male and smokers were more likely to have poorer knowledge but family history of CRC was associated with better knowledge. Since screening of these higher risk individuals could lead to greater yield of colorectal neoplasm, educational interventions targeted to male smokers were recommended.     

The Detection of the Methylated Wif-1 Gene Is More Accurate than a Fecal Occult Blood Test for Colorectal Cancer Screening

Background

The clinical benefit of guaiac fecal occult blood tests (FOBT) is now well established for colorectal cancer screening. Growing evidence has demonstrated that epigenetic modifications and fecal microbiota changes, also known as dysbiosis, are associated with CRC pathogenesis and might be used as surrogate markers of CRC.

Patients and Methods

We performed a cross-sectional study that included all consecutive subjects that were referred (from 2003 to 2007) for screening colonoscopies. Prior to colonoscopy, effluents (fresh stools, sera-S and urine-U) were harvested and FOBTs performed. Methylation levels were measured in stools, S and U for 3 genes (Wif1, ALX-4, and Vimentin) selected from a panel of 63 genes; Kras mutations and seven dominant and subdominant bacterial populations in stools were quantified. Calibration was assessed with the Hosmer-Lemeshow chi-square, and discrimination was determined by calculating the C-statistic (Area Under Curve) and Net Reclassification Improvement index.

Results

There were 247 individuals (mean age 60.8±12.4 years, 52% of males) in the study group, and 90 (36%) of these individuals were patients with advanced polyps or invasive adenocarcinomas. A multivariate model adjusted for age and FOBT led to a C-statistic of 0.83 [0.77–0.88]. After supplementary sequential (one-by-one) adjustment, Wif-1 methylation (S or U) and fecal microbiota dysbiosis led to increases of the C-statistic to 0.90 [0.84–0.94] (p = 0.02) and 0.81 [0.74–0.86] (p = 0.49), respectively. When adjusted jointly for FOBT and Wif-1 methylation or fecal microbiota dysbiosis, the increase of the C-statistic was even more significant (0.91 and 0.85, p<0.001 and p = 0.10, respectively).

Conclusion

The detection of methylated Wif-1 in either S or U has a higher performance accuracy compared to guaiac FOBT for advanced colorectal neoplasia screening. Conversely, fecal microbiota dysbiosis detection was not more accurate. Blood and urine testing could be used in those individuals reluctant to undergo stool testing.     

Detection of Colorectal Serrated Polyps by Stool DNA Testing: Comparison with Fecal Immunochemical Testing for Occult Blood (FIT)

Objectives

Precursors to 1/3 of colorectal cancer (CRC), serrated polyps have been under-detected by screening due to their inconspicuous, non-hemorrhagic, and proximal nature. A new multi-target stool DNA test (multi-target sDNA) shows high sensitivity for both CRC and advanced adenomas. Screen detection of serrated polyps by this approach requires further validation. We sought to assess and compare noninvasive detection of sessile serrated polyps (SSP) ≥1 cm by sDNA and an occult blood fecal immunochemical test (FIT).

Methods

In a blinded prospective study, a single stool sample used for both tests was collected from 456 asymptomatic adults prior to screening or surveillance colonoscopy (criterion standard). All 29 patients with SSP≥1 cm were included as cases and all 232 with no neoplastic findings as controls. Buffered stool samples were processed and frozen on receipt; Exact Sciences performed sDNA in batches using optimized analytical methods. The sDNA multi-marker panel targets methylated BMP3 (mBMP3) and NDRG4, mutant KRAS, β-actin, and hemoglobin. FIT (Polymedco OC-FIT Check) was performed in separate lab ≤2 days post defecation and evaluated at cutoffs of 50 (FIT-50) and 100 ng/ml (FIT-100).

Results

Median ages: cases 61 (range 57–77), controls 62 (52–70), p = NS. Women comprised 59% and 51%, p = NS, respectively. SSP median size was 1.2 cm (1–3 cm), 93% were proximal, and 64% had synchronous diminutive polyps. Among multi-target sDNA markers, mBMP3 proved highly discriminant for detection of SSP≥1 cm (AUC = 0.87, p<0.00001); other DNA markers provided no incremental sensitivity. Hemoglobin alone showed no discrimination (AUC = 0.50, p = NS). At matched specificities, detection of SSP≥1 cm by stool mBMP3 was significantly greater than by FIT-50 (66% vs 10%, p = 0.0003) or FIT-100 (63% vs 0%, p<0.0001).

Conclusions

In a screening and surveillance setting, SSP≥1 cm can be detected noninvasively by stool assay of exfoliated DNA markers, especially mBMP3. FIT appears to have no value in SSP detection.     

Antenatal Screening for Down Syndrome Using Serum Placental Growth Factor with the Combined,Quadruple, Serum Integrated and Integrated Tests

Objective

To estimate the value of first or second trimester placental growth factor (PlGF) as an additional antenatal screening marker for Down syndrome.

Design

Nested case-control study.

Setting

Antenatal screening service.

Population or Sample

532 Down syndrome pregnancies and 1,155 matched unaffected pregnancies.

Methods

Stored maternal serum samples (−40°C) were assayed for PlGF. Monte Carlo simulation was used to estimate the screening performance of PlGF with the Combined, Quadruple, serum Integrated and Integrated tests.

Main Outcome Measures

Median PlGF levels in affected and unaffected pregnancies and screening performance (detection rates [DR] for specified false-positive rates [FPR] and vice versa).

Results

First trimester median PlGF was 15%, 28% and 39% lower in Down syndrome than unaffected pregnancies at 11, 12 and 13 completed weeks’ gestation respectively (all p<0.001). Second trimester median PlGF was 31% lower at 14 weeks (p<0.001), and the difference decreased (6% lower at 17 weeks). At a 90% DR with first trimester markers measured at 13 weeks, adding PlGF decreased the FPR from 11.1 to 5.1% using the Combined test, 9.3% to 4.5% using the serum Integrated test, and 3.4% to 1.5% using the Integrated test (or 1.5 to 1.4% with first trimester markers measured at 11 weeks). Adding PlGF to the Quadruple test (measured at 15 weeks) decreased the FPR from 10.0% to 9.6% at a 90% DR.

Conclusions

First trimester PlGF measurements improve the performance of antenatal screening for Down syndrome using the Combined, serum Integrated and Integrated tests. Second trimester PlGF measurements are of limited value.     

Increased Expression of ATG10 in Colorectal Cancer Is Associated with Lymphovascular Invasion and Lymph Node Metastasis

Background

Autophagy has paradoxical and complex functions in cancer development, and autophagy-related genes (ATG) are key regulators in autophagy. Until now, more than 30 different ATG proteins have been identified in yeast, and their mammalian counterparts also have been reported. Although the roles of a few ATG proteins in cancer have been characterized, the role of ATG10 is almost completely unknown.

Methodology/Principal Findings

To investigate the clinicopathological role of ATG10 in colorectal cancer, we analyzed ATG10 expression in colorectal cancer tissues and cell lines. Protein expression analysis showed that ATG10 is highly increased in colorectal cancer (tissue - 18/37 cases, 48%; cell line –8/12 cell lines, 66%). Immunohistochemical analysis with clinicopathological features indicated a strong association of the up-regulation of ATG10 with tumor lymph node metastasis (p = 0.005) and invasion (p<0.001). Moreover, both 5-year disease free survival and overall survival rates of patients bearing tumors that did not express ATG10 were significantly higher than those of patients bearing ATG10-expressing tumors (p = 0.012).

Conclusion/Significance

Increased expression of ATG10 in colorectal cancer is associated with lymphovascular invasion and lymph node metastasis indicating that ATG10 may be a potential prognostic maker in colorectal cancer.     

Multiple Marker Detection in Peripheral Blood for NSCLC Diagnosis

Background

Non-invasive early detection of lung cancer could reduce the number of patients diagnosed with advanced disease, which is associated with a poor prognosis. We analyzed the diagnostic accuracy of a panel of peripheral blood markers in detecting non small cell lung cancer (NSCLC).

Methods

100 healthy donors and 100 patients with NSCLC were enrolled onto this study. Free circulating DNA, circulating mRNA expression of peptidylarginine deiminase type 4 (PAD4/PADI4), pro-platelet basic protein (PPBP) and haptoglobin were evaluated using a Real-Time PCR-based method.

Results

Free circulating DNA, PADI4, PPBP and haptoglobin levels were significantly higher in NSCLC patients than in healthy donors (p<0.0001, p<0.0001, p = 0.0002 and p = 0.0001, respectively). The fitted logistic regression model demonstrated a significant direct association between marker expression and lung cancer risk. The odds ratios of individual markers were 6.93 (95% CI 4.15–11.58; p<0.0001) for free DNA, 6.99 (95% CI 3.75–13.03; p<0.0001) for PADI4, 2.85 (95% CI 1.71–4.75; p<0.0001) for PPBP and 1.16 (95% CI 1.01–1.33; p = 0.031) for haptoglobin. Free DNA in combination with PPBP and PADI4 gave an area under the ROC curve of 0.93, 95% CI = 0.90–0.97, with sensitivity and specificity over 90%.

Conclusions

Free circulating DNA analysis combined with PPBP and PADI4 expression determination appears to accurately discriminate between healthy donors and NSCLC patients. This non-invasive multimarker approach warrants further research to assess its potential role in the diagnostic or screening workup of subjects with suspected lung cancer.     

Performance of Epigenetic Markers SEPT9 and ALX4 in Plasma for Detection of Colorectal Precancerous Lesions

Background

Screening for colorectal cancer (CRC) has shown to reduce cancer-related mortality, however, acceptance and compliance to current programmes are poor. Developing new, more acceptable non-invasive tests for the detection of cancerous and precancerous colorectal lesions would not only allow preselection of individuals for colonoscopy, but may also prevent cancer by removal of precancerous lesions.

Methods

Plasma from 128 individuals (cohort I – exploratory study: 73 cases / 55 controls ) was used to test the performance of a single marker, SEPT9, using a real-time quantitative PCR assay. To validate performance of SEPT9, plasma of 76 individuals (cohort II – validation study: 54 cases / 22 controls) was assessed. Additionally, improvement of predictive capability considering SEPT9 and additionally ALX4 methylation was investigated within these patients.

Results

In both cohorts combined, methylation of SEPT9 was observed in 9% of controls (3/33), 29% of patients with colorectal precancerous lesions (27/94) and 73% of colorectal cancer patients (24/33). The presence of both SEPT9 and ALX4 markers was analysed in cohort II and was observed in 5% of controls (1/22) and 37% of patients with polyps (18/49). Interestingly, also 3/5 (60%) patients with colorectal cancer were tested positive by the two marker panel in plasma.

Conclusions

While these data confirm the detection rate of SEPT9 as a biomarker for colorectal cancer, they also show that methylated DNA from advanced precancerous colorectal lesions can be detected using a panel of two DNA methylation markers, ALX4 and SEPT9. If confirmed in larger studies these data indicate that screening for colorectal precancerous lesions with a blood-based test may be as feasible as screening for invasive cancer.     

Sleep Extension Improves Neurocognitive Functions in Chronically Sleep-Deprived Obese Individuals

Background

Sleep deprivation and obesity, are associated with neurocognitive impairments. Effects of sleep deprivation and obesity on cognition are unknown, and the cognitive long-term effects of improvement of sleep have not been prospectively assessed in short sleeping, obese individuals.

Objective

To characterize neurocognitive functions and assess its reversibility.

Design

Prospective cohort study.

Setting

Tertiary Referral Research Clinical Center.

Patients

A cohort of 121 short-sleeping (<6.5 h/night) obese (BMI 30–55 kg/m²) men and pre-menopausal women.

Intervention

Sleep extension (468±88 days) with life-style modifications.

Measurements

Neurocognitive functions, sleep quality and sleep duration.

Results

At baseline, 44% of the individuals had an impaired global deficit score (t-score 0–39). Impaired global deficit score was associated with worse subjective sleep quality (p = 0.02), and lower urinary dopamine levels (p = 0.001). Memory was impaired in 33%; attention in 35%; motor skills in 42%; and executive function in 51% of individuals. At the final evaluation (N = 74), subjective sleep quality improved by 24% (p<0.001), self-reported sleep duration increased by 11% by questionnaires (p<0.001) and by 4% by diaries (p = 0.04), and daytime sleepiness tended to improve (p = 0.10). Global cognitive function and attention improved by 7% and 10%, respectively (both p = 0.001), and memory and executive functions tended to improve (p = 0.07 and p = 0.06). Serum cortisol increased by 17% (p = 0.02). In a multivariate mixed model, subjective sleep quality and sleep efficiency, urinary free cortisol and dopamine and plasma total ghrelin accounted for 1/5 of the variability in global cognitive function.

Limitations

Drop-out rate.

Conclusions

Chronically sleep-deprived obese individuals exhibit substantial neurocognitive deficits that are partially reversible upon improvement of sleep in a non-pharmacological way. These findings have clinical implications for large segments of the US population.

Trail registration

www.ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00261898","term_id":"NCT00261898"}}NCT00261898. NIDDK protocol 06-DK-0036     

Prognostic Value of FDG PET Imaging in Patients with Laryngeal Cancer

Background and Purpose

To investigate the prognostic value of ¹⁸F-fluorodeoxyglucose positron emission tomography (FDG-PET) in patients with laryngeal cancer.

Materials and Methods

The study included 51 patients of whom 30 underwent definitive radiotherapy with or without chemotherapy and 21 underwent radical surgery with or without adjuvant chemoradiation therapy. FDG uptake by both the primary lesion and the neck node was measured using the maximum standardized uptake value (SUVmax). The effects of clinicopathological factors including primary tumor SUVmax and nodal SUVmax on progression-free survival, local control, nodal progression-free survival, and distant metastasis-free survival were evaluated using the log-rank test and Cox method.

Results

The median duration of follow-up was 48.6 months (range 8 to 82.1 months). Univariate analysis showed that nodal SUVmax, N status, and tumor TNM stage were significantly associated with recurrence, whereas primary tumor SUVmax, age, treatment strategy and T status were not. Multivariate analysis demonstrated that only the nodal SUVmax was a significantly unfavorable factor for progression-free survival (p = 0.029, hazard ratio 0.54, 95% CI 0.38-0.87) and nodal progression-free survival (p = 0.023, hazard ratio 0.51, 95% CI 0.34-0.81). ROC curve analysis and log-rank test showed that patients with a high nodal SUVmax (≧4) had a significantly lower progression-free survival rate than those with a low SUVmax (<4; p<0.0001).

Conclusions

The pretreatment SUVmax of nodal disease in patients with laryngeal cancer is prognostic for recurrence.     

Prognostic Value of Myeloid Differentiation Primary Response 88 and Toll-Like Receptor 4 in Breast Cancer Patients

Purpose

Breast cancer remains a major cause of death in women worldwide, and tumor metastasis is the leading cause of death in breast cancer patients after conventional treatment. Chronic inflammation is often related to the occurrence and growth of various malignancies. This study evaluated the prognosis of breast cancer patients based on contributors to the innate immune response: myeloid differentiation primary response 88 (MyD88) and Toll-like receptor 4 (TLR4).

Methods

We analyzed data from 205 breast invasive ductal carcinoma (IDC) patients who were treated at the Department of Breast Surgery, Key Laboratory of Breast Cancer in Shanghai, Fudan University Shanghai Cancer Center, from 2002 to 2006. Overall survival (OS) and disease-free survival (DFS) were compared.

Results

In total, 152 patients (74.15%) were disease-free without relapse or metastasis, whereas 53 (25.85%) patients developed recurrence or metastasis. A significant positive correlation was observed between MyD88 and TLR4 expression (p<0.001). Patients with high expression were more likely to experience death and recurrence/metastasis events (p<0.05). Patients with low MyD88 or TLR4 expression levels had better DFS and OS than patients with high expression levels (log-rank test: p<0.001). Patients with low MyD88 and TLR4 expression levels had better DFS and OS than patients with high expression levels of either (log-rank test: p<0.001). In a multivariate analysis, high MyD88 expression was an independent predictive factor for decreased DFS (adjusted HR, 3.324; 95% CI, 1.663–6.641; p = 0.001) and OS (adjusted HR, 4.500; 95% CI, 1.546–13.098; p = 0.006).

Conclusions

TLR4-MyD88 signaling pathway activation or MyD88 activation alone may be a risk factor for poor prognosis in breast cancer. Therefore, TLR4-MyD88 signaling pathway activation in tumor biology provides a novel potential target for breast cancer therapy.     

Inter-Physician Variation in Follow-Up Colonoscopies after Screening Colonoscopy

Background and Aims

Surveillance is an integral part of the colorectal cancer (CRC) screening process. We aimed to investigate inter-physician variation in follow-up procedures after screening colonoscopy in an opportunistic CRC screening program.

Methods

A historical cohort study in the German statutory health insurance system was conducted. 55,301 individuals who underwent screening colonoscopy in 2006 in Bavaria, Germany, and who were not diagnosed with CRC were included. Utilization of follow-up colonoscopies performed by the same physician (328 physicians overall) within 3 years was ascertained. Mixed effects logistic regression modelling was used to assess the effect of physicians and other potential predictors (screening result, age group, and sex) on re-utilization of colonoscopy. Physicians were grouped into quintiles according to individual effects estimated in a preliminary model. Predicted probabilities of follow-up colonoscopy by screening result and physician group were calculated.

Results

The observed rate of follow-up colonoscopy was 6.2% (95% confidence interval: 5.9-6.4%), 18.6% (17.8-19.4%), and 37.0% (35.5-38.4%) after negative colonoscopy, low-risk adenoma and high-risk adenoma detection, respectively. All considered predictors were statistically significantly associated with follow-up colonoscopy. The predicted probabilities of follow-up colonoscopy ranged from 1.7% (1.4-2.0%) to 11.0% (10.2-11.7%), from 7.3% (6.2-8.5%) to 35.1% (32.6-37.7%), and from 17.9% (15.5-20.6%) to 56.9% (53.5-60.3%) in the 1^st quintile (lowest rates of follow-up) and 5^th quintile (highest rates of follow-up) of physicians after negative colonoscopy, low-risk adenoma and high-risk adenoma detection, respectively.

Conclusions

This study suggests substantial inter-physician variation in follow-up habits after screening colonoscopy. Interventions, including organizational changes in CRC screening should be considered to reduce this variation.