Annekatrien Depla

Transanal endoscopic microsurgery versus endoscopic mucosal resection for large rectal adenomas (TREND-study)

BackgroundRecent non-randomized studies suggest that extended endoscopic mucosal resection (EMR) is equally effective in removing large rectal adenomas as transanal endoscopic microsurgery (TEM). If equally effective, EMR might be a more cost-effective approach as this strategy does not require expensive equipment, general anesthesia and hospital admission. Furthermore, EMR appears to be associated with fewer complications.The aim of this study is to compare the cost-effectiveness and cost-utility of TEM and EMR for the resection of large rectal adenomas.Methods/designMulticenter randomized trial among 15 hospitals in the Netherlands. Patients with a rectal adenoma ≥ 3 cm, located between 1–15 cm ab ano, will be randomized to a TEM- or EMR-treatment strategy. For TEM, patients will be treated under general anesthesia, adenomas will be dissected en-bloc by a full-thickness excision, and patients will be admitted to the hospital. For EMR, no or conscious sedation is used, lesions will be resected through the submucosal plane in a piecemeal fashion, and patients will be discharged from the hospital. Residual adenoma that is visible during the first surveillance endoscopy at 3 months will be removed endoscopically in both treatment strategies and is considered as part of the primary treatment.Primary outcome measure is the proportion of patients with recurrence after 3 months. Secondary outcome measures are: 2) number of days not spent in hospital from initial treatment until 2 years afterwards; 3) major and minor morbidity; 4) disease specific and general quality of life; 5) anorectal function; 6) health care utilization and costs. A cost-effectiveness and cost-utility analysis of EMR against TEM for large rectal adenomas will be performed from a societal perspective with respectively the costs per recurrence free patient and the cost per quality adjusted life year as outcome measures.Based on comparable recurrence rates for TEM and EMR of 3.3% and considering an upper-limit of 10% for EMR to be non-inferior (beta-error 0.2 and one-sided alpha-error 0.05), 89 patients are needed per group.DiscussionThe TREND study is the first randomized trial evaluating whether TEM or EMR is more cost-effective for the treatment of large rectal adenomas.Trial registration number(trialregister.nl) NTR1422

Serum Degradome Markers for the Detection of Breast Cancer

Many proteins have been proposed as potential biomarkers for breast cancer. Yet, validation of their discriminative value using quantitative methods has scarcely been performed. In this study, we investigated the discriminative value of six peptides that were previously proposed to be generated by breast cancer specific exoproteases: bradykinin, des-Arg(9)-bradykinin, Hyp(3)-bradykinin, and fragments of fibrinogen alpha-chain (Fib-alpha ([605-629])), complement component 4a (C4a ([1337-1350])), and interalpha trypsin inhibitor heavy chain 4 (ITIH4 ([666-687])). Their absolute serum concentrations were measured with a completely validated liquid chromatography-tandem mass spectrometric assay (LC-MS/MS) and compared between 62 newly diagnosed breast cancer patients and 62 controls matched for age and sample storage duration. Both ITIH4 ([666-687]) and des-Arg(9)-bradykinin showed statistically significantly higher median concentrations in breast cancer samples than in matched control samples. Additionally, we analyzed serum samples collected after surgical removal of the tumor, in which median ITIH4 ([666-687]) and des-Arg(9)-bradykinin concentrations were significantly decreased and not statistically significantly different from concentrations in the controls anymore. In a combined analysis, ITIH4 (666-687]) and des-Arg(9)-bradykinin independently contributed to the discrimination between cases and controls. In this study, we confirmed that the exoprotease breakdown peptides, ITIH4 (666-687]) and des-Arg(9)-bradykinin, differed between breast cancer cases and controls, supporting the potential of degradome markers for the diagnosis of breast cancer.

Influence of variations in sample handling on SELDI-TOF MS serum protein profiles for colorectal cancer

Sample handling can have a profound effect on serum protein profiles, challenging results obtained with archived sera under non‐standardized sample collection. Here, we evaluate the influence of variations in sample handling on previous serum protein profiles for colorectal cancer (CRC) (Engwegen et al.,. World J. Gastroenterol. 2006, 12, 1536–1544). Sera were prospectively obtained from individuals with an indication for colonoscopy (n = 150: 65 controls, 52 adenomatous polyps, 29 CRC, 4 unknown), as well as from normal volunteers (n = 8). Protein profiles were acquired by SELDI‐TOF MS on CM10 chips at pH 5. We assessed the influence of storage temperature, type of collection tube, coagulation temperature and freeze‐thaw cycles on the serum protein profile. Several peptides occurred only in samples stored at –20°C, indicating proteolytic degradation during storage. One was a previous CRC biomarker candidate, an N‐terminal albumin fragment (m/z 3087), and two others complement C3f and a fragment thereof (m/z 2022 and 1863). Overall differences in protein profiles were also seen for different collection tubes, coagulation temperature and freeze‐thaw cycles. However, three of five of our previously defined CRC biomarker candidates are stable to variations in the sample handling protocol, justifying their further validation in prospective studies.

Expression of insulin-like growth factor system components in colorectal tissue and its relation with serum IGF levels.

CONTEXT The insulin-like growth factor (IGF)-system has been implicated in colorectal tumor carcinogenesis. Although both tumor expression levels and serum concentrations of IGF-system components are related to colorectal cancer risk, it is unknown whether IGF levels in tissue and serum are correlated. OBJECTIVE The objective of this study was to determine expression levels of various IGF-system components in different locations of the colorectum, and to investigate whether normal tissue IGF expression levels are correlated with serum IGF-I and IGF-II concentrations. DESIGN Biopsies from macroscopically normal mucosa at four locations in the colorectum (ascending, transverse, sigmoid colon, and rectum) and a fasting serum sample were obtained from 48 asymptomatic patients at increased risk of colorectal cancer. Expression levels of IGF-I, IGF-II, IGF-IR, IGF-IIR, and IGFBP-3 messenger RNA (mRNA) in tissue were quantitatively evaluated using real-time RT-PCR. Expression of IGF-IR protein in the ascending colon and rectum tissue specimens was assessed semi-quantitatively by immunohistochemistry. Serum IGF-I and IGF-II concentrations were determined using immunometric assays. RESULTS With the exception of IGF-IIR, mRNA levels of all the IGF-system components investigated, as well as IGF-IR protein expression, were significantly higher in the rectum compared with the ascending colon (p<or=0.001). Serum IGF-I and IGF-II concentrations did not correlate with any of the parameters studied in colorectal tissues. CONCLUSIONS Our results indicate that in humans IGF-system components are differentially expressed in the colorectum. Moreover, our findings suggest that local and circulating components of the IGF-system are differentially regulated. However, due to large intra-individual variation in mRNA expression, we cannot formally exclude undetected but existing routes of co-regulation.

Patients' perception of colonoscopy: patients with inflammatory bowel disease and irritable bowel syndrome experience the largest burden.

Background Colonoscopy is a frequently performed procedure worldwide with a negative perception, leading to reluctance to undergo the procedure. Perceptions could differ depending on the specific indication for the colonoscopy. Aims To compare patient satisfaction with the colonoscopy procedure between five different patient groups: inflammatory bowel disease (IBD), familial predisposition for cancer, adenoma/carcinoma surveillance, symptoms suggestive of cancer, and irritable bowel syndrome (IBS). Methods A prospective questionnaire study was carried out in two regional hospitals and two tertiary teaching hospitals in the Netherlands. A total of 797 consecutive patients scheduled for colonoscopy between October 2009 and June 2010, 146 (18%) IBD, 153 (19%) adenoma or carcinoma surveillance, 104 (13%) familial predisposition, 280 (35%) symptoms suggestive of cancer, and 114 (14%) IBS-like symptoms, were included. Two questionnaires were administered: one on the day of the procedure and another 6 weeks after the procedure. The main outcome measurements were embarrassment, pain, burden, most burdensome aspect, and overall level of satisfaction. Results Patients with IBD and IBS reported significantly more embarrassment and burden from the bowel preparation phase (P=0.040 and 0.018, respectively) and more pain during the colonoscopy procedure (P=0.018). This difference in pain was also observed when adjusting for volume of sedation administered, familiarity with the endoscopist, duration of the colonoscopy, or whether or not an intervention was performed. All patient groups were less satisfied with the procedure at 6 weeks than directly after the colonoscopy; they recalled more embarrassment and burden, but less pain. Conclusion Patient groups, defined by indication for colonoscopy, experience the colonoscopy procedure differently.

Hemorrhoids detected at colonoscopy: an infrequent cause of false-positive fecal immunochemical test results

BACKGROUND Colorectal cancer screening by fecal immunochemical tests (FITs) is hampered by frequent false-positive (FP) results and thereby the risk of complications and strain on colonoscopy capacity. Hemorrhoids might be a plausible cause of FP results. OBJECTIVE To determine the contribution of hemorrhoids to the frequency of FP FIT results. DESIGN Retrospective analysis from prospective cohort study. SETTING Five large teaching hospitals, including 1 academic hospital. PATIENTS All subjects scheduled for elective colonoscopy. INTERVENTIONS FIT before bowel preparation. MAIN OUTCOME MEASUREMENTS Frequency of FP FIT results in subjects with hemorrhoids as the only relevant abnormality compared with FP FIT results in subjects with no relevant abnormalities. Logistic regression analysis to determine colonic abnormalities influencing FP results. RESULTS In 2855 patients, 434 had positive FIT results: 213 had advanced neoplasia and 221 had FP results. In 9 individuals (4.1%; 95% CI, 1.4-6.8) with an FP FIT result, hemorrhoids were the only abnormality. In univariate unadjusted analysis, subjects with hemorrhoids as the only abnormality did not have more positive results (9/134; 6.7%) compared with subjects without any abnormalities (43/886; 4.9%; P = .396). Logistic regression identified hemorrhoids, nonadvanced polyps, and a group of miscellaneous abnormalities, all significantly influencing false positivity. Of 1000 subjects with hemorrhoids, 67 would have FP results, of whom 18 would have FP results because of hemorrhoids only. LIMITATIONS Potential underreporting of hemorrhoids; high-risk individuals. CONCLUSIONS Hemorrhoids in individuals participating in colorectal cancer screening will probably not lead to a substantial number of false-positive test results.

Faecal immunochemical test accuracy in patients referred for surveillance colonoscopy: a multi-centre cohort study

BackgroundGiven the increasing burden on colonoscopy capacity, it has been suggested that faecal immunochemical test (FIT) results could guide surveillance colonoscopy intervals. Against this background, we have evaluated the test accuracy of single and double FIT sampling to detect colorectal cancer (CRC) and/or advanced adenomas in an asymptomatic colonoscopy-controlled high-risk population.MethodsCohort study of asymptomatic high-risk patients (personal history of adenomas/CRC or family history of CRC), who provided one or two FITs before elective colonoscopy. Test accuracy of FIT for detection of CRC and advanced adenomas was determined (cut-off level 50 ng/ml).Results1,041 patients provided a FIT (516 personal history of adenomas, 172 personal history of CRC and 353 family history of CRC). Five CRCs (0.5%) and 101 advanced adenomas (9.7%) were detected by colonoscopy. Single FIT sampling resulted in a sensitivity, specificity, PPV and NPV for CRC of 80%, 89%, 3% and 99.9%, respectively, and for advanced adenoma of 28%, 91%, 24% and 92%, respectively. Double FIT sampling did not result in a significantly higher sensitivity for advanced neoplasia. Simulation of multiple screening rounds indicated that sensitivity of FIT for advanced adenoma could reach 81% after 5 screening rounds.ConclusionsIn once-only FIT sampling before surveillance colonoscopy, 70% of advanced neoplasia were missed. A simulation approach indicates that multiple screening rounds may be more promising in detecting advanced neoplasia and could potentially alleviate endoscopic burden.

Detection of Colorectal Cancer by Serum and Tissue Protein Profiling: A Prospective Study in a Population at Risk

Colorectal cancer (CRC) is the second most common cause of cancer-related death in Europe and its prognosis is largely dependent on stage at diagnosis. Currently, there are no suitable tumour markers for early detection of CRC. In a retrospective study we previously found discriminative CRC serum protein profiles with surface enhanced laser desorption ionisation–-time of flight mass spectrometry (SELDI-TOF MS). We now aimed at prospective validation of these profiles. Additionally, we assessed their applicability for follow-up after surgery and investigated tissue protein profiles of patients with CRC and adenomatous polyps (AP). Serum and tissue samples were collected from patients without known malignancy with an indication for colonoscopy and patients with AP and CRC during colonoscopy. Serum samples of controls (CON; n = 359), patients with AP (n = 177) and CRC (n = 73), as well as tissue samples from AP (n = 52) and CRC (n = 47) were analysed as described previously. Peak intensities were compared by non-parametric testing. Discriminative power of differentially expressed proteins was assessed with support vector machines (SVM). We confirmed the decreased serum levels of apolipoprotein C-1 in CRC in the current population. No differences were observed between CON and AP. Apolipoprotein C-I levels did not change significantly within 1 month post-surgery, although a gradual return to normal levels was observed. Several proteins differed between AP and CRC tissue, among which a peak with similar mass as apolipoprotein C-1. This peak was increased in CRC compared to AP. Although we prospectively validated the serum decrease of apolipoprotein C-1 in CRC, serum protein profiles did not yield SVM classifiers with suitable sensitivity and specificity for classification of our patient groups.

MR Spectroscopy-derived Proton Density Fat Fraction Is Superior to Controlled Attenuation Parameter for Detecting and Grading Hepatic Steatosis

Purpose To prospectively compare the diagnostic accuracy of controlled attenuation parameter (CAP) obtained with transient elastography and proton density fat fraction (PDFF) obtained with proton magnetic resonance (MR) spectroscopy with results of liver biopsy in a cohort of adult patients suspected of having nonalcoholic fatty liver disease (NAFLD). Materials and Methods The institutional review board approved this study. Informed consent was obtained from all patients. The authors evaluated 55 patients suspected of having NAFLD (40 men, 15 women). Patients had a median age of 52.3 years (interquartile range [IQR], 43.7-57.6 years) and a median body mass index of 27.8 kg/m2 (IQR, 26.0-33.1 kg/m2). CAP and PDFF measurements were obtained on the same day, within 27 days of biopsy (IQR, 7-44 days). CAP and PDFF were compared between steatosis grades by using the Jonckheere-Terpstra test. Diagnostic accuracies of CAP and PDFF for grading steatosis were assessed with receiver operating characteristic (ROC) analysis. Within-weeks reproducibility (CAP and PDFF) and within-session repeatability were assessed with linear regression analyses, intraclass correlation coefficients, and coefficients of variation. Results Steatosis grades at liver biopsy were distributed as follows: S0, five patients; S1, 24 patients; S2, 17 patients; and S3, nine patients. Both PDFF and CAP helped detect histologically proven steatosis (≥S1), but PDFF showed better diagnostic accuracy than CAP in terms of the area under the ROC curve (0.99 vs 0.77, respectively; P = .0334). PDFF, but not CAP, enabled the grading of steatosis (P < .0001). For within-weeks reproducibility, the intraclass correlation coefficient with PDFF was higher than that with CAP (0.95 vs 0.65, respectively; P = .0015); coefficients of variation were similar (19% vs 11%, P = .55). Within-session repeatability of CAP was good, with a coefficient of variation of 4.5%. Conclusion MR spectroscopy-derived PDFF is superior to CAP in detecting and grading liver steatosis in human NAFLD.

Effectiveness of Cognitive-Behavioral Therapy on Quality of Life, Anxiety, and Depressive Symptoms Among Patients With Inflammatory Bowel Disease: A Multicenter Randomized Controlled Trial

Objective: Inflammatory bowel disease (IBD) is characterized by a low level of quality of life (QoL) and a high prevalence of anxiety and depression, especially in patients with poor QoL. We examined the effect of IBD-specific cognitive–behavioral therapy (CBT) on QoL, anxiety, and depression in IBD patients with poor mental QoL. Method: This study is a parallel-group multicenter randomized controlled trial. One hundred eighteen IBD patients with a low level of QoL (score ⩽23 on the mental health subscale of the Medical Outcomes Study Short Form 36 Health Survey [SF-36]) were included from 2 academic medical centers (Academic Medical Center Amsterdam, VU University Medical Centre Amsterdam) and 2 peripheral medical centers (Flevo Hospital, Slotervaart Hospital) in the Netherlands. Patients were randomized to an experimental group receiving CBT (n = 59) versus a wait-list control group (n = 59) receiving standard medical care for 3.5 months, followed by CBT. Both groups completed baseline and 3.5 months follow-up assessments. The primary outcome was a self-report questionnaire and disease-specific QoL (Inflammatory Bowel Disease Questionnaire [IBDQ]). Secondary outcomes were depression (Hospital Anxiety and Depression Scale–Depression Subscale [HADS-D], Center for Epidemiologic Studies Depression Scale [CES-D]), anxiety (HADS–Anxiety Subscale [HADS-A]) and generic QoL (SF-36). Results: Data were analyzed both on intention to treat as well as on per protocol analysis (completed ≥5 sessions). CBT had a positive effect on disease-specific-QoL (Cohen’s d = .64 for IBDQ total score), depression (Cohen’s d = .48 for HADS-D and .78 for CES-D), anxiety (Cohen’s d = .58 for HADS-A), and generic QoL (Cohen’s d = 1.08 for Mental Component Summary of the SF-36; all ps < .01). Conclusions: IBD-specific CBT is effective in improving QoL and in decreasing anxiety and depression in IBD patients with poor QoL. Clinicians should incorporate screening on poor mental QoL and consider offering CBT.