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"Brenner, Bruce"
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Aberrant crypt foci as predictors of colorectal neoplasia on repeat colonoscopy
Objective To estimate the risk for colorectal neoplasia detected on repeat colonoscopy in relation to aberrant crypt foci (ACF) frequency reported during the previous baseline examination. Methods From July 2003 until December 2008, patients had a colonoscopy with an ACF study using a magnifying colonoscope. The distal 20 cm section of colon was sprayed with Méthylène Blue to ascertain the ACF frequency, the independent variable. Patients were categorized into low and high ACF count using the median as the cut point. Data collected from consenting patients included age, gender, height, weight, ethnicity, smoking history, family history of colorectal cancer (CRC), and personal history of colorectal neoplasia. A follow-up colonoscopy was performed at an interval as dictated by clinical surveillance guidelines. The main outcome was surveillance detected advanced colorectal neoplasia (SDAN) detected on repeat colonoscopy. Logistic Regression was used to calculate risk of SDAN on repeat colonoscopy in relation to baseline ACF count. Results 74 patients had a baseline ACF exam and a repeat surveillance colonoscopy. The median ACF was six and thus a high ACF count was > 6 ACF and a low ACF count was < 6 ACF. Patients diagnosed with SDAN were more likely to have had a high ACF number at baseline compared to patients without these lesions at follow-up (adjusted odds ratio = 12.27; 95% confidence interval: 2.00-75.25) controlling for age, sex, smoking, history of prior adenoma, family history of colon cancer, obesity, and time interval to surveillance exam. A sub analysis of our results demonstrated that this relationship was observed in 48 patients who were undergoing a surveillance colonoscopy for a previous adenoma and not those receiving surveillance for a family history of neoplasia. Conclusions Increased number of ACF in the distal colorectum was independently associated with substantial risk for future advanced neoplasia. This relationship was observed in patients undergoing surveillance for previous adenomas. Thus, ACF may serve as potential biomarkers in patients with adenomas to help identify patients who may need additional surveillance.
Journal Article
Increased Frequency of Serrated Aberrant Crypt Foci Among Smokers
The American College of Gastroenterology has published guidelines recently that suggest that smokers with a history of >20 pack years may need screening for colorectal cancer (CRC) at an earlier age than non-smokers. Aberrant crypt foci (ACF) may represent important precursors for colorectal neoplasms and potential surrogate biomarkers. Clarifying the role of ACF in relation to known CRC risk factors such as smoking may have important implications for screening as well as our understanding of tobacco use and colorectal carcinogenesis. Our goal was to examine whether smoking at least 20 pack years was associated with an increased frequency of ACF.
We gathered detailed smoking history, personal and family history of CRC, and other epidemiologic data (age, gender, height, weight, ethnicity, and medication use) from 125 patients undergoing routine screening or surveillance colonoscopy. We used a magnifying colonoscope (Olympus Close Focus Colonoscope XCF-Q160ALE, Olympus Corporation, Tokyo, Japan) and examined the distal 20 cm section of colon after staining with 0.5% methylene blue. ACF were counted and characterized histologically. Hyperplastic ACF were further characterized as either serrated or non-serrated.
Smoking at least 20 pack years was associated with an increased likelihood (adjusted odds ratio (OR)=3.45; 95% confidence interval (CI)=1.93-6.18) of having more than the median number of ACF (> or = 15) compared with non-smokers. Similarly, patients with a personal history of advanced neoplasia were more likely (adjusted OR=3.42; 95% CI=1.01-11.67) to have a greater than median number of ACF compared with patients without this diagnosis. Smokers were more likely than non-smokers to have serrated ACF (P=0.002).
Smoking at least 20 pack years seems to be associated with increased number of ACF in the rectum and distal sigmoid, especially those with serrated histology. Our data support ACG guidelines for earlier screening for CRC among smokers and add to our understanding of how colorectal carcinogenesis is related to tobacco use.
Journal Article
Genomic Instability Measured by Inter-(Simple Sequence Repeat) PCR and High-Resolution Microsatellite Instability are Prognostic of Colorectal Carcinoma Survival After Surgical Resection
Background
During the multiyear progression to colorectal cancer, numerous genomic alterations arise in events ranging from single base mutations to gains or losses of entire chromosomes. A single genetic change might not stand out as an independent predictor of outcome. The goal of this study was to determine if more comprehensive measurements of genomic instability provide clinically relevant prognostic information.
Methods
Our study included 65 sporadic colorectal cancer patients diagnosed from 1987 to 1991 with last follow-up ascertained in 2006. We estimated an overall tally of alterations using the genome-wide sampling technique of inter-(simple sequence repeat [SSR]) polymerase chain reaction (PCR), and evaluated its relationship with all-cause survival. We also extended and sensitized the Bethesda criteria for microsatellite instability (MSI), by analyzing 348 microsatellite markers instead of the normal five. We expanded the MSI categories into four levels: MSI stable (MSS), very low-level MSI, moderately low-level MSI, and classical high-level MSI.
Results
Tumors with genomic instability above the median value of 2.6% as measured by inter-SSR PCR, were associated with far greater risk of death compared to tumors with lower levels of genomic instability. Adverse outcome was most pronounced for patients presenting with stage 3 disease. A gradient of increased survival was observed across increasing MSI levels but did not reach statistical significance.
Conclusion
Our findings suggest genomic instabilities quantified by inter-SSR PCR and increased precision in MSI values may be clinically useful tools for estimating prognosis in colorectal cancer.
Journal Article
Number of Aberrant Crypt Foci Associated with Adiposity and IGF1 Bioavailability
Background Dysregulation of the insulin-like growth factor (IGF) system, a common consequence of adiposityinduced insulin resistance, may be a key underlying mechanism linking excess body weight with colon cancer. Evidence has been derived from studies of cancer and polyps. Supporting data about aberrant crypt foci (ACF), putative pre-polyp changes, have been generated only from animal studies to date. Methods We randomly selected 26 patients with sexspecific elevated waist-hip-ratio (WHR) and 26 with normal values from a series of 150 patients seeking routine colonoscopy at the University of Connecticut Health Center. Cross- sectional analyses were performed of ACF number (< 5, ≥5) in relation to total IGF1, IGF-binding protein-3 (IGFBP3), insulin, body mass index (BMI), WHR and waist circumference (WC). Visualized ACF in the 20 cm of the distal colon were counted using advanced endoscopic imaging. Results Patients with ≥ 5 ACF had higher BMI, WHR, and WC compared with patients with ≥ 5 ACF (p = 0.04, p = 0.03, and p = 0.01, respectively). IGFBP3 was reduced (p = 0.02) and IGFl: IGFBP3 molar ratio was greater (p = 0.03) in patients with ≥5 ACF. We did not observe significant associations between ACF number and insulin or total IGF1. Conclusions Our study provides the first report in humans of a possible association of ACF prevalence and IGF1 bioavailability as characterized by IGF1: IGFBP3 molar ratio and IGFBP3 level. More research is needed to determine whether this relationship is varied by ACF features (e.g., size, dysplasia, molecular changes), synchronous cancer and polyps, and is modified by colon cancer risk factors.
Journal Article
Molecular markers in colorectal cancer
Care must be taken with any such studies, at several levels. To begin with, the markers must be where they are intended to be. The study by Zhou and colleagues reports the use of eleven markers on the long arm of chromosome 18, but three are on 18p instead of 18q.11 The SNP marker WIAF-3833, described by Zhou and colleagues as being on chromosome 8p, is on chromosome 16.(11) Second, the results are reported in the aggregate for all markers examined on each chromosomal arm, instead of being reported individually. The assumption that instability does not occur within chromosomal arms for sporadic colon cancer, and that allelic imbalance for a single marker anywhere on a chromosomal arm suffices to establish loss of the entire arm, is unproven and contradicted by recent findings.10,12 Studies with high-resolution ordered Bac microarrays (microarrays created from individual bacterial artificial chromosomes and assembled in a precise order such as to represent the entire human genome) for several other tumours further point to numerous events occurring within tumour-cell genomes and the need to precisely examine particular chromosomal regions, ultimately at the level of the individual gene.12,13 Several genes associated with colon cancer have been described, especially on 18q, and allelic imbalances affecting one such gene would be expected to have consequences differing from those imbalances affecting another.14
Journal Article
Laparoscopic Approach for Gallstone Ileus in Geriatric Patients
We report two patients who presented with small bowel obstruction secondary to gallstones in the ileum. Both patients were geriatric women with multiple comorbidities. The first patient was a 73-year-old woman who presented with a gallstone eroding and obstructing the duodenum (Bouveret's syndrome) secondary to gallbladder cancer with diffuse metastatic spread to the liver. The stone was disimpacted endoscopically using lithotripsy. The patient presented two days later after the stone had migrated downstream into the small bowel causing obstruction requiring surgical intervention. Second patient was an 81-year-old woman who presented with small bowel obstruction caused by a gallbladder stone impacted in the distal ileum. Both patients were managed laparoscopically with a mini laparotomy to extract the affected segment of bowel loop via small incision on the anterior abdominal wall at the port site with enterolithotomy. Both patients were discharged by postoperative day four with no complications. We conclude that, in elderly patients with multiple comorbidities presenting with gallstone ileus, laparoscopic approach provides early recovery with minimal pain.
Journal Article
A Case of Diffuse Metastatic Melanoma With Massive Spontaneous Hemoperitoneum
The incidence rate for melanoma continues to rise in the USA. The majority of melanoma cases are detected at an early stage and are amenable to surgical excision. Advanced melanoma with diffuse intraabdominal metastasis is rare. We present a case of a 50-year-old female with no known primary or history of melanoma who presented with massive intraabdominal bleeding secondary to diffuse metastatic melanoma with peritoneal implants. Diagnosing metastatic melanoma could be challenging. Clinicians should be aware of hemoperitoneum or peritoneal carcinomatosis as potential manifestations of malignant melanoma to expedite appropriate management.
Journal Article