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1.  Fecal Occult Blood Test for Colorectal Cancer Screening 
Executive Summary
The colorectal cancer (CRC) screening project was undertaken by the Medical Advisory Secretariat (MAS) in collaboration with the Cancer Care Ontario (CCO).
In November 2007, the Ontario Health Technology Advisory Committee (OHTAC) MAS to conduct an evidence-based analysis of the available data with respect to colorectal cancer diagnosis and prevention. The general purpose of the project was to investigate the effectiveness, cost effectiveness, and safety of the various methods and techniques used for colorectal cancer screening in average risk people, 50 years of age and older.
The options currently offered for colorectal cancer screening were reviewed and five technologies were selected for review:
Computed tomographic (CT) colonography
Magnetic resonance (MR) colonography
Wireless capsule endoscopy (PillCam Colon)
Fecal occult blood test (FOBT)
Flexible sigmoidoscopy
In this review, colonoscopy was considered as the “gold standard” technique by which the effectiveness of all other modalities could be evaluated. An economic analysis was also conducted to determine cost-effectiveness of different screening modalities.
Evidence-based analyses have been prepared for each of these technologies, as well as summary document that includes an economic analysis, all of which are presented at the MAS Web site: http://www.health.gov.on.ca/english/providers/program/mas/tech/techmn.html
Objective
The objective of this evidence review is to examine the effectiveness and cost-effectiveness of fecal occult blood testing (FOBT), including guaiac FOBT (gFOBT) and immunochemical FOBT (iFOBT), for use in colorectal cancer (CRC) screening in asymptomatic, average-risk adults.
Specifically:
Is the use of gFOBT or iFOBT associated with a reduction in CRC and overall mortality?
What are the sensitivity and specificity of gFOBT and iFOBT for the detection of 1) CRC and 2) large polyps (≥ 1 cm)?
Clinical Need
CRC is the most common cause of non-tobacco related cancer death in Canada. It has been estimated that in 2007, 7,800 people were diagnosed with CRC in Ontario and 3,250 died from the disease, making the province’s incidence and mortality rate of CRC amongst the highest in the world.
Description of Technology/Therapy
There are two general types of FOBT that are categorized according to the analyte detected: guaiac FOBT (gFOBT) and immunochemical FOBT (iFOBT). Blood in the stool is a nonspecific finding but may originate from CRC or larger (>1 cm) polyps (small adenomatous polyps do not tend to bleed). Bleeding from cancers and larger polyps may be intermittent and not always detectable in a single sample. The FOBT thus requires regular testing that consists of collecting specimens from consecutive bowel movements. A positive gFOBT or iFOBT involves a diagnostic workup with colonoscopy to examine the entire colon in order to rule out the presence of cancer or advanced neoplasia.
Methods of Evidence-Based Analysis
A literature search was conducted from January 2003 to June 2008 that included OVID MEDLINE, MEDLINE In-Process and Other Non-Indexed Citations, EMBASE, the Cumulative Index to Nursing & Allied Health Literature (CINAHL), The Cochrane Library, and the International Agency for Health Technology Assessment/Centre for Review and Dissemination.
Inclusion Criteria
Patients at average risk for CRC
All patients must be at least 50 years of age
Biennial FOBT as a screening modality and use of colonoscopy as the reference standard
Systematic reviews and randomized controlled trials (RCTs)
Outcomes: CRC mortality, overall mortality, sensitivity, specificity, adverse effects
Exclusion Criteria
Studies involving fewer than 100 patients
Studies that do not report sufficient data for analysis
Comparisons of Interest
Evidence exists for these comparisons of interest:
gFOBT compared with the reference “gold standard” colonoscopy (or double-contrast barium enema where colonoscopy is incomplete or contraindicated)
iFOBT compared with the reference gold standard colonoscopy (or DCBE where colonoscopy is incomplete or contraindicated)
gFOBT compared with iFOBT
The quality of the diagnostic studies was examined according to the ‘GRADE Working Group criteria’ for grading quality of evidence and strength of recommendations for diagnostic tests and strategies.
Summary of Findings
Single-Test Studies
There is limited direct/indirect evidence that iFOBT has sensitivity/specificity superior to that of unrehydrated gFOBT for CRC detection:
sensitivity for gFOBT:
pooled iFOBT sensitivity:
There is evidence that iFOBT and gFOBT have lower sensitivities for adenoma detection than for CRC detection:
sensitivity for rehydrated gFOBT
pooled iFOBT sensitivity
Repeated-Test Studies
No trials have examined CRC mortality outcomes after repeated testing of iFOBT.
Two RCTs from the United Kingdom and Denmark showed significant reduction in CRC mortality using unrehydrated gFOBT biennially
Relative risk reductions of 13% (UK trial) and 16% (Danish trial); absolute difference of 0.1% (UK trial) and 0.2% (Danish trial).
No significant reduction in overall mortality
Interval cancers (CRC that develop in the intervals between routine screening)
United Kingdom trial: 236 CRCs detected by positive test, 236 interval CRCs after negative test
Danish trial: 120 CRCs detected by positive test, 146 interval CRCs after negative test
Unrehydrated gFOBT has low sensitivity for CRC detection (45% in the UK trial and 54% in the Danish trial).
true positive rate
false positive rate
true negative rate
false negative rate
Guaiac FOBT – GRADE Quality of Evidence for Interventions
CRC indicates colorectal cancer; FOBT, fecal occult blood test; GRADE, Grading of Recommendations Assessment, Development and Evaluation; RCT, randomized controlled trial.
Unlikely to be an important uncertainty.
GRADE Quality of Evidence for Diagnostic Tests: Implications of Testing Focusing on Accuracy
Benefit from diagnosis and treatment after confirmatory colonoscopy
Small risk of bowel perforation during colonoscopy
Benefit of reassurance
Anxiety/worry leading up to confirmatory colonoscopy
Small risk of bowel perforation during confirmatory colonoscopy
Detriment from delayed diagnosis
Some uncertainty (until after confirmatory colonoscopy)
No Uncertainty
Uncertainty
Uncertainty
FOBT indicates fecal occult blood test; GRADE, Grading of Recommendations Assessment, Development and Evaluation.
Immunochemical FOBT – GRADE Quality of Evidence for Diagnostic Studies
FN indicates false negative; FOBT, fecal occult blood test; FP, false positive; Development and Evaluation; TN, true negative; TP, true positive.
Uncertainty until after confirmatory colonoscopy
Stress/worry for patient until confirmatory colonoscopy
Detrimental effects due to delayed diagnosis.
For these 3 reasons, downgrade quality from High to Moderate.
For these 3 reasons, downgrade quality from Moderate to Low.
Considerations for the Ontario Health System
Executive Summary Table 4 shows the potential system pressures and benefit/risk analysis for the use of FOBT and colonoscopy to screen for CRC in average-risk adults, ages 50 and over in Ontario.
Summary of Potential System Pressures for FOBT Screening
Prevent and detect
Detect
Every 10 years
Must repeat at regular intervals
Every 2 years
Must repeat at regular intervals
Observational studies
RCTs
Used as gold standard in studies
Intervention GRADE quality: High (gFOBT)
Diagnostic GRADE quality: Low (iFOBT)
No RCTs examining the effectiveness of repeated iFOBT on CRC mortality reduction were identified
Limited direct/indirect evidence that iFOBT has superior sensitivity/specificity to unrehydrated gFOBT for detection of CRC
0.1% risk of serious bleeding and perforation requiring surgery
0.3% risk of serious complications (stroke/bleeding requiring hospitalization/ myocardial infarction)
High interval cancer rate
The small benefit in CRC mortality reduction (absolute difference 0.1% to 0.2%) also coincides with a 0.3% risk of serious complications.
No food 1 day prior to exam
Office/hospital visit
Complete bowel preparation
Sedation
Eliminate citrus fruit and juices and vitamin C from diet for 3 days prior to/during stool collection.
Person applies 2 samples per bowel movement (each occurring on 3 different days) onto test areas of FOBT cards.
Increased demand for colonoscopies and colonoscopists or nurses who perform colonoscopies.
Patient receives kit from family physician, pharmacist
Patients mail completed FOBT kit to participating laboratory
Results sent back to patient
Increased demand for colonoscopies for positive patients
Removal of polyp during colonoscopy or surgery
Referral to colonoscopy
Cost-effective
Cost-effective
2nd of 5 choices in a patient survey study
5th of 5 choices in a patient survey study
FOBT indicates fecal occult blood test;; gFOBT, guaiac FOBT; GRADE, Grading of Recommendations Assessment, Development and Evaluation; iFOBT, immunochemical FOBT; RCT, randomized controlled trial.
PMCID: PMC3377532  PMID: 23074514
2.  Patient- and system-related barriers for the earlier diagnosis of colorectal cancer 
BMC Family Practice  2009;10:65.
Background
A cohort of colorectal cancer (CRC) patients represents an opportunity to study missed opportunities for earlier diagnosis. Primary objective: To study the epidemiology of diagnostic delays and failures to offer/complete CRC screening. Secondary objective: To identify system- and patient-related factors that may contribute to diagnostic delays or failures to offer/complete CRC screening.
Methods
Setting: Rural Veterans Administration (VA) Healthcare system. Participants: CRC cases diagnosed within the VA between 1/1/2000 and 3/1/2007. Data sources: progress notes, orders, and pathology, laboratory, and imaging results obtained between 1/1/1995 and 12/31/2007. Completed CRC screening was defined as a fecal occult blood test or flexible sigmoidoscopy (both within five years), or colonoscopy (within 10 years); delayed diagnosis was defined as a gap of more than six months between an abnormal test result and evidence of clinician response. A summary abstract of the antecedent clinical care for each patient was created by a certified gastroenterologist (GI), who jointly reviewed and coded the abstracts with a general internist (TW).
Results
The study population consisted of 150 CRC cases that met the inclusion criteria. The mean age was 69.04 (range 35-91); 99 (66%) were diagnosed due to symptoms; 61 cases (46%) had delays associated with system factors; of them, 57 (38% of the total) had delayed responses to abnormal findings. Fifteen of the cases (10%) had prompt symptom evaluations but received no CRC screening; no patient factors were identified as potentially contributing to the failure to screen/offer to screen. In total, 97 (65%) of the cases had missed opportunities for early diagnosis and 57 (38%) had patient factors that likely contributed to the diagnostic delay or apparent failure to screen/offer to screen.
Conclusion
Missed opportunities for earlier CRC diagnosis were frequent. Additional studies of clinical data management, focusing on following up abnormal findings, and offering/completing CRC screening, are needed.
doi:10.1186/1471-2296-10-65
PMCID: PMC2758830  PMID: 19754964
3.  Impact of antiplatelet treatment on colorectal cancer staging characteristics 
AIM: To evaluate whether antiplatelet medication leads to an earlier stage colorectal cancer (CRC) diagnosis.
METHODS: From January 2002 until March 2010, patients that presented to our institution with the initial diagnosis of CRC and were submitted to an open curative CRC resection or a palliative procedure were retrospectively reviewed. Exclusion criteria were the use of antithrombotic medication, i.e., coumarins, and appendiceal malignancies. Data acquired from medical files included age, gender, past medical history, antithrombotic treatment received prior to endoscopic diagnosis, preoperative imaging staging, location of the tumor, surgical and final histopathological report. Patients that did not receive any antithrombotic medication prior to the endoscopic diagnosis comprised the control group of the study, while patients that were on antiplatelet medication comprised the antiplatelet group. Primary end point was a comparison of CRC stage in the two groups of the study. CRC presenting symptoms and the incidence of each cancer stage in the two groups were also evaluated.
RESULTS: A total of 387 patients with the diagnosis of CRC were submitted to our department for further surgical treatment. Ninety-eight patients (25.32%), with a median age of 71 years (range 52-91 years), were included in the antiplatelet group, while 289 (74.67%) patients, with a median age of 67 years (range 41-90 years), were not in any thrombosis prophylaxis medication (control group). Thirty-one patients were treated with some kind of palliative procedure, either endoscopic, such as endoscopic stent placement, or surgical, such as de-compressive colostomy or deviation. Coronary disease (77.55% - 76 patients), stroke recurrence prevention (14.28% - 14 patients) and peripheral arterial disease (8.16% - 8 patients) were the indications for the administration of antiplatelet treatment (aspirin, clopidogrel, ticlopidine or dipyridamole) in the antiplatelet group. All patients on aspirin treatment received a dosage of 100 mg/d, while the minimum prophylactic dosages were also used for the rest of the antiplatelet drugs. Investigation of an iron deficiency anemia (147 patients), per rectum blood loss (84 patients), bowel obstruction and/or perforation (81 patients), bowel habits alterations (32 patients), non-specific symptoms, such as weight loss, intermittent abdominal pain and fatigue, (22 patients) or population screening (21 patients) were the indications for the endoscopic investigation in both groups. Bleeding, either chronic presenting as anemia or acute was significantly higher (P = 0.002) for the antiplatelet arm of the study (71 patients - 72.4% of the antiplatelet group vs 160 patients - 55.3% of the control group). The mean tumor, node and metastasis stage was 2.57 ± 0.96 for the control group, 2.27 ± 0.93 for the antiplatelet group (P = 0.007) and 2.19 ± 0.92 for the subgroup of patients taking aspirin (P = 0.003). The incidence of advanced disease (stage IV) was lower for the antiplatelet group of the study (P = 0.033).
CONCLUSION: The adverse effect of bleeding that is justifiably attached to this drug category seems to have a favorable impact on the staging characteristics of CRC.
doi:10.4253/wjge.v4.i9.409
PMCID: PMC3487189  PMID: 23125899
Colorectal cancer; Antiplatelets; Cancer stage; Abdominal surgery; Colonoscopy
4.  Characteristics and Predictors of Missed Opportunities in Lung Cancer Diagnosis: An Electronic Health Record–Based Study 
Journal of Clinical Oncology  2010;28(20):3307-3315.
Purpose
Understanding delays in cancer diagnosis requires detailed information about timely recognition and follow-up of signs and symptoms. This information has been difficult to ascertain from paper-based records. We used an integrated electronic health record (EHR) to identify characteristics and predictors of missed opportunities for earlier diagnosis of lung cancer.
Methods
Using a retrospective cohort design, we evaluated 587 patients of primary lung cancer at two tertiary care facilities. Two physicians independently reviewed each case, and disagreements were resolved by consensus. Type I missed opportunities were defined as failure to recognize predefined clinical clues (ie, no documented follow-up) within 7 days. Type II missed opportunities were defined as failure to complete a requested follow-up action within 30 days.
Results
Reviewers identified missed opportunities in 222 (37.8%) of 587 patients. Median time to diagnosis in cases with and without missed opportunities was 132 days and 19 days, respectively (P < .001). Abnormal chest x-ray was the clue most frequently associated with type I missed opportunities (62%). Follow-up on abnormal chest x-ray (odds ratio [OR], 2.07; 95% CI, 1.04 to 4.13) and completion of first needle biopsy (OR, 3.02; 95% CI, 1.76 to 5.18) were associated with type II missed opportunities. Patient adherence contributed to 44% of patients with missed opportunities.
Conclusion
Preventable delays in lung cancer diagnosis arose mostly from failure to recognize documented abnormal imaging results and failure to complete key diagnostic procedures in a timely manner. Potential solutions include EHR-based strategies to improve recognition of abnormal imaging and track patients with suspected cancers.
doi:10.1200/JCO.2009.25.6636
PMCID: PMC2903328  PMID: 20530272
5.  Lagtimes in diagnosis and treatment colorectal cancer 
Background Lagtimes to diagnostic colonoscopy have been used as practice performance measures.
Aim To evaluate the duration, determinants, and outcomes of lagtimes between referral for endoscopic evaluation and colorectal cancer (CRC) diagnosis.
Methods We examined the medical records of 289 patients with CRC and evaluated lagtimes, their potential determinants, and their association with CRC stage at diagnosis as well as overall survival.
Results Median lag between referral and CRC diagnosis was 41 days (41.5% >60 days, 30.1%>90 days). The only significant predictor of lagtime was the initiating event for referral: abnormal symptom, laboratory test, or imaging study was associated with shortest, and presence of family history was associated with longest lag times, respectively. Longer lagtimes were associated with lower mortality risk, but this was completely explained by earlier CRC stage. An analysis restricted to 100 patients referred for abnormal CRC screening tests found no association between duration of lag and CRC stage or mortality.
Conclusions There seems to be no meaningful association between mortality in patients with CRC and lagtimes between referral for colonoscopy and CRC diagnosis for periods up to 2-3 months. On the contrary, longer lagtimes were inversely associated with CRC stage at the time of diagnosis.
doi:10.1111/j.1365-2036.2008.03826.x
PMCID: PMC2596579  PMID: 18691351
6.  Investigation of Clinical Manifestations in Korean Colorectal Cancer Patients 
Annals of Coloproctology  2013;29(4):139-143.
Purpose
Early diagnostic work-up in patients with clinical symptoms of colorectal cancer (CRC) is important to achieve good treatment results. In this study, we investigated clinical symptoms when a diagnosis of CRC was made in patients who had a surgical resection, especially focusing on the relevance of constipation to CRC.
Methods
The clinical symptoms of 17,415 CRC patients who had curative surgery from January 2010 to December 2012 were collected from 24 training hospitals of surgery.
Results
The number of symptomatic patients before the diagnosis of CRC was 11,085 (63.7%). Hematochezia or melena, abdominal pain, anemia, and constipation were more often found in female than male patients while bowel habit change was more common in male patients. Considering age, bowel habit change and hematochezia or melena were more common in patients younger than 60. Anemia and constipation, however, were more common in patients older than 60. According to the group classification based on age, patients older than 60 had experienced more constipation (P = 0.049). Moreover, patients with constipation tended to have a more advanced disease status (P < 0.001).
Conclusion
In patients who had surgery due to CRC, bleeding, abdominal pain, bowel habit change and constipation were the most frequent symptoms before diagnosis. Although whether or not constipation is a cause of CRC is unclear, it is one of the important clinical symptoms that presents in patients with CRC, and patients with a symptom of constipation tend to present with a more advanced CRC stage.
doi:10.3393/ac.2013.29.4.139
PMCID: PMC3767862  PMID: 24032113
Colorectal neoplasms; Clinical manifestations; Constipation
7.  Cognitive Errors and Logistical Breakdowns Contributing to Missed and Delayed Diagnoses of Breast and Colorectal Cancers: A Process Analysis of Closed Malpractice Claims 
Journal of General Internal Medicine  2012;27(11):1416-1423.
PURPOSE
To erform a process analysis of missed and delayed diagnoses of breast and colorectal cancers to identify: (1) the cognitive and logistical factors that lead to these diagnostic errors, and (2) prevention strategies.
METHODS
Using 56 cases (43 breast, 13 colon) of missed and delayed diagnosis, we performed structured analyses to identify specific points in the diagnostic process in which errors occurred. Each error was classified as either a cognitive error or logistical breakdown. Finally, two physician-investigators identified strategies to prevent the errors in each case.
RESULTS
Virtually all cases involved one or more cognitive errors (53/56, 95 %) and approximately half (31/56, 55 %) involved logistical breakdowns. The clinical activity most prone to cognitive error was the selection of the diagnostic strategy, both during the office visit (25/56, 45 %) and during interpretation of test results (22/50, 44 %). Arrangement of follow-up visits with a primary care physician (8/29, 28 %) or specialist physician (7/29, 26 %) were especially prone to logistical breakdowns. Adherence to current clinical guidelines could have prevented at least one error in 66 % of cases and assistance from a patient advocate could have prevented at least one error in 48 % of cases.
CONCLUSIONS
Cognitive errors and logistical breakdowns are common among missed and delayed diagnoses of breast and colorectal cancers. Prevention strategies should focus on ensuring improving the effectiveness and use of clinical guidelines in the selection of diagnostic strategy, both during office visits and when interpreting test results. Tools to facilitate communication and to ensure that follow-up visits occur should also be considered.
doi:10.1007/s11606-012-2107-4
PMCID: PMC3475819  PMID: 22610909
diagnosis errors; medical errors; breast cancer; colo-rectal cancer; malpractice
8.  Post-Referral Colonoscopy Delays in Diagnosis of Colorectal Cancer: A Mixed-Methods Analysis 
Quality management in health care  2012;21(4):252-261.
Background
Delays in colorectal cancer (CRC) diagnosis are one of the most common reasons for malpractice claims and lead to poor outcomes. However, they are not well studied.
Aims
We used a mixed quantitative-qualitative approach to analyze post-referral colonoscopy delays in CRC patients and explored referring physician’s perception of processes surrounding these delays.
Methods
Two physician-raters conducted independent electronic health record reviews of new CRC cases in a large integrated safety-net system to determine post-referral colonoscopy delays, which we defined as failures to perform colonoscopy within 60 days of referral for an established indication(s). To explore perceptions of colonoscopy processes, we conducted semi-structured interviews with a sample of primary care physicians (PCPs) and used a content analysis approach.
Results
Of 104 CRC cases that met inclusion criteria, reviewers agreed on the presence of post-referral colonoscopy delays in 35 (33.7%) cases; κ = 0.99 (95% CI, 0.83–0.99). The median time between first referral and completion of colonoscopy was 123.0 days (range 62.0–938.0; IQR=90.0 days). In about two-thirds of instances (64.8%), the reason for delay was a delayed future appointment with the gastroenterology service. On interviews, PCPs attributed long delays in scheduling to reduced endoscopic capacity and inefficient processes related to colonoscopy referral and scheduling, including considerable ambiguity regarding referral guidelines. Many suggested that navigation models be applied to streamline CRC diagnosis.
Conclusion
Post-referral delays in CRC diagnosis are potentially preventable. A comprehensive mixed-methods methodology might be useful for others to identify the steps in the diagnostic process that are in most need for improvement.
doi:10.1097/QMH.0b013e31826d1f28
PMCID: PMC3702372  PMID: 23011072
Diagnostic delays; colorectal cancer; primary care; referrals; practice patterns
9.  Does delay in diagnosing colorectal cancer in symptomatic patients affect tumor stage and survival? A population-based observational study 
BMC Cancer  2010;10:332.
Background
Diagnosing colorectal cancer (CRC) at an early stage improves survival. To what extent any delay affects outcome once patients are symptomatic is still unclear.
Our objectives were to evaluate the association between diagnostic delay and survival in symptomatic patients with early stage CRC and late stage CRC.
Methods
Prospective population-based observational study evaluating daily clinical practice in Northern Holland. Diagnostic delay was determined through questionnaire-interviews. Dukes' stage was classified into two groups: early stage (Dukes A or B) and late stage (Dukes C or D) cancer. Patients were followed up for 3.5 years after diagnosis.
Results
In total, 272 patients were available for analysis. Early stage CRC was present in 136 patients while 136 patients had late stage CRC. The mean total diagnostic delay (SE) was 31 (1.5) weeks in all CRC patients. No significant difference was observed in the mean total diagnostic delay in early versus late stage CRC (p = 0.27).
In early stage CRC, no difference in survival was observed between patients with total diagnostic delay shorter and longer than the median (Kaplan-Meier, log-rank p = 0.93).
In late stage CRC, patients with a diagnostic delay shorter than the median had a shorter survival than patients with a diagnostic delay longer than the median (log-rank p = 0.01). In the multivariate Cox regression model with survival as dependent variable and median delay, age, open access endoscopy, number and type of symptoms as independent variables, the odd's ratio for survival in patients with long delay (>median) versus short delay (≤median) was 1.8 (95% confidence interval (CI) 1.1 to 3.0; p = 0.01). Tumor-site was not associated with patient survival. When separating late stage CRC in Dukes C and Dukes D tumors, a shorter delay was associated with a shorter survival in Dukes D tumors only and not in Dukes C tumors.
Conclusion
In symptomatic CRC patients, a longer diagnostic and therapeutic delay in routine clinical practice was not associated with an adverse effect on survival. The time to CRC diagnosis and initiation of treatment did not differ between early stage and late stage colorectal cancer.
doi:10.1186/1471-2407-10-332
PMCID: PMC2907342  PMID: 20584274
10.  Reducing Referral Delays in Colorectal Cancer Diagnosis: Is It about How You Ask? 
Objectives
Delays in colorectal cancer (CRC) diagnosis related to colonoscopy referrals are not well studied. We tested whether certain details of information transmitted through computerized provider order entry (CPOE)-based referrals affected timeliness of diagnostic colonoscopy for patients with newly diagnosed colorectal cancer (CRC).
Methods
We studied a 6-year cohort of all newly diagnosed patients with CRC at a large tertiary care Veterans Affairs hospital and its affiliated multispecialty clinics. Referring providers included primary care clinicians, resident trainees, and other specialists. From the colonoscopy referral preceding CRC diagnosis, we determined request date, type and frequency of diagnostic clues provided (symptoms, signs, test results), notation of urgency, and documented evidence of verbal contact between referring provider and consultant to expedite referral. We compared distributions of proportions of diagnostic clues between patients with > 60 and ≤ 60 day lag and examined predictors of lag time.
Results
Of 367 electronic referrals identified with a median lag of 57 days, 178 (48.5%) had lag > 60 days. Referrals associated with longer lag times included those with “positive fecal occult blood test” (92 days, P<0.0001), “hematochezia” (75 days, P=0.02), “history of polyps” (221 days, P=0.0006), and when “screening” (versus specific symptoms) was given as reason for diagnostic colonoscopy (203 days, P=0.002). Independent predictors of shorter wait times included 3 diagnostic clues, notation of urgency, and documentation of verbal contact.
Conclusions
Attention to certain details of diagnostic information provided to consultants through CPOE-based referrals may help reduce delays in CRC diagnosis.
doi:10.1136/qshc.2009.033712
PMCID: PMC2965264  PMID: 20584706
delayed cancer diagnosis; colorectal cancer; colonoscopy referrals; computerized order entry; electronic medical records; primary care
11.  Conclusions from a study of venous invasion in stage IV colorectal adenocarcinoma 
Journal of Clinical Pathology  2002;55(1):17-21.
Aims: Venous invasion is an established predictor of prognosis in colorectal cancer (CRC). The reported incidence of venous invasion in CRC specimens varies between 10% and 89.5%, mainly as a result of interobserver variability and differences in specimen processing (for example, staining with haematoxylin and eosin (H+E) alone versus the addition of an elastic fibre stain). This study was performed with three purposes in mind, namely: (1) To assess and compare the incidence of venous invasion diagnosed on H+E stained tissue versus tissue stained with both H+E and an elastic fibre stain. (2) To estimate the inherent false negative rate associated with the diagnosis of venous invasion by histopathological evaluation of resected CRC specimens. (3) To compare the resulting data regarding incidence, quantity, site, and type of venous invasion to the pertinent literature.
Methods: Venous invasion was assessed on sections from 81 CRCs resected from patients with synchronous distant metastases (hepatic and non-hepatic). Only stage IV tumours were studied for the following reasons: (1) it can be assumed that in all patients with distant haematogenous metastases venous invasion had occurred, thus enabling the false negative rate to be calculated; (2) there can be no dispute about the clinical relevance of the various characteristics of venous invasion identified in the tumours of patients with synchronous distant haematogenous metastases; and (3) to eliminate the effect of variance in tumour stage on the incidence of venous invasion. Initially, H+E stained sections were studied for venous invasion. Sections that were negative or questionable with regard to venous invasion were then stained with an elastic fibre stain, and a second search for venous invasion was carried out. Venous invasion was characterised by incidence, quantity, type, and site. The χ2 test for independence was used to compare the incidence of venous invasion in colonic versus rectal and rectosigmoid primary tumours, and in patients with hepatic versus non-hepatic metastases.
Results: Venous invasion was identified in 42 (51.9%) (of the 81 specimens on H+E stained sections. The addition of the elastic fibre stain enabled the diagnosis of venous invasion in 15 (38.5%) of the remaining 39 specimens, increasing the overall incidence to 57 of 81 cases (70.4%). Of the 57 positive specimens, venous invasion was minimal in 27 (47.4%), intermediate in five, (8.8%) and massive in 25 (43.9%). Only intramural veins were involved in 18 (31.6%), only extramural veins in 26 (45.6%), and both intramural and extramural veins in 13 (22.8%) of the 57 positive specimens. The filling type of venous invasion was found in 41 (71.9%), the floating type in 28 (49.1%), and the infiltrating type in six (10.5%) of the 57 positive specimens. There was no significant difference between the incidence of venous invasion in the colon (42 of 60; 70%) versus rectal and rectosigmoid tumours (15 of 21; 71.4%; p = 0.8539), nor in the incidence of venous invasion in patients with hepatic (49 of 70; 70%) versus non-hepatic (eight of 11; 72.7%) metastases (p = 0.9018).
Conclusions: The addition of an elastic fibre stain enables the identification of venous invasion in a considerable proportion of sections from CRC tumours that are falsely negative for venous invasion on H+E stain alone. The inherent chance of missing venous invasion on histopathological evaluation of CRC tumours stained with H+E and elastic fibre stains is at least 10.5%, and may be as high as 29.6%. In a large proportion of stage IV CRCs, despite the presence of synchronous distant metastases, only a minimal extent of venous invasion (that is, one to two involved veins) is demonstrable in the primary tumour. This suggests that only minimal venous invasion is required for the seeding of clinically relevant haematogenous metastases, and emphasises the careful, dedicated search for venous invasion that is required from the pathologist. Although extramural venous invasion was predominant in stage IV CRCs, in a considerable proportion of tumours (about a third) only intramural venous invasion was found. This suggests that intramural venous invasion may also seed clinically relevant haematogenous metastases, and should therefore also be considered as an indicator of poor prognosis.
PMCID: PMC1769571  PMID: 11825918
colorectal adenocarcinoma; synchronous distant metastases; venous invasion
12.  Factors associated with delays to medical assessment and diagnosis for patients with colorectal cancer 
Canadian Family Physician  2012;58(9):e495-e501.
Abstract
Objective
To identify factors associated with delays to medical assessment and diagnosis for patients with colorectal cancer (CRC).
Design
Data were collected through a standardized questionnaire. Clinical records were also reviewed. When necessary, patients were contacted by a member of the study team to collect missing data and confirm information.
Setting
Cross Cancer Institute in Edmonton, Alta.
Participants
Patients newly diagnosed with a histologically proven colorectal adenocarcinoma were identified and eligible for the study.
Main outcome measures
Associations between symptoms, tumour stage at operation, symptom duration, and tumour location were sought to identify factors associated with a delay in diagnosis of CRC.
Results
Surveys were completed by 93 patients. A total of 49% of patients had symptoms of CRC present for 1 month or less before seeing a physician, and 51% had symptoms for longer than 1 month. Seventy-five (86%) patients initially presented to family physicians for assessment, while 12 (14%) patients presented to the emergency department for their first physician encounters. Only 33 (38%) patients had digital rectal examinations during their first visits. Women were more likely to present to physicians with longer than 1 month of symptoms, while men were more likely to present with less than 1 month of symptoms (P = .03). Abdominal pain, blood in the stool, and change in stool size were the most frequent symptoms encountered. Twenty-two (26%) patients delayed seeking treatment because they thought their symptoms were not serious and 12 (14%) believed that their family physicians had taken inappropriate action. Fifteen (18%) patients attributed their delays to waiting too long for specialist referral and diagnostic tests.
Conclusion
This study highlights the important role patients and physicians both play in delays in the diagnosis of CRC. Efforts to diminish future delays must focus on educating the public and practising physicians about important symptoms and signs of CRC. Additionally, the value of a digital rectal examination must be emphasized, along with continued promotion of CRC screening.
PMCID: PMC3440290  PMID: 22972740
13.  Types and Origins of Diagnostic Errors in Primary Care Settings 
JAMA internal medicine  2013;173(6):418-425.
Importance
Diagnostic errors are an understudied aspect of ambulatory patient safety.
Objectives
To determine the types of diseases missed and the diagnostic process involved in the cases of confirmed diagnosis errors in primary care settings and to determine whether record reviews could shed light on potential contributory factors to inform future interventions.
Design
We reviewed medical records of diagnostic errors detected at two sites through electronic health records-based triggers. Triggers were based on patterns of patients’ unexpected return visits after an initial primary care “index” visit.
Setting
A larger urban Veterans Affairs facility and a large integrated private health care system.
Participants
Our study focused on 190 unique instances of diagnostic errors detected in primary care visits between October 1, 2006, and September 30, 2007.
Main Outcome Measures
Through medical record reviews, we collected data on presenting symptoms at the index visit, types of diagnoses missed, process breakdowns, potential contributory factors, and potential for harm from errors.
Results
In 190 cases, a total of 68 unique diagnoses were missed. Most missed diagnoses were common conditions in primary care, with pneumonia (6.7%), decompensated congestive heart failure (5.7%), acute renal failure (5.3%), cancer (primary) (5.3%), and urinary tract infection or pyelonephritis (4.8%) being most common. Process breakdowns most frequently involved the patient-practitioner clinical encounter (78.9%) but were also related to referrals (19.5%), patient-related factors (16.3%), follow-up and tracking of diagnostic information (14.7%), and performance and interpretation of diagnostic tests (13.6%). A total of 43.7% of cases involved more than one of these processes. Patient- practitioner encounter breakdowns were primarily related to problems with history-taking (56.3%), examination (47.4%), and/or ordering diagnostic tests for further work-up (57.4%). Most errors were associated with potential for moderate-to-severe harm.
Conclusions and Relevance
Diagnostic errors identified in our study involved a large variety of common diseases and had significant potential for harm. Most errors were related to process breakdowns in the patient-practitioner clinical encounter. Preventive interventions should target common contributory factors across diagnoses, especially those that involve data gathering and synthesis in the patient- practitioner encounter.
doi:10.1001/jamainternmed.2013.2777
PMCID: PMC3690001  PMID: 23440149
diagnostic errors; patient safety; follow-up; primary care; electronic health records
14.  Effect of Flexible Sigmoidoscopy-Based Screening on Incidence and Mortality of Colorectal Cancer: A Systematic Review and Meta-Analysis of Randomized Controlled Trials 
PLoS Medicine  2012;9(12):e1001352.
A systematic review and meta-analysis of randomized trials conducted by B. Joseph Elmunzer and colleagues reports that that flexible sigmoidoscopy-based screening reduces the incidence of colorectal cancer in average-risk patients, as compared to usual care or no screening.
Background
Randomized controlled trials (RCTs) have yielded varying estimates of the benefit of flexible sigmoidoscopy (FS) screening for colorectal cancer (CRC). Our objective was to more precisely estimate the effect of FS-based screening on the incidence and mortality of CRC by performing a meta-analysis of published RCTs.
Methods and Findings
Medline and Embase databases were searched for eligible articles published between 1966 and 28 May 2012. After screening 3,319 citations and 29 potentially relevant articles, two reviewers identified five RCTs evaluating the effect of FS screening on the incidence and mortality of CRC. The reviewers independently extracted relevant data; discrepancies were resolved by consensus. The quality of included studies was assessed using criteria set out by the Evidence-Based Gastroenterology Steering Group. Random effects meta-analysis was performed.
The five RCTs meeting eligibility criteria were determined to be of high methodologic quality and enrolled 416,159 total subjects. Four European studies compared FS to no screening and one study from the United States compared FS to usual care. By intention to treat analysis, FS-based screening was associated with an 18% relative risk reduction in the incidence of CRC (0.82, 95% CI 0.73–0.91, p<0.001, number needed to screen [NNS] to prevent one case of CRC = 361), a 33% reduction in the incidence of left-sided CRC (RR 0.67, 95% CI 0.59–0.76, p<0.001, NNS = 332), and a 28% reduction in the mortality of CRC (relative risk [RR] 0.72, 95% CI 0.65–0.80, p<0.001, NNS = 850). The efficacy estimate, the amount of benefit for those who actually adhered to the recommended treatment, suggested that FS screening reduced CRC incidence by 32% (p<0.001), and CRC-related mortality by 50% (p<0.001).
Limitations of this meta-analysis include heterogeneity in the design of the included trials, absence of studies from Africa, Asia, or South America, and lack of studies comparing FS with colonoscopy or stool-based testing.
Conclusions
This meta-analysis of randomized controlled trials demonstrates that FS-based screening significantly reduces the incidence and mortality of colorectal cancer in average-risk patients.
Please see later in the article for the Editors' Summary
Editor's Summary
Background
Colorectal cancer (CRC) is the second leading cause of cancer-related death in the United States. Regular CRC screening has been shown to reduce the risk of dying from CRC by 16%, and CRC screening can identify early stage cancers in otherwise healthy people, which allows for early treatment and management of the disease. Screening for colorectal cancer is frequently performed using a flexible sigmoidoscopy (FS), which is a thin, flexible tube with a tiny camera and light on the end, allowing a doctor to look at the inside wall of the bowel and remove any small growths or polyps. Although screening may detect early cancers, the life-saving and health benefits of screening are uncertain because the polyp may not necessarily progress. This could lead to anxiety and unnecessary interventions and treatments amongst those screened. Randomized controlled trials (RCTs) are needed to determine all of the risks involved in cancer screenings, however the guidelines that recommend FS-based screening do not rely upon RCT data. Recently, the results of four large-scale RCTs evaluating FS screening for CRC have been published. The conflicting results with respect to the incidence and mortality of CRC in these studies have called into question the effectiveness of endoscopic screening.
Why Was This Study Done?
The results of RCTs measuring the risks and outcomes of CRC screening have shown varying estimates of the benefits of using FS screening. If better estimates of the risks and benefits of FS screening are developed, then the current CRC screening guidelines may be updated to reflect this new information. In this study, the authors show the results of a meta-analysis of published RCTs, which more precisely estimates the effects of FS-based screening on the incidence and mortality of colorectal cancer.
What Did the Researchers Do and Find?
The researchers used the Medline and Embase databases to find relevant studies from 1966 to May 28, 2012. After screening 3,319 citations and 29 potentially relevant articles, five RCTs of high methodologic quality and 416,159 total subjects evaluating the effect of FS screening on the incidence and mortality of CRC were identified. The data were extracted and random effects meta-analysis was performed. The meta-analysis revealed that FS-based screening was associated with an 18% relative risk reduction in the incidence of CRC (0.82, 95% CI 0.73–0.91, p<0.001, number needed to screen (NNS) to prevent one case of CRC = 361), a 33% reduction in the incidence of left-sided CRC (RR 0.67, 95% CI 0.59–0.76, p<0.001, NNS = 332), and a 28% reduction in the mortality of CRC (RR 0.72, 95% CI 0.65–0.80, p<0.001, NNS = 850). The amount of benefit for those who adhered to the recommended treatment suggested that FS screening reduced CRC incidence by 32% (p<0.001), and CRC-related mortality by 50% (p<0.001).
What Do These Findings Mean?
This meta-analysis of RCTs evaluating the effect of FS on CRC incidence and mortality demonstrates that a FS-based strategy for screening is very effective in reducing the incidence and mortality of CRC in patients. The current recommendations for endoscopic screening are based on observational studies, which may not accurately reflect the effect of FS-based screening on the incidence and mortality of CRC. Here, the authors performed a systematic review and meta-analysis of five recent RCTs to better estimate the true effect of FS-based screening on the incidence and mortality of CRC. Thus, the results of this meta-analysis may affect health policy, and directly impact patients and clinicians.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001352.
Cancer research UK provides comprehensive information about screening for colorectal cancers as does the UK National Screening Committee
PubMed Health has general information about colon cancer
The National Cancer Institute also has comprehensive resources on colorectal cancer and treatment
The Mayo Clinic provides an overview of all aspects of colon cancer
doi:10.1371/journal.pmed.1001352
PMCID: PMC3514315  PMID: 23226108
15.  Correlation of Pretreatment Hemoglobin and Platelet Counts with Clinicopathological Features in Colorectal Cancer in Saudi Population 
Background/Aims:
In Saudi Arabia, colorectal cancers (CRCs) are registered as the second most common cancers. However, no data has been reported about correlation of the severity of the anemia and pretreatment platelets level with clinicopathological features of CRCs. We aimed to evaluate the association between pretreatment hemoglobin and platelets level and the clinicopathological features of CRC patients in Saudi Arabia.
Materials and Methods:
Between September 2005 and November 2011, One hundred and fifty-four confirmed CRC patients underwent thorough physical examination, blood investigations, endoscopic ultrasonography (EUS), and computed tomography (CT) for staging before surgery. Findings of physical assessment, EUS, CT, and pathological specimens were correlated with pretreatment hemoglobin and platelets levels the Pearson-Kendall tau correlative coefficients.
Results:
The mean age of cohort was 56.6 years (range: 26-89). Left-sided CRC were predominant (97 patients; 63%). Mean size of primary tumor was 6 cms (1-18) SD ± 3.55. Mean values of hemoglobin, red blood cells, hematocrit, white blood cells, and platelets were 11.9 SD ± 2.3, 35.5 SD ± 5.7, 4.43 × 106/mL SD ± 0.6, 7.67 106/mL SD ± 2.44, and 343 × 103/mL SD ± 164.4, respectively. Pretreatment hemoglobin was inversely correlated with primary tumor size (R: 0.71, R2: 1.55, P = 0.0001) and nodal status (R: 0.02, R2: 0.05, P = 0.01). Right-sided CRC had significantly low pretreatment hemoglobin levels (P = 0.001). Interestingly, pretreatment thrombocytosis was seen only in right-sided CRC (P = 0.0001).
Conclusion:
Pretreatment anemia and thrombocytosis were found mainly in right-sided CRCs and advanced primary and nodal stages. Pretreatment hemoglobin and thrombocytosis can be considered as useful prognostic markers in CRC patients.
doi:10.4103/1319-3767.129479
PMCID: PMC3987154  PMID: 24705152
Colorectal cancers; correlation; pretreatment hemoglobin levels; platelet counts; Saudi population
16.  Identification of Lynch Syndrome Among Patients With Colorectal Cancer 
JAMA : the journal of the American Medical Association  2012;308(15):10.1001/jama.2012.13088.
Context
Lynch syndrome is the most common form of hereditary colorectal cancer (CRC) and is caused by germline mutations in DNA mismatch repair (MMR) genes. Identification of gene carriers currently relies on germline analysis in patients with MMR-deficient tumors, but criteria to select individuals in whom tumor MMR testing should be performed are unclear.
Objective
To establish a highly sensitive and efficient strategy for the identification of MMR gene mutation carriers among CRC probands.
Design, Setting, and Patients
Pooled-data analysis of 4 large cohorts of newly diagnosed CRC probands recruited between 1994 and 2010 (n = 10 206) from the Colon Cancer Family Registry, the EPICOLON project, the Ohio State University, and the University of Helsinki examining personal, tumor-related, and family characteristics, as well as microsatellite instability, tumor MMR immunostaining, and germline MMR mutational status data.
Main Outcome Measures
Performance characteristics of selected strategies (Bethesda guidelines, Jerusalem recommendations, and those derived from a bivariate/multivariate analysis of variables associated with Lynch syndrome) were compared with tumor MMR testing of all CRC patients (universal screening).
Results
Of 10 206 informative, unrelated CRC probands, 312 (3.1%) were MMR gene mutation carriers. In the population-based cohorts (n=3671 probands), the universal screening approach (sensitivity, 100%;95% CI, 99.3%–100%; specificity, 93.0%; 95% CI, 92.0%–93.7%; diagnostic yield, 2.2%; 95% CI, 1.7%–2.7%) was superior to the use of Bethesda guidelines (sensitivity, 87.8%; 95% CI, 78.9%–93.2%; specificity, 97.5%; 95% CI, 96.9%–98.0%; diagnostic yield, 2.0%; 95% CI, 1.5%–2.4%; P <.001), Jerusalem recommendations (sensitivity, 85.4%; 95% CI, 77.1%–93.6%; specificity, 96.7%; 95% CI, 96.0%–97.2%; diagnostic yield, 1.9%; 95% CI, 1.4%–2.3%; P < .001), and a selective strategy based on tumor MMR testing of cases with CRC diagnosed at age 70 years or younger and in older patients fulfilling the Bethesda guidelines (sensitivity, 95.1%; 95% CI, 89.8%–99.0%; specificity, 95.5%; 95% CI, 94.7%–96.1%; diagnostic yield, 2.1%; 95% CI, 1.6%–2.6%; P <.001). This selective strategy missed 4.9% of Lynch syndrome cases but resulted in 34.8% fewer cases requiring tumor MMR testing and 28.6% fewer cases undergoing germline mutational analysis than the universal approach.
Conclusion
Universal tumor MMR testing among CRC probands had a greater sensitivity for the identification of Lynch syndrome compared with multiple alternative strategies, although the increase in the diagnostic yield was modest.
doi:10.1001/jama.2012.13088
PMCID: PMC3873721  PMID: 23073952
17.  Late Presentation of Colorectal Cancer in a Vulnerable Population 
Objectives
Health care delivery to vulnerable populations is a significant challenge as such systems simultaneously face financial challenges and resource limitations. Complex medical conditions, such as colorectal cancer (CRC), may identify disparities in access or delivery that affect clinical outcomes. Our objective was to examine CRC stage at presentation and mortality in a vulnerable population compared with nationally representative data.
Methods
From 1996–2009, consecutive CRC cases from San Francisco General Hospital (SFGH) were identified. Representative CRC cases were identified from the Surveillance, Epidemiology and End Results (SEER) database over the same time period. Demographic data, stage at presentation, survival after diagnosis, and utilization of surgical services were examined in both cohorts and by race/ethnicity. In addition, in patients who had established care at SFGH for at least one year, we examined utilization of CRC screening tests prior to CRC diagnosis.
Results
289 stage 1 to 4 CRC cases were identified at SFGH. Fifty-five percent of the SFGH cohort presented with advanced disease (stage 3 and 4) compared with 44% in the SEER cohort (adjusted odds-ratio (aOR) 1.28, 95% confidence interval (CI) 1.01–1.61, p=0.04). Increased risk of late stage at presentation at SFGH compared with SEER was most evident among blacks (aOR 1.80, 95% CI 1.02–3.17, p=0.04) and Asians (aOR 1.41, 95% CI 0.97–2.05, p=0.07). There was weak evidence for worse survival at SFGH compared with SEER overall (adjusted hazard ratio (aHR) 1.19, 95% CI 0.99–1.45). However, this varied by race (p=0.002), with poorer survival at SFGH among whites (HR 2.13, 95% CI 1.51–3.02) and possibly blacks (HR 1.38, 95% CI 0.95–2.01), but some evidence for better survival among Asians (HR 0.77, 95% CI 0.53–1.12). Among CRC patients at SFGH, Asians and Hispanics had significantly better survival than whites and blacks. Of the 56% patients receiving care at SFGH for at least 1 year, only 22% had received any form of CRC screening.
Conclusions
In this study comparing history of screening, stage at presentation, and mortality among CRC cases at SFGH with the SEER cancer registry, we found that SFGH cases were more likely to present with late CRC, in particular blacks and Asians, and mostly had shorter survival, especially whites and blacks. The screening rates among SFGH patients in care for at least 1 year at diagnosis were low, and may have contributed to late stage at presentation. These findings provide an opportunity to examine access and utilization by race/ethnicity in a vulnerable population and to identify areas where quality of CRC care can be improved.
doi:10.1038/ajg.2012.256
PMCID: PMC3740533  PMID: 23552303
18.  Systematic review of clinical features of suspected colorectal cancer in primary care 
Canadian Family Physician  2014;60(8):e405-e415.
Abstract
Objective
To systematically review the diagnostic accuracy of clinical features associated with colorectal cancer (CRC) presenting in primary care.
Data sources
MEDLINE and EMBASE were searched for studies in primary care that provided information on clinical features predictive of CRC. Positive predictive values were used to guide the determination of clinical features associated with increased risk of CRC.
Study selection
Systematic reviews or primary studies that provided possible clinical features predictive of CRC were included.
Synthesis
Clinical features of patients presenting in primary care that are associated with increased risk of CRC, listed in descending order of association, included palpable rectal or abdominal mass; rectal bleeding combined with weight loss; iron deficiency anemia; rectal bleeding mixed with stool; rectal bleeding in the absence of perianal symptoms; rectal bleeding combined with change in bowel habits; dark rectal bleeding; rectal bleeding and diarrhea; and change in bowel habits. Being male and increasing age were also, in general, associated with increased risk of CRC.
Conclusion
Recognition of clinical features associated with increased risk of CRC by FPs might help with earlier identification and referral among patients presenting in primary care. This review might help inform providers and CRC diagnostic assessment programs about indications for assessment and further investigation.
PMCID: PMC4131977  PMID: 25122831
19.  Risk Factors for Colorectal Cancer in Patients with Multiple Serrated Polyps: A Cross-Sectional Case Series from Genetics Clinics 
PLoS ONE  2010;5(7):e11636.
Background
Patients with multiple serrated polyps are at an increased risk for developing colorectal cancer (CRC). Recent reports have linked cigarette smoking with the subset of CRC that develops from serrated polyps. The aim of this work therefore was to investigate the association between smoking and the risk of CRC in high-risk genetics clinic patients presenting with multiple serrated polyps.
Methods and Findings
We identified 151 Caucasian individuals with multiple serrated polyps including at least 5 outside the rectum, and classified patients into non-smokers, current or former smokers at the time of initial diagnosis of polyposis. Cases were individuals with multiple serrated polyps who presented with CRC. Controls were individuals with multiple serrated polyps and no CRC. Multivariate logistic regression was performed to estimate associations between smoking and CRC with adjustment for age at first presentation, sex and co-existing traditional adenomas, a feature that has been consistently linked with CRC risk in patients with multiple serrated polyps. CRC was present in 56 (37%) individuals at presentation. Patients with at least one adenoma were 4 times more likely to present with CRC compared with patients without adenomas (OR = 4.09; 95%CI 1.27 to 13.14; P = 0.02). For females, the odds of CRC decreased by 90% in current smokers as compared to never smokers (OR = 0.10; 95%CI 0.02 to 0.47; P = 0.004) after adjusting for age and adenomas. For males, there was no relationship between current smoking and CRC. There was no statistical evidence of an association between former smoking and CRC for both sexes.
Conclusion
A decreased odds for CRC was identified in females with multiple serrated polyps who currently smoke, independent of age and the presence of a traditional adenoma. Investigations into the biological basis for these observations could lead to non-smoking-related therapies being developed to decrease the risk of CRC and colectomy in these patients.
doi:10.1371/journal.pone.0011636
PMCID: PMC2905435  PMID: 20661287
20.  Intact and cleaved forms of the urokinase receptor enhance discrimination of cancer from non-malignant conditions in patients presenting with symptoms related to colorectal cancer 
British Journal of Cancer  2009;101(6):992-997.
Background:
Colorectal cancer (CRC) is a leading cause of cancer-related morbidity and mortality in developed countries. It is known that early detection results in improved survival, and consequently there is a need for improved diagnostic tools in CRC. The plasma level of soluble urokinase plasminogen activator receptor (suPAR) was proposed as a marker in CRC patients. This study was undertaken to evaluate the individual molecular forms of suPAR as discriminators in a group of patients undergoing endoscopical examination following symptoms related to colorectal cancer.
Methods:
In a case–control study comprising 308 patients undergoing endoscopical examination following CRC-related symptoms, 77 CRC patients with adenocarcinoma were age and gender matched to: 77 patients with adenomas; 77 with other non-malignant findings, and 77 with no findings. The different uPAR forms were measured in citrate plasma collected before endoscopical examination, using three different Time Resolved – Fluorescence Immuno Assays (TR-FIA's).
Results:
All soluble uPAR forms were found to be significantly higher in cancer patients than in patients presenting with other non-malignant findings; uPAR(I) P=0.0006, suPAR(I–III) P<0.0001 and suPAR(I–III)+(II–III) P<0.0001, whereas no significant difference was found when performing similar comparisons for patients presenting with adenomas. The odds ratio (OR) for the comparison of uPAR(I) in patients with CRC to subjects with other non-malignant findings was 3.44 (95% CI:1.86–6.37). CRC patients had a mean elevated level of 20.9% (95% CI:10.2–32.6) for suPAR(I–III) and 18.5% (95% CI:9.0–28.8) for suPAR(I–III)+(II–III) compared with subjects with non-malignant findings.
Conclusions:
The findings confirm reports on increased uPAR expression in cancer patients and in particular elevated levels of suPAR in blood from CRC patients and indicate that suPAR levels in blood are increasing during carcinogenesis. Although none of the measured uPAR forms were cancer specific, our findings suggest that uPAR expression could be useful in the early detection of CRC when combined with other markers and clinical variables.
doi:10.1038/sj.bjc.6605228
PMCID: PMC2743369  PMID: 19672256
uPAR; colorectal cancer; detection
21.  Prevalence of screening in patients newly diagnosed with colorectal cancer in Ontario 
OBJECTIVES:
The primary objective was to determine the proportion of individuals with a new diagnosis of colorectal cancer (CRC) in Ontario in whom the cancer was screen detected. The secondary objectives were to determine the cancer stage at diagnosis and the indications for the procedure in patients who received their first colonoscopy.
PATIENTS AND METHODS:
Individuals admitted to a hospital with a new diagnosis of CRC were randomly selected after stratifying by hospital type (teaching or community). The Canadian Institute for Health Information’s Discharge Abstract Database was used to identify individuals with a first diagnosis of CRC during calendar year (CY) 2000, and Ontario Health Insurance Plan data were used to identify people 50 to 74 years of age who had their first colonoscopy during CY 2000. Up to 20 individuals were selected for each group (CRC or colonoscopy) in each of seven randomly selected community hospitals and three randomly selected teaching hospitals. Data were abstracted from the hospital charts.
RESULTS:
The hospital charts of 152 patients with a new diagnosis of CRC were examined. Of the 133 patients in whom screening status could be determined, eight had screen-detected cancers (6.0%). Of the 99 patients (65% of the sample) in whom stage could be determined, 43 (43.4%) had advanced disease (tumour-node-metastasis stage III or IV) at diagnosis. The hospital charts of 184 patients who underwent their first colonoscopy were examined. Of the 175 patients in whom the indication for colonoscopy could be determined, 45 underwent the procedure for screening purposes, 10 were for diagnostic workup of anemia and 120 for evaluation of symptoms.
CONCLUSIONS:
The low proportion (6%) of screen-detected CRC and the high proportion of patients (43.4%) with advanced disease at diagnosis reflect the lack of an organized screening program.
PMCID: PMC2658572  PMID: 18080051
Cancer stage; Colorectal cancer; Screening
22.  Low expression of novel lncRNA RP11-462C24.1 suggests a biomarker of poor prognosis in colorectal cancer 
Long noncoding RNAs (lncRNAs) have recently emerged as a major class of regulatory molecules, which were involved in a broad range of biological processes and complex diseases. Research on lncRNAs may shed light on tumorigenesis and progression of colorectal cancer (CRC). The purpose of the present study was to identify lncRNAs correlated with CRC and then investigate their potential functions. We selected 92 patients for this prospective study and then collected the tumor samples and clinical records. First, the global lncRNA expression profiles in tumor and adjacent normal tissues of patients with non-metastatic CRC and patients with metastatic CRC were measured by microarray assay. Then, a noteworthy lncRNAs RP11-462C24.1 whose function was previously unknown was explored in detail on the aspect of the association of its expression level and clinicopathological features of CRC and patients’ survival. We found that RP11-462C24.1 expression level was lower in cancer tissues compared with adjacent normal samples (P < 0.001). Furthermore, its expression level was lower in CRC patients with metastasis than those without metastasis (P = 0.049). That is, RP11-462C24.1 expression level decreased as the malignant degree of CRC increased. In addition, low expression of RP11-462C24.1 significantly correlated with more distant metastasis (P = 0.011). The areas under ROC curves were 0.78 and 0.65 for RP11-462C24.1, distinguishing CRC from normal tissue and distinguishing CRC without metastasis from CRC with metastasis, respectively. Multivariate analysis identified that RP11-462C24.1 was an independent predictor for patients prognosis (P = 0.005). Furthermore, Kaplan–Meier analysis showed that patients with low expression of RP11-462C24.1 had a poor disease-free survival (P < 0.001). This is the first study that correlates RP11-462C24.1 expression profile with malignancy grade in human CRC. Our results showed that RP11-462C24.1 could be a potential novel prognostic marker for CRC, and thus, provided a new strategy for CRC diagnosis. Meanwhile, our findings indicated the potential roles of RP11-462C24.1 in tumorigenesis and progression of CRC, which gave a clue for future studies.
Electronic supplementary material
The online version of this article (doi:10.1007/s12032-014-0031-7) contains supplementary material, which is available to authorized users.
doi:10.1007/s12032-014-0031-7
PMCID: PMC4079943  PMID: 24908062
Colorectal cancer; Long noncoding RNAs; Microarray; RP11-462C24.1; Survival
23.  Epidemiology and clinical findings of colorectal carcinoma in two tertiary care hospitals in Benghazi, Libya 
Avicenna Journal of Medicine  2014;4(4):94-98.
Aim:
The aim is to determine the pattern of patients with colorectal cancer (CRC) seen in two tertiary hospitals in Benghazi, Libya.
Materials and methods:
The cohort includes all patients of CRC who were presented between January 2007 and December 2009 to the Oncology Department, Aljomhoria Hospital and 7th October Hospital, Benghazi. Patient's age, gender, clinical presentation, location of cancer involvement, and histopathologic diagnosis were reviewed. Tumor staging was carried out according to Astler Coller modification of Duke's system, dividing it into stage A to C depending upon the extent of local involvement and regional node spread. Stage D was added to account for distant metastasis in accordance with Turnbull modification.
Results:
A total of 152 patients with CRC were included, 84 males (55%) and 68 females (45%) with a male to female ratio of 1.2:1.0. The mean age was 57.4 ± 12.92 years (range 21–87 years). 18 (11.8%) patients were below 40 years of age. The most common presenting symptoms were rectal bleeding and abdominal pain and were together present in 71% of the patients. The majority (67.8%) of tumors arise from rectum and sigmoid colon. More than one-third of the patients had poorly differentiated adenocarcinoma. Sixty patients (39.5%) presented in stage D, whereas 30.9% (47/152) and 29.6% (45/152) of patients were in stage B and stage C, respectively. None of the patients had stage A at presentation. The radiological evaluation showed presence of liver metastasis in 14 patients (9.2%) and pulmonary metastasis in two patients (1.3%). Anemia was found in 56 patients (36.8%). It was more common in females (P = 0.01) and in the right sided tumors (66.7%) than left sided tumors (29.5%) (P = 0.001).
Conclusion:
The majority of CRC patients in Benghazi were diagnosed in locally advanced or metastatic stage. In order to achieve early detection of CRC, a comprehensive cancer education program and screening of high risk population for CRC should be considered in this part of Libya.
doi:10.4103/2231-0770.140659
PMCID: PMC4183903  PMID: 25298952
Colon cancer; colorectal carcinoma; epidemiology; Libya
24.  Association of estrogen receptor beta variants and serum levels of estradiol with risk of colorectal cancer: a case control study 
BMC Cancer  2012;12:276.
Background
Endogenous estrogens may play a vital role in colorectal tumorigenesis. Estrogen receptor beta is the predominant subtype which mediates the biological effect of estrogens, while loss of expression of estrogen receptor beta has been indicated as a common step in the development of colorectal cancer (CRC). Epidemiological studies have revealed several functional polymorphisms of estrogen receptor beta (ESR2) for cancer risk, but relevant study in CRC is limited, particularly in men. This study aimed to investigate the association of circulating estradiol and variations of ESR2 with CRC risk in men.
Methods
We initiated a case–control study consisting of 390 patients with CRC and 445 healthy controls in men only. We genotyped ESR2 single nucleotide polymorphisms (SNPs) rs1256049 and rs4986938 and measured serum estradiol concentration using chemilluminescence immunoassay. Multivariable logistic regression model was performed to evaluate the associations between these variables and CRC risk.
Results
ESR2 rs1256049 CT/TT genotypes were associated with reduced risk of CRC (odds ratio [OR], 0.7, 95% confidence interval [CI], 0.5–1.0), while rs4986938 CT/TT genotypes were associated with increased risk of CRC (OR, 1.5, 95% CI, 1.0–2.1). In addition, the CRC risk increased with the number of risk genotypes of these two SNPs in a dose–response manner (Ptrend, 0.003). Specifically, subjects carrying risk genotypes of both SNPs had the highest risk of CRC (OR, 2.0, 95% CI, 1.3–3.3.). Moreover, serum estradiol concentration alone was associated with risk of CRC in men (OR, 1.2, 95% CI, 1.0–1.3). However, individuals presenting both rs4986938 CT/TT genotypes and high level of serum estradiol had a high risk of CRC (OR, 2.3, 95% CI, 1.4–3.9), compared with those presenting CC genotype and low level of serum estradiol. The similar joint results were not observed for SNP rs1256049.
Conclusions
These results suggest that endogenous estrogen and genetic variations in ESR2 may individually, or more likely jointly, affect CRC risk in male Han Chinese population, while larger studies are needed to validate our findings.
doi:10.1186/1471-2407-12-276
PMCID: PMC3472165  PMID: 22759347
Colorectal cancer; Endogenous estrogen; Estrogen receptors; Single nucleotide polymorphisms
25.  miR-133b, a muscle-specific microRNA, is a novel prognostic marker that participates in the progression of human colorectal cancer via regulation of CXCR4 expression 
Molecular Cancer  2013;12:164.
Background
MicroRNA-133b (miR-133b), which is a muscle-specific microRNA, has been reported to be downregulated in human colorectal carcinoma (CRC) when compared to adjacent non-tumor tissue. However, its diagnostic value and role in CRC have yet to be described. CXC chemokine receptor-4 (CXCR4), which participates in multiple cell processes such as cell invasion-related signaling pathways, was predicted to be a potential target of miR-133b. The aim of this study was to investigate the associations and functions of miR-133b and CXCR4 in CRC initiation and invasion.
Methods
Mature miR-133b and CXCR4 expression levels were detected in 31 tumor samples and their adjacent, non-tumor tissues from patients with CRC, as well as in 6 CRC cell lines, using real-time quantitative RT-PCR (qRT-PCR). Luciferase reporter assays and Western blots were used to validate CXCR4 as a putative target gene of miR-133b. Regulation of CXCR4 expression by miR-133b was assessed using qRT-PCR and Western blot analysis, and the effects of exogenous miR-133b and CXCR4 on cell invasion and migration were evaluated in vitro using the SW-480 and SW-620 CRC cell lines.
Results
A significant downregulation of miR-133b was observed in 93.55% of CRC tissues, and the expression of miR-133b was much lower in metastatic tumors (stage C and D, stratified by the Modified Dukes Staging System) than in primary tumors (stage A and B). In contrast, CXCR4 protein expression significantly increased in 52.63% of CRC samples, and increased CXCR4 expression in CRC was associated with advanced tumor stage. CXCR4 was shown to be a direct target of miR-133b by luciferase reporter assays, and transfection of miR-133b mimics inhibited invasion and stimulated apoptosis of SW-480 and SW-620 CRC cells.
Conclusions
Our study demonstrated that downregulated miR-133b contributed to increased cell invasion and migration in CRC by negatively regulating CXCR4. These findings may be significant for the development of therapy target for CRC.
doi:10.1186/1476-4598-12-164
PMCID: PMC3866930  PMID: 24330809
CXCR4; miR-133b; Colorectal cancer; Tumor progression; Metastasis; Targeted therapy

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