A gene expression signature of genetic instability in colon cancer

Genetic instability plays a central role in the development and progression of human cancer. Two major classes of genetic instability, microsatellite instability (MSI) and chromosome instability (microsatellite stable; MSS), are best understood in the context of colon cancer, where MSI tumors represent approximately 15% of cases, and compared with MSS tumors, more often arise in the proximal colon and display favorable clinical outcome. To further explore molecular differences, we profiled gene expression in a set of 18 colon cancer cell lines using cDNA microarrays representing approximately 21,000 different genes. Supervised analysis identified a robust expression signature distinguishing MSI and MSS samples. As few as eight genes predicted with high accuracy the underlying genetic instability in the original and in three independent sample sets, comprising 13 colon cancer cell lines, 61 colorectal tumors, and 87 gastric tumors. Notably, the MSI signature was retained despite genetically correcting the underlying instability, suggesting the signature reflects a legacy of the tumor having arisen from MSI, rather than sensing the ongoing state of MSI. Our findings support a model in which MSI and MSS preferentially target different genes and pathways in cancer. Further, among the MSI signature genes, our findings implicate a role of elevated metallothionein expression in the clinical behavior of MSI cancers.     

Homozygosity mapping with SNP arrays confirms 3p21 as a recessive locus for gray platelet syndrome and narrows the interval significantly

Gray platelet syndrome (GPS) is an inherited bleeding disorder characterized by thrombocytopenia and the absence of α-granules in platelets. Patients with GPS present with mild to moderate bleeding and many develop myelofibrosis. The genetic cause of GPS is unknown. We present 2 Native American families with a total of 5 affected persons and a single affected patient of Pakistani origin in which GPS appears to be inherited in an autosomal recessive manner. Homozygosity mapping using the Affymetrix 6.0 chips demonstrates that all 6 GPS-affected persons studied are homozygous for a 1.7-Mb region in 3p21. Linkage analysis confirmed the region with a logarithm of the odds score of 2.7. Data from our families enabled us to significantly decrease the size of the critical region for GPS from the previously reported 9.4-Mb region at 3p21.     

The quality of screening colonoscopies in an office-based endoscopy clinic

BACKGROUND:

Wait times for hospital screening colonoscopy have increased dramatically in recent years, resulting in an increase in patient referrals to office-based endoscopy clinics. There is no formal regulation of office endoscopy, and it has been suggested that the quality of service in some office locations may be inferior to hospital procedures.

OBJECTIVE:

To compare the quality of office-based screening colonos-copies at a clinic in Oakville, Ontario, with published benchmarks for cecal intubation, withdrawal times, polyp detection, adenoma detection, cancer detection and patient complications.

METHODS:

Demographic information on consecutive patients and colonoscopy reports by all nine gastroenterologists at the Oakville Endoscopy Centre between August 2006 and December 2007 were prospectively obtained.

RESULTS:

A total of 3741 colonoscopies were analyzed. The mean age of patients was 57.1 years and 51.9% were women. The cecal intubation rate was 98.98% with an average withdrawal time of 9.75 min. A total of 3857 polyps were retrieved from 1725 patients (46.11%), and 1721 adenomas were detected in 953 patients (25.47%). A total of 126 patients (3.37%) had advanced polyps and 18 (0.48%) were diagnosed with colon cancer. One patient (0.027%) had a colonic perforation and two patients had postpolypectomy bleeding (0.053%). These results meet or exceed published benchmarks for quality colonoscopy.

CONCLUSIONS:

The Oakville Endoscopy Centre data demonstrate that office-based colonoscopies, performed by well-trained physicians using adequate sedation and hospital-grade equipment, result in outcomes at least equal to or better than those of published academic/community hospital practices and are therefore a viable option for the future of screening colonoscopy in Canada.     

No telomere shortening in marrow stroma from patients with MDS

Telomere shortening with age may lead to genomic instability and an increased risk of cancer. Given the role of the microenvironment in the pathophysiology of the myelodysplastic syndrome (MDS), primarily a disease of older age, we determined telomere length in primary cultured marrow stroma cells using quantitative fluorescent in situ hybridization (qFISH) and quantitative polymerase chain reaction (qPCR). qFISH showed comparable rates of decrease in telomere length with age in MDS patients and age-matched healthy controls. Telomere length assessment by qPCR showed similar results. These findings suggest a lack of significant differences between MDS patients and healthy controls in terms of telomere stability in marrow stroma in contrast to that observed in hematopoietic cells. In conclusion, this demonstrates that, although MDS stroma cells and hematopoietic cells share the same microenvironment, the stromal cells do not share the processes that contribute to accelerated telomere attrition, suggesting that stromal cell proliferative potential is not limiting in MDS.     

Human intestinal capillariasis (Capillaria philippinensis) in Taiwan

Capillaria philippinensis was first reported in 1963 in the Philippines. Major outbreaks have occurred in the Philippines and Thailand. This article reviews the known 30 intestinal capillariasis cases in Taiwan from January 1983 to December 2003. The infected cases were diagnosed each year with the exception of 1984 and 2002, making Taiwan a Capillaria-prevalent area. Two Taiwanese aboriginal tribes, the Ami and Paiwan, presented a high prevalence. The males and elderly also had a high infection rate. Nine cases were diagnosed by histopathological biopsied specimens. About half of the 30 cases denied having consumed raw or undercooked fish. All cases recovered to health after receiving medication, with no deaths or recurrences.     

Fructose- and Sorbitol-reduced Diet Improves Mood and Gastrointestinal Disturbances in Fructose Malabsorbers

Background: Fructose malabsorption is characterized by the inability to absorb fructose efficiently. As a consequence fructose reaches the colon where it is broken down by bacteria to short fatty acids, CO₂ and H₂. Bloating, cramps, osmotic diarrhea and other symptoms of irritable bowel syndrome are the consequences and can be seen in about 50% of fructose malabsorbers. We have previously shown that fructose malabsorption is associated with early signs of mental depression and low serum tryptophan concentrations. It was therefore of interest whether a fructose-reduced diet could not only improve gastrointestinal complaints but also depressive signs seen in fructose malabsorbers. Methods: Fifty-three adults (12 males, 41 females), who were identified as fructose malabsorbers according to their breath-H₂ concentrations, filled out a Beck's depression inventory-questionnaire, and a questionnaire with arbitrary scales for measurement of meteorism, stool frequency and quality of life for a 4-week period before dietary intervention and 4 weeks after dietary change as for fructose- and sorbitol-reduced diet. Results: Depression scores were reduced by 65.2% after 4 weeks of diet (P < 0.0001), and there was a significant reduction of meteorism (P < 0.0001) and stool frequency (P < 0.01). Improvement of signs of depression and of meteorism was more pronounced in females than in males. Conclusion: Fructose- and sorbitol-reduced diet in subjects with fructose malabsorption does not only reduce gastrointestinal symptoms but also improves mood and early signs of depression.     

Hypothermia is an independent predictor of mortality in ruptured abdominal aortic aneurysms

Hypothermia is known to significantly increase mortality in trauma patients, but the effect of hypothermia on outcomes in ruptured abdominal aortic aneurysms (RAAA) has not been evaluated. The authors reviewed their experience from 1990 to 1999 in 100 consecutive patients who presented with RAAA and survived at least to the operating room for surgical treatment. There were 70 men and 30 women, with a mean overall age of 74 +/-8 years. Overall mortality was 47%. Univariate ANOVA (analysis of variants) showed significant correlation with mortality for decreased intraoperative temperature, decreased intraoperative systolic blood pressure, increased intraoperative base deficit, increased blood volume transfused, increased crystalloid volume (all p < 0.001); decreased preoperative hemoglobin (p = 0.015); and increased age (p = 0.026). Patient sex, initial preoperative temperature, preoperative systolic blood pressure, and operating room time were not correlated with mortality in the univariate analysis. Using these same clinical variables, multiple logistic regression analysis showed only 2 factors independently correlated with mortality: lowest intraoperative temperature (p = 0.006) and intraoperative base deficit (p = 0.009). The mean lowest temperature for survivors was 35 +/-1 degrees C and for nonsurvivors 33 +/-2 degrees C (p < 0.001). When patients were grouped by lowest intraoperative temperature, those whose temperature was < 32 degrees C (n = 15) had a mortality rate of 91%, whereas patients with a temperature between 32 and 35 degrees C (n = 50) had a mortality rate of 60%. In the group that remained at or > 35 degrees C (n = 35) the mortality rate was only 9%. A nomogram of predicted mortality versus temperature was constructed from these data and showed that for temperatures of 36, 34, and 32 degrees C the predicted mortality was 15%, 49%, and 84%, respectively. The authors conclude that hypothermia is a strong independent contributor to mortality in patients with ruptured abdominal aortic aneurysms and that very aggressive measures to prevent hypothermia are warranted during the resuscitation and treatment of these patients.