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Endoscopist–Related Factors Associated With Proximal Serrated Polyp Detection
684
SELECTED SUMMARIES
on this topic has been limited by the challenges in obtaining the detailed, high-quality data necessary to build such models. In the future, investigators should consider using data collected from polyp prevention studies to derive and validate a more robust risk model for advanced colorectal neoplasia. Furthermore, the US MultiSociety Task Force should strongly consider the use of simulation models to inform its guideline development. Such an approach has been embraced by the US Preventive Services Task Force, which utilized data from the National Cancer Institute Cancer Intervention and Surveillance Modeling Network to inform its 2008 CRC screening guideline. Simulation models can be used to address clinical questions that are difficult to answer with empiric data, such as the optimal age at which to discontinue post-polypectomy surveillance and the best way to use serial endoscopic data over time. By combining data from clinical trials and simulation models, we can provide clinicians with better tools to efficiently target care to individual patients. SAMEER D. SAINI VA Center for Clinical Management Research VA Ann Arbor Healthcare System and Division of Gastroenterology and Hepatology University of Michigan Medical School Ann Arbor, Michigan
ENDOSCOPIST–RELATED FACTORS ASSOCIATED WITH PROXIMAL SERRATED POLYP DETECTION de Wijkerslooth TR, Stoop EM, et al. Differences in proximal serrated polyp detection among endoscopists are associated with variability in withdrawal time. Gastrointest Endosc 2013;77:617–623. Proximal serrated polyps have attracted more attention based on their premalignant potential and association with synchronous and metachronous lesions (Gastroenterology 2010;139:1497–1502). In addition, interval cancers, believed to be a major limitation of colonoscopy in the proximal colon (Gastroenterology 2007;132:96–102), have been attributed to the serrated pathway. Lesions in this pathway and interval cancers share a common proximal location as well as common molecular mutations (Am J Gastroenterol 2010;105:1189–1195). Detection and removal of conventional adenomas has been well studied with much emphasis focused on patient-, procedure-, and endoscopist-related factors. Prior work examining these factors has led to the development of quality measures intended to improve the performance of colonoscopy in preventing colorectal cancer (N Engl J Med 2006;355:2533–2541; N Engl J Med 2010;362:1795–1803). Similar factors and measures are being evaluated for serrated polyps, particularly for the clinically important proximal lesions. These measures are important in light of a recent study that demonstrated that endoscopists are
GASTROENTEROLOGY Vol. 145, No. 3
better at detecting and removing proximal advanced adenomas than proximal serrated polyps (Am J Gastroenterol 2012;107:1213–1219). A recent study by de Wijkerslooth et al examined the impact of patient and endoscopist factors on proximal serrated polyp detection (Gastrointest Endosc 2013;77: 617–623). This well-executed study was performed within a large, prospective study of consecutive consenting patients undergoing screening colonoscopy as part of a trial comparing colonoscopy to computed tomographic colonography. Patients with a personal history of colorectal neoplasia or inflammatory bowel disease and those with a full colon examination in the previous 5 years were excluded. The main outcome for this analysis was the detection of one or more proximal serrated polyps in a per-patient analysis. Dedicated research staff recorded a number of colonoscopy variables, including cecal intubation time, withdrawal time, endoscopist, field of view (140 or 170 ), definition of the colonoscope (high or low), use of a plastic colonoscope cap, timing of the colonoscopy (morning/afternoon), and use of the antispasmodic butylscopolamine. Quality of bowel preparation was assessed using the well-validated Ottawa bowel preparation score and patient comfort by the Gloucester score. All of the 1354 colonoscopies were performed at 2 academic medical centers by 5 gastroenterologists with 6 years of endoscopy experience. In addition, data were culled from only those examinations that were performed by gastroenterologists with 1000 career and 50 studyrelated colonoscopies. The endoscopists who were selected had performed most of the study endoscopies (1354/1407; 96%). Withdrawal time was recorded with a stopwatch and was 6 minutes after subtracting the time needed for polypectomies. The median net withdrawal time was 10 minutes (interquartile range, 8–15). Proximal serrated polyps were detected in 167 patients for a proximal serrated polyp detection rate of 12%. The corresponding adenoma detection rate (ADR) was 29%. Endoscopists varied significantly in both their proximal serrated polyp detection rate (6% to 22%; P < .001) and ADR (24% to 40%; P ¼ .001). Median intubation (5–13 minutes) and withdrawal (8–16 minutes) times also differed significantly among endoscopists (P < .001). Older age, male gender, lower Ottawa score, and a longer withdrawal time were correlated with a higher ADR. Proximal serrated polyp detection rate was associated with intubation and withdrawal times as well as butylscopolamine use in univariate analysis. After multivariable analysis, which included patient- and colonoscopy-related factors, withdrawal time was the only factor significantly associated with the proximal serrated polyp detection rate. Thus, the authors conclude that a longer withdrawal time was associated with better proximal serrated polyp detection. Comment. The authors of this study observed that a higher proximal serrated polyp detection rate was
September 2013
associated with a longer withdrawal time among 5 colonoscopists. Differences in endoscopist withdrawal time might account for the observed proximal serrated polyp detection rate variation in recent studies which could not account for this factor (Clin Gastroenterol Hepatol 2011;9:42–46). The results of the current study are also important because they demonstrate that a higher proximal serrated polyp detection rate can be potentially achieved through the use of a longer colonoscopy withdrawal time. Liang et al also observed a correlation between longer withdrawal time and serrated detection rate in colonoscopies performed by 6 colorectal surgeons (Colorectal Dis 2012;14:1323–1327). However, the current study has several aspects that improve on the design of this and previous studies and thus contribute to current knowledge regarding serrated polyp detection. Whereas the study by Liang et al was retrospective, the current study is prospective. A benefit of this design is that it allowed the investigators to instruct the participating endoscopists to remove all of the observed polyps prior to study initiation. This removed the possibility that an endoscopist selectively removed polyps perhaps owing to an ability to discriminate, in real time, adenomas from serrated polyps. The prospective design also allowed these investigators to collect colon preparation data by using a validated score. This is a potential confounding factor that was not collected in previous studies examining serrated polyp detection (Clin Gastroenterol Hepatol 2011;9:42–46; Am J Gastroenterol 2010;105:2656–2664; Gastrointest Endosc 2012;75:515–520). Interestingly, the Ottawa score for bowel preparation correlated with adenoma but not proximal serrated polyp detection. To the authors’ credit, they repeated the multivariable analysis with proximal bowel score alone and observed similar results. The authors postulated that perhaps excess stool might be adherent to the mucous cap in patients with an inadequate colon preparation. This adherent stool combined with an increase in washing might allow for better detection of serrated polyps. The Liang study examined all serrated lesions, whereas this study focused on proximal lesions, which may be more important given a recent expert panel’s recommendation regarding management of these lesions (Am J Gastroenterol 2012;107:1315–1329). The current study also utilized only gastroenterologists. This is important, because endoscopist training has been shown to be an important predictor of interval cancers with gastroenterologists having the lowest rates (Clin Gastroenterol Hepatol 2010;8:275–279; Am J Gastroenterol 2010;105:663–673). With the use of all gastroenterologists, the current study eliminates training variation as a potential confounder. The authors collected many endoscopic factors that might affect adenoma and serrated polyp detection, including intubation and withdrawal times, technical aspects of the colonoscopes, Gloucester discomfort scale, and timing of the examination. There are a few other
SELECTED SUMMARIES 685
variables that might impact serrated polyp detection. These procedures were performed at academic centers, but no information was provided regarding the participation of gastroenterology trainee fellows. Many studies have shown that ADR increases with fellow involvement (Clin Gastroenterol Hepatol 2010;8:439–442; Am J Gastroenterol 2008;103:2841–2846), but the impact on serrated detection is unknown. The authors accounted for a few patient-related factors such as age and gender in their analysis. However, other risk factors associated with serrated polyps, including smoking, obesity, and diabetes, were not included (J Clin Gastroenterol 2011;45:694–699). Differences in these characteristics among patients examined by the 5 endoscopists might explain the observed variation in proximal serrated polyp detection rate. The most important limitation of this study as stated by the authors is that there are only 5 participating endoscopists in this study. Adequate detection of polyps is likely a result of the attention and training of those performing the procedure. Previous investigators have demonstrated the powerful effect of endoscopist on adenoma (Am J Gastroenterol 2007;102:856–861) and proximal serrated polyp detection (Clin Gastroenterol Hepatol 2011;9:42–46). Endoscopists can differ in many important factors including their assessment of colon preparation (Endoscopy 2006;38:456–460). Given the small numbers of endoscopists, we are limited in conclusions that can be made regarding endoscopist characteristics and serrated polyp detection rates. However, there are some interesting observations regarding the performance of the study endoscopists and the possible impact on the results. The most senior gastroenterologist performed nearly one half of all the study colonoscopies (653/1354; 48%). This endoscopist had the lowest ADR and proximal serrated polyp detection rate as well and reduced the overall study ADR and PSPDR by 25% and 66%, respectively. One would expect colonoscopists with the highest ADR to also have the highest proximal serrated polyp detection rate. However, the endoscopist with the highest proximal serrated polyp detection rate was third in adenoma detection, and the endoscopist with the highest ADR was fourth in proximal serrated polyp detection rate. Thus, it is not surprising that there was no correlation observed between ADR and proximal serrated polyp detection rate in the current study (calculated Pearson correlation coefficient, 0.64). This is much lower compared to the studies by Kahi (r ¼ 0.86) and Liang et al (r ¼ 0.85). In addition, the correlation between withdrawal time and ADR in this study was much lower (r ¼ 0.57) compared with that for withdrawal time and proximal serrated polyp detection rate (r ¼ 0.86). Again, the small numbers may preclude any definite conclusions. However, are these findings unique to this study or does adenoma detection require different skills than serrated polyp detection? A subanalysis examining proximal adenomas might have
686
SELECTED SUMMARIES
GASTROENTEROLOGY Vol. 145, No. 3
been useful in determining if this observation was related to anatomic location. Finally, regarding the overall findings, the average proximal serrated polyp detection rate in the current study (12%; range, 6%–22%) is similar to the detection rate in the study by Kahi et al (average 13%; range, 1%–18%). However, the average ADR is slightly lower in the current study (29%) compared with the Indiana study (38%). As stated, this could be owing to one endoscopist’s data “skewing the results.” Overall, the results are well within the suggested proximal serrated polyp detection rate of 5% for a corresponding ADR of 20%. Of note, all of the endoscopists have a median withdrawal time of 8 minutes, which is longer than current minimum recommendation for average withdrawal time (Am J Gastroenterol 2009;104:739–750). These withdrawal times along with the overall high ADR and proximal serrated polyp detection rate provide the reader with important reassurance that the colonoscopies in this study were performed with great care. In conclusion, the current study demonstrates that proximal serrated polyp detection rate, like ADR, varies among endoscopists. Furthermore, proximal serrated polyp detection rate, like ADR, is strongly correlated with the withdrawal time. A major strength of this study is that these investigators demonstrated this correlation after controlling for important patient factors including age and gender, as well as procedure factors such as bowel preparation. Clearly, spending more time looking in the colon increases the yield of polyp detection, either adenomatous or serrated. However, there are still unanswered questions. Unlike the 20% recommendation for ADR, there is no current “standard” for proximal serrated polyp detection rate that has been validated longitudinally. Another unknown is the optimal withdrawal time that endoscopists should “shoot for” to achieve this desired proximal serrated polyp detection rate. A minimum 6 minutes average withdrawal time is recommended for achieving an acceptable ADR, but does this recommendation need to be increased to achieve the “standard” proximal serrated polyp detection rate? Data from this study suggest that a withdrawal time of 8 minutes would be more than adequate to achieve the standard proximal serrated polyp detection rate of 5% in screening colonoscopy as recommended by Kahi et al. However, more studies are needed to determine the standard for proximal serrated polyp detection rate as well as the optimal minimum withdrawal time. TARUN RUSTAGI Section of Digestive Diseases Yale University School of Medicine New Haven, Connecticut JOSEPH C. ANDERSON Department of Veterans Affairs Medical Center White River Junction, Vermont and The Geisel School of Medicine at Dartmouth Medical Hanover, New Hampshire
LANDSCAPE OF GENETIC ABERRATIONS DETECTED IN HUMAN COLORECTAL CANCERS The Cancer Genome Atlas Network. Comprehensive molecular characterization of human colon and rectal cancer. Nature 2012;487:330–337. The Cancer Genome Atlas Project aimed to comprehensively profile genomic changes in many human cancer types. The project first targeted glioblastoma multiforme, lung cancer, and ovarian cancer, and in 2009 expanded to >20 different types of cancer. The results for glioblastoma multiforme and ovarian cancer have been so far published. To reveal the genetic aberrations accumulated in colorectal cancers, in their recently published paper in the Nature, researchers of the Cancer Genome Atlas Network conducted comprehensive multidimensional analyses, including exome sequence, DNA copy number, promoter methylation, and messenger RNA and microRNA expression in 276 samples of human colorectal carcinomas (CRC) as well as low-depth-of-coverage whole-genome sequencing in 97 CRC samples. Through extensive screening and subsequent validation experiments, they demonstrated that approximately 16% of the human CRC possesses a mutation rate of >12/106 bases, which they designated hypermutated CRC. Interestingly, three quarters of hypermutated CRC had high levels of microsatellite instability (MSI), and many hypermutated CRCs also showed CpG island methylator phenotype and/or mismatch-repair genes MLH1 methylation. The remaining one fourth of hypermutated CRC had somatic mutations in one or more mismatch repair genes or polymerase ε aberrations, and the mutation rate was >100/ 106 bases. On the other hand, non-hypermutated CRC had mutations not only in the well-known tumor-related genes, such as APC, TP53, KRAS, PIK3CA, SMAD4, but also in several other genes, including SMAD2, CTNNB1, FAM123B, SOX9, and ARID1A. Interestingly, TP53 and APC were significantly less mutated in hypermutated CRC than in non-hypermutated CRC. By contrast, BRAF (V600E), which was rarely mutated in non-hypermutated CRC, had a high mutation rate in hypermutated CRC. They deduced that these findings indicated different sequences of genetic events between hypermutated and non-hypermutated tumors. One thing to be noted is that although colon cancers differ from rectal cancers anatomically, they have very similar genomic alteration patterns, especially in nonhypermutated cancer. As for the biologic functions of the identified mutated genes, FAM123B, also known as WTX, is an X-linked negative regulator of WNT signaling, and SOX9 is related to differentiation in the intestinal stem cell niche. ARID1A is involved in chromatin remodeling, and mutations of ARID1A were recently reported in various types of gastrointestinal tumors, including gastric and liver cancers. This analysis also showed that IGF2 is among the most frequently overexpressed or amplified genes. IGF2
SELECTED SUMMARIES
on this topic has been limited by the challenges in obtaining the detailed, high-quality data necessary to build such models. In the future, investigators should consider using data collected from polyp prevention studies to derive and validate a more robust risk model for advanced colorectal neoplasia. Furthermore, the US MultiSociety Task Force should strongly consider the use of simulation models to inform its guideline development. Such an approach has been embraced by the US Preventive Services Task Force, which utilized data from the National Cancer Institute Cancer Intervention and Surveillance Modeling Network to inform its 2008 CRC screening guideline. Simulation models can be used to address clinical questions that are difficult to answer with empiric data, such as the optimal age at which to discontinue post-polypectomy surveillance and the best way to use serial endoscopic data over time. By combining data from clinical trials and simulation models, we can provide clinicians with better tools to efficiently target care to individual patients. SAMEER D. SAINI VA Center for Clinical Management Research VA Ann Arbor Healthcare System and Division of Gastroenterology and Hepatology University of Michigan Medical School Ann Arbor, Michigan
ENDOSCOPIST–RELATED FACTORS ASSOCIATED WITH PROXIMAL SERRATED POLYP DETECTION de Wijkerslooth TR, Stoop EM, et al. Differences in proximal serrated polyp detection among endoscopists are associated with variability in withdrawal time. Gastrointest Endosc 2013;77:617–623. Proximal serrated polyps have attracted more attention based on their premalignant potential and association with synchronous and metachronous lesions (Gastroenterology 2010;139:1497–1502). In addition, interval cancers, believed to be a major limitation of colonoscopy in the proximal colon (Gastroenterology 2007;132:96–102), have been attributed to the serrated pathway. Lesions in this pathway and interval cancers share a common proximal location as well as common molecular mutations (Am J Gastroenterol 2010;105:1189–1195). Detection and removal of conventional adenomas has been well studied with much emphasis focused on patient-, procedure-, and endoscopist-related factors. Prior work examining these factors has led to the development of quality measures intended to improve the performance of colonoscopy in preventing colorectal cancer (N Engl J Med 2006;355:2533–2541; N Engl J Med 2010;362:1795–1803). Similar factors and measures are being evaluated for serrated polyps, particularly for the clinically important proximal lesions. These measures are important in light of a recent study that demonstrated that endoscopists are
GASTROENTEROLOGY Vol. 145, No. 3
better at detecting and removing proximal advanced adenomas than proximal serrated polyps (Am J Gastroenterol 2012;107:1213–1219). A recent study by de Wijkerslooth et al examined the impact of patient and endoscopist factors on proximal serrated polyp detection (Gastrointest Endosc 2013;77: 617–623). This well-executed study was performed within a large, prospective study of consecutive consenting patients undergoing screening colonoscopy as part of a trial comparing colonoscopy to computed tomographic colonography. Patients with a personal history of colorectal neoplasia or inflammatory bowel disease and those with a full colon examination in the previous 5 years were excluded. The main outcome for this analysis was the detection of one or more proximal serrated polyps in a per-patient analysis. Dedicated research staff recorded a number of colonoscopy variables, including cecal intubation time, withdrawal time, endoscopist, field of view (140 or 170 ), definition of the colonoscope (high or low), use of a plastic colonoscope cap, timing of the colonoscopy (morning/afternoon), and use of the antispasmodic butylscopolamine. Quality of bowel preparation was assessed using the well-validated Ottawa bowel preparation score and patient comfort by the Gloucester score. All of the 1354 colonoscopies were performed at 2 academic medical centers by 5 gastroenterologists with 6 years of endoscopy experience. In addition, data were culled from only those examinations that were performed by gastroenterologists with 1000 career and 50 studyrelated colonoscopies. The endoscopists who were selected had performed most of the study endoscopies (1354/1407; 96%). Withdrawal time was recorded with a stopwatch and was 6 minutes after subtracting the time needed for polypectomies. The median net withdrawal time was 10 minutes (interquartile range, 8–15). Proximal serrated polyps were detected in 167 patients for a proximal serrated polyp detection rate of 12%. The corresponding adenoma detection rate (ADR) was 29%. Endoscopists varied significantly in both their proximal serrated polyp detection rate (6% to 22%; P < .001) and ADR (24% to 40%; P ¼ .001). Median intubation (5–13 minutes) and withdrawal (8–16 minutes) times also differed significantly among endoscopists (P < .001). Older age, male gender, lower Ottawa score, and a longer withdrawal time were correlated with a higher ADR. Proximal serrated polyp detection rate was associated with intubation and withdrawal times as well as butylscopolamine use in univariate analysis. After multivariable analysis, which included patient- and colonoscopy-related factors, withdrawal time was the only factor significantly associated with the proximal serrated polyp detection rate. Thus, the authors conclude that a longer withdrawal time was associated with better proximal serrated polyp detection. Comment. The authors of this study observed that a higher proximal serrated polyp detection rate was
September 2013
associated with a longer withdrawal time among 5 colonoscopists. Differences in endoscopist withdrawal time might account for the observed proximal serrated polyp detection rate variation in recent studies which could not account for this factor (Clin Gastroenterol Hepatol 2011;9:42–46). The results of the current study are also important because they demonstrate that a higher proximal serrated polyp detection rate can be potentially achieved through the use of a longer colonoscopy withdrawal time. Liang et al also observed a correlation between longer withdrawal time and serrated detection rate in colonoscopies performed by 6 colorectal surgeons (Colorectal Dis 2012;14:1323–1327). However, the current study has several aspects that improve on the design of this and previous studies and thus contribute to current knowledge regarding serrated polyp detection. Whereas the study by Liang et al was retrospective, the current study is prospective. A benefit of this design is that it allowed the investigators to instruct the participating endoscopists to remove all of the observed polyps prior to study initiation. This removed the possibility that an endoscopist selectively removed polyps perhaps owing to an ability to discriminate, in real time, adenomas from serrated polyps. The prospective design also allowed these investigators to collect colon preparation data by using a validated score. This is a potential confounding factor that was not collected in previous studies examining serrated polyp detection (Clin Gastroenterol Hepatol 2011;9:42–46; Am J Gastroenterol 2010;105:2656–2664; Gastrointest Endosc 2012;75:515–520). Interestingly, the Ottawa score for bowel preparation correlated with adenoma but not proximal serrated polyp detection. To the authors’ credit, they repeated the multivariable analysis with proximal bowel score alone and observed similar results. The authors postulated that perhaps excess stool might be adherent to the mucous cap in patients with an inadequate colon preparation. This adherent stool combined with an increase in washing might allow for better detection of serrated polyps. The Liang study examined all serrated lesions, whereas this study focused on proximal lesions, which may be more important given a recent expert panel’s recommendation regarding management of these lesions (Am J Gastroenterol 2012;107:1315–1329). The current study also utilized only gastroenterologists. This is important, because endoscopist training has been shown to be an important predictor of interval cancers with gastroenterologists having the lowest rates (Clin Gastroenterol Hepatol 2010;8:275–279; Am J Gastroenterol 2010;105:663–673). With the use of all gastroenterologists, the current study eliminates training variation as a potential confounder. The authors collected many endoscopic factors that might affect adenoma and serrated polyp detection, including intubation and withdrawal times, technical aspects of the colonoscopes, Gloucester discomfort scale, and timing of the examination. There are a few other
SELECTED SUMMARIES 685
variables that might impact serrated polyp detection. These procedures were performed at academic centers, but no information was provided regarding the participation of gastroenterology trainee fellows. Many studies have shown that ADR increases with fellow involvement (Clin Gastroenterol Hepatol 2010;8:439–442; Am J Gastroenterol 2008;103:2841–2846), but the impact on serrated detection is unknown. The authors accounted for a few patient-related factors such as age and gender in their analysis. However, other risk factors associated with serrated polyps, including smoking, obesity, and diabetes, were not included (J Clin Gastroenterol 2011;45:694–699). Differences in these characteristics among patients examined by the 5 endoscopists might explain the observed variation in proximal serrated polyp detection rate. The most important limitation of this study as stated by the authors is that there are only 5 participating endoscopists in this study. Adequate detection of polyps is likely a result of the attention and training of those performing the procedure. Previous investigators have demonstrated the powerful effect of endoscopist on adenoma (Am J Gastroenterol 2007;102:856–861) and proximal serrated polyp detection (Clin Gastroenterol Hepatol 2011;9:42–46). Endoscopists can differ in many important factors including their assessment of colon preparation (Endoscopy 2006;38:456–460). Given the small numbers of endoscopists, we are limited in conclusions that can be made regarding endoscopist characteristics and serrated polyp detection rates. However, there are some interesting observations regarding the performance of the study endoscopists and the possible impact on the results. The most senior gastroenterologist performed nearly one half of all the study colonoscopies (653/1354; 48%). This endoscopist had the lowest ADR and proximal serrated polyp detection rate as well and reduced the overall study ADR and PSPDR by 25% and 66%, respectively. One would expect colonoscopists with the highest ADR to also have the highest proximal serrated polyp detection rate. However, the endoscopist with the highest proximal serrated polyp detection rate was third in adenoma detection, and the endoscopist with the highest ADR was fourth in proximal serrated polyp detection rate. Thus, it is not surprising that there was no correlation observed between ADR and proximal serrated polyp detection rate in the current study (calculated Pearson correlation coefficient, 0.64). This is much lower compared to the studies by Kahi (r ¼ 0.86) and Liang et al (r ¼ 0.85). In addition, the correlation between withdrawal time and ADR in this study was much lower (r ¼ 0.57) compared with that for withdrawal time and proximal serrated polyp detection rate (r ¼ 0.86). Again, the small numbers may preclude any definite conclusions. However, are these findings unique to this study or does adenoma detection require different skills than serrated polyp detection? A subanalysis examining proximal adenomas might have
686
SELECTED SUMMARIES
GASTROENTEROLOGY Vol. 145, No. 3
been useful in determining if this observation was related to anatomic location. Finally, regarding the overall findings, the average proximal serrated polyp detection rate in the current study (12%; range, 6%–22%) is similar to the detection rate in the study by Kahi et al (average 13%; range, 1%–18%). However, the average ADR is slightly lower in the current study (29%) compared with the Indiana study (38%). As stated, this could be owing to one endoscopist’s data “skewing the results.” Overall, the results are well within the suggested proximal serrated polyp detection rate of 5% for a corresponding ADR of 20%. Of note, all of the endoscopists have a median withdrawal time of 8 minutes, which is longer than current minimum recommendation for average withdrawal time (Am J Gastroenterol 2009;104:739–750). These withdrawal times along with the overall high ADR and proximal serrated polyp detection rate provide the reader with important reassurance that the colonoscopies in this study were performed with great care. In conclusion, the current study demonstrates that proximal serrated polyp detection rate, like ADR, varies among endoscopists. Furthermore, proximal serrated polyp detection rate, like ADR, is strongly correlated with the withdrawal time. A major strength of this study is that these investigators demonstrated this correlation after controlling for important patient factors including age and gender, as well as procedure factors such as bowel preparation. Clearly, spending more time looking in the colon increases the yield of polyp detection, either adenomatous or serrated. However, there are still unanswered questions. Unlike the 20% recommendation for ADR, there is no current “standard” for proximal serrated polyp detection rate that has been validated longitudinally. Another unknown is the optimal withdrawal time that endoscopists should “shoot for” to achieve this desired proximal serrated polyp detection rate. A minimum 6 minutes average withdrawal time is recommended for achieving an acceptable ADR, but does this recommendation need to be increased to achieve the “standard” proximal serrated polyp detection rate? Data from this study suggest that a withdrawal time of 8 minutes would be more than adequate to achieve the standard proximal serrated polyp detection rate of 5% in screening colonoscopy as recommended by Kahi et al. However, more studies are needed to determine the standard for proximal serrated polyp detection rate as well as the optimal minimum withdrawal time. TARUN RUSTAGI Section of Digestive Diseases Yale University School of Medicine New Haven, Connecticut JOSEPH C. ANDERSON Department of Veterans Affairs Medical Center White River Junction, Vermont and The Geisel School of Medicine at Dartmouth Medical Hanover, New Hampshire
LANDSCAPE OF GENETIC ABERRATIONS DETECTED IN HUMAN COLORECTAL CANCERS The Cancer Genome Atlas Network. Comprehensive molecular characterization of human colon and rectal cancer. Nature 2012;487:330–337. The Cancer Genome Atlas Project aimed to comprehensively profile genomic changes in many human cancer types. The project first targeted glioblastoma multiforme, lung cancer, and ovarian cancer, and in 2009 expanded to >20 different types of cancer. The results for glioblastoma multiforme and ovarian cancer have been so far published. To reveal the genetic aberrations accumulated in colorectal cancers, in their recently published paper in the Nature, researchers of the Cancer Genome Atlas Network conducted comprehensive multidimensional analyses, including exome sequence, DNA copy number, promoter methylation, and messenger RNA and microRNA expression in 276 samples of human colorectal carcinomas (CRC) as well as low-depth-of-coverage whole-genome sequencing in 97 CRC samples. Through extensive screening and subsequent validation experiments, they demonstrated that approximately 16% of the human CRC possesses a mutation rate of >12/106 bases, which they designated hypermutated CRC. Interestingly, three quarters of hypermutated CRC had high levels of microsatellite instability (MSI), and many hypermutated CRCs also showed CpG island methylator phenotype and/or mismatch-repair genes MLH1 methylation. The remaining one fourth of hypermutated CRC had somatic mutations in one or more mismatch repair genes or polymerase ε aberrations, and the mutation rate was >100/ 106 bases. On the other hand, non-hypermutated CRC had mutations not only in the well-known tumor-related genes, such as APC, TP53, KRAS, PIK3CA, SMAD4, but also in several other genes, including SMAD2, CTNNB1, FAM123B, SOX9, and ARID1A. Interestingly, TP53 and APC were significantly less mutated in hypermutated CRC than in non-hypermutated CRC. By contrast, BRAF (V600E), which was rarely mutated in non-hypermutated CRC, had a high mutation rate in hypermutated CRC. They deduced that these findings indicated different sequences of genetic events between hypermutated and non-hypermutated tumors. One thing to be noted is that although colon cancers differ from rectal cancers anatomically, they have very similar genomic alteration patterns, especially in nonhypermutated cancer. As for the biologic functions of the identified mutated genes, FAM123B, also known as WTX, is an X-linked negative regulator of WNT signaling, and SOX9 is related to differentiation in the intestinal stem cell niche. ARID1A is involved in chromatin remodeling, and mutations of ARID1A were recently reported in various types of gastrointestinal tumors, including gastric and liver cancers. This analysis also showed that IGF2 is among the most frequently overexpressed or amplified genes. IGF2