Jan J. Koornstra

Increased colorectal cancer risk during follow-up in patients with hyperplastic polyposis syndrome: a multicentre cohort study

Background and aims Patients with hyperplastic polyposis syndrome (HPS) receive endoscopic surveillance to prevent malignant progression of polyps. However, the optimal treatment and surveillance protocol for these patients is unknown. The aim of this study was to describe the clinical and pathological features of a large HPS cohort during multiple years of endoscopic surveillance. Methods Databases were searched for patients with HPS, who were analysed retrospectively. Endoscopy reports and histopathology reports were collected to evaluate frequency of endoscopic surveillance and to obtain information regarding polyp and the presence of colorectal cancer (CRC). Results In 77 patients with HPS, 1984 polyps were identified during a mean follow-up period of 5.6 years (range: 0.5–26.6). In 27 (35%) patients CRC was detected of which 22 (28.5%) at initial endoscopy. CRC was detected during surveillance in five patients (cumulative incidence: 6.5%) after a median follow-up time of 1.3 years and a median interval of 11 months. Of these interval CRCs, 4/5 were detected in diminutive serrated polyps (range: 4–16 mm). The cumulative risk of CRC under surveillance was 7% at 5 years. At multivariate logistic regression, an increasing number of hyperplastic polyps (OR 1.05, p=0.013) and serrated adenomas (OR 1.09, p=0.048) was significantly associated with CRC presence. Conclusions HPS patients undergoing endoscopic surveillance have an increased CRC risk. The number of serrated polyps is positively correlated with the presence of CRC in HPS, thus supporting a ‘serrated pathway’ to CRC. To prevent malignant progression, adequate detection and removal of all polyps seems advisable. If this is not feasible, surgical resection should be considered.

Increased risk of fundic gland polyps during long-term proton pump inhibitor therapy

It is controversial whether proton pump inhibitor use leads to fundic gland polyp development.

One to 2-year surveillance intervals reduce risk of colorectal cancer in families with Lynch syndrome

BACKGROUND & AIMS Two percent to 4% of all cases of colorectal cancer (CRC) are associated with Lynch syndrome. Dominant clustering of CRC (non-Lynch syndrome) accounts for 1%-3% of the cases. Because carcinogenesis is accelerated in Lynch syndrome, an intensive colonoscopic surveillance program has been recommended since 1995. The aim of the study was to evaluate the effectiveness of this program. METHODS The study included 205 Lynch syndrome families with identified mutations in one of the mismatch repair genes (745 mutation carriers). We also analyzed data from non-Lynch syndrome families (46 families, 344 relatives). Patients were observed from January 1, 1995, until January 1, 2009. End points of the study were CRC or date of the last colonoscopy. RESULTS After a mean follow-up of 7.2 years, 33 patients developed CRC under surveillance. The cumulative risk of CRC was 6% after the 10-year follow-up period. The risk of CRC was higher in carriers older than 40 years and in carriers of MLH1 and MSH2 mutations. After a mean follow-up of 7.0 years, 6 cases of CRC were detected among non-Lynch syndrome families. The risk of CRC was significantly higher among families with Lynch syndrome, compared with those without. CONCLUSIONS With surveillance intervals of 1-2 years, members of families with Lynch syndrome have a lower risk of developing CRC than with surveillance intervals of 2-3 years. Because of the low risk of CRC in non-Lynch syndrome families, a less intensive surveillance protocol can be recommended.

Tissue Distribution of the Death Ligand TRAIL and Its Receptors

Recombinant human (rh) TNF-related apoptosis-inducing ligand (TRAIL) harbors potential as an anticancer agent. RhTRAIL induces apoptosis via the TRAIL receptors TRAIL-R1 and TRAIL-R2 in tumors and is non-toxic to nonhuman primates. Because limited data are available about TRAIL receptor distribution, we performed an immunohistochemical (IHC) analysis of the expression of TRAIL-R1, TRAIL-R2, the anti-apoptotic TRAIL receptor TRAIL-R3, and TRAIL in normal human and chimpanzee tissues. In humans, hepatocytes stained positive for TRAIL and TRAIL receptors and bile duct epithelium for TRAIL, TRAIL-R1, and TRAIL-R3. In brains, neurons expressed TRAIL-R1, TRAIL-R2, TRAIL-R3 but no TRAIL. In kidneys, TRAIL-R3 was negative, tubuli contorti expressed TRAIL-R1, TRAIL-R2, and TRAIL, and cells in Henles loop expressed only TRAIL-R2. Heart myocytes showed positivity for all proteins studied. In colon, TRAIL-R1, TRAIL-R2, and TRAIL were present. Germ and Leydig cells were positive for all proteins studied. Endothelium in liver, heart, kidney, and testis lacked TRAIL-R1 and TRAIL-R2. In alveolar septa and bronchial epithelium TRAIL-R2 was expressed, brain vascular endothelium expressed TRAIL-R2 and TRAIL-R3, and in heart vascular endothelium only TRAIL-R3 was present. Only a few differences were observed between human and chimpanzee liver, brain, and kidney. In contrast to human, chimpanzee bile duct epithelium lacked TRAIL, TRAIL-R1, and TRAIL-R3, lung and colon showed no TRAIL or its receptors, TRAIL-R3 was absent in germ and Leydig cells, and vascular endothelium showed only TRAIL-R2 expression in the brain. In conclusion, comparable expression of TRAIL and TRAIL receptors was observed in human and chimpanzee tissues. Lack of liver toxicity in chimpanzees after rhTRAIL administration despite TRAIL-R1 and TRAIL-R2 expression is reassuring for rhTRAIL application in humans. (J Histochem Cytochem 52:821–831, 2004)

Non-steroidal anti-inflammatory drugs and molecular carcinogenesis of colorectal carcinomas

CONTEXT Colorectal cancer is the second most common cause of cancer-related mortality in the west. The high incidence and mortality make effective prevention an important public-health and economic issue. Non-steroidal anti-inflammatory drugs (NSAIDs) can inhibit colorectal carcinogenesis and are among the few agents known to be chemopreventive. Randomised trials have shown that sulindac and celecoxib suppress the development of adenomatous polyps and cause regression of existing polyps in patients with familial adenomatous polyposis (FAP), who have a high risk for developing colorectal cancer. The mechanisms by which NSAIDs inhibit neoplastic growth are not fully known. STARTING POINT Two recently reported randomised placebo-controlled trials show a chemopreventive effect of aspirin in populations other than those with FAP (Robert Sandler and colleagues, N Engl J Med 2003; 348: 883-90; John Baron and colleagues, N Engl J Med 2003; 348: 891-99). In the Sandler study 635 patients with colorectal cancer were randomised to receive 325 mg aspirin or placebo daily. After a follow-up of around 31 months, the mean number of adenomas was lower in the aspirin group than in the placebo group, corresponding to a relative risk of any recurrent adenoma in the aspirin group of 0.65. In the Baron study 1121 patients with colorectal adenomas were assigned to receive 81 or 325 mg aspirin or placebo daily. Follow-up colonoscopy, 32 months after the index endoscopy, showed an incidence of one or more adenomas of 38% in the 81 mg aspirin group, 45% in the 325 mg aspirin group, and 47% in the placebo group. Together, these studies indicate a moderate chemopreventive effect of aspirin in populations with an intermediate risk of developing colorectal cancer. WHERE NEXT? The anticancer properties of NSAIDs have been demonstrated in vitro and in animal studies, epidemiological reports, and intervention studies. Several mechanisms through which NSAIDs alter colonic carcinogenesis have been elucidated, including the induction of apoptosis in neoplastic cells, via mechanisms dependent and independent of cyclo-oxygenase. Some studies have suggested an important role for the cell-cycle regulating protein p21 in mediating the chemopreventive effect of sulindac. A decrease in p21 expression may be one of the main oncogenic events in the development of colorectal cancer. Thus p21 could be the molecular link in the chemopreventive effects of NSAIDs.

Management of extracolonic tumours in patients with Lynch syndrome

Hereditary nonpolyposis colorectal cancer, or Lynch syndrome, is responsible for 2-3% of all colorectal cancers. Lynch syndrome is also associated with a high risk of extracolonic cancers, including endometrial, stomach, small bowel, pancreas, biliary tract, ovary, urinary tract, brain, and skin cancer. In this Review, we discuss the risks, surveillance tests, and guidelines for the management of extracolonic tumours associated with Lynch syndrome. For all types of extracolonic cancer, evidence supporting surveillance is scarce. A benefit of surveillance is evident only for endometrial cancer, where transvaginal ultrasound and endometrial sampling detect tumours in early stages. Surveillance is generally recommended for urinary tract and gastric cancer, especially in families with more than one member with these types of cancer. For the other types of cancer, surveillance is typically not recommended. Prophylactic hysterectomy and bilateral salpingo-oophorectomy should be considered for women with Lynch syndrome who are past childbearing age, especially during surgery for colorectal cancer. No data show efficacy of chemopreventive drugs in reducing the risk of extracolonic cancers for patients with Lynch syndrome.

Expression of TRAIL (TNF‐related apoptosis‐inducing ligand) and its receptors in normal colonic mucosa, adenomas, and carcinomas

Tumour necrosis factor‐related apoptosis‐inducing ligand (TRAIL) induces apoptosis in tumour cell lines. Four membrane‐bound receptors for TRAIL have been identified, two apoptosis‐mediating receptors, DR4 and DR5, and two apoptosis‐inhibiting receptors, DcR1 and DcR2. The aim of this study was to examine the role of TRAIL and its receptors in colorectal cancer development. The immunohistochemical expression and localization of TRAIL and its receptors were investigated in normal mucosa (n = 10), adenomas (n = 19), and carcinomas (n = 21). Correlations between the expression of TRAIL and its receptors and the degree of apoptosis (assessed by M30 expression) and histopathological characteristics were explored. TRAIL and its receptors were expressed in normal mucosal epithelium. Expression of the receptors was seen in adenomas and carcinomas. TRAIL expression was lost in a subset of colorectal tumours, more frequently in carcinomas than in adenomas (p < 0.05). DR4 and DR5 staining was stronger in neoplastic cells than in normal cells and was accompanied by a higher degree of apoptosis. No differences were found between tumour and normal cells regarding DcR1 and DcR2 expression. No correlations were found between TRAIL or TRAIL receptor expression and histopathological characteristics. In conclusion, marked changes were seen in the course of the adenoma–carcinoma sequence with respect to the expression of TRAIL and TRAIL receptors DR4 and DR5. The stronger expression of DR4 and DR5 in neoplastic cells than in normal cells, together with a higher degree of apoptosis, suggests a possible functional role for these receptors in apoptosis induction in neoplastic colorectal cells. Copyright

Risk factors for incomplete small-bowel capsule endoscopy

BACKGROUND In 20% to 30% of capsule endoscopy (CE) procedures, the capsule does not reach the cecum within recording time, with incomplete imaging of the small bowel, which limits the value of CE. OBJECTIVE To identify possible risk factors for incomplete small-bowel CE examinations. DESIGN Data from consecutive CE procedures performed between September 2003 and August 2007 were analyzed. All patients had received the same preparation before the CE procedure, including the administration of a prokinetic agent. SETTING Single-center retrospective study. PATIENTS A total of 291 CE studies. MAIN OUTCOME MEASUREMENTS Data were collected regarding patient demographics and potential risk factors. Cecal incompletion rates were calculated. Risk factors were analyzed by using a binary regression analysis. RESULTS CE was incomplete in 55 cases (19%). The gastric transit time was significantly longer in patients with incomplete CE procedures than in patients with complete CE procedures (median 45 minutes vs 21 minutes, P= .005). Previous small-bowel surgery, hospitalization, moderate or poor bowel cleansing, and a gastric transit time longer than 45 minutes were identified as independent risk factors for incomplete CE procedures. LIMITATION A retrospective study design. CONCLUSIONS The identification of several risk factors for incomplete CE procedures allows for selectively targeting these factors in future procedures to reduce the risk of incomplete CE examinations.

Increased colorectal cancer risk in first-degree relatives of patients with hyperplastic polyposis syndrome

Introduction Hyperplastic polyposis syndrome (HPS) is characterised by the presence of multiple colorectal hyperplastic polyps and is associated with an increased colorectal cancer (CRC) risk. For first-degree relatives of HPS patients (FDRs) this has not been adequately quantified. Reliable evidence concerning the magnitude of a possible excess risk is necessary to determine whether preventive measures, like screening colonoscopies, in FDRs are justified. Aims and methods We analysed the incidence rate of CRC in FDRs and compared this with the general population through person-year analysis after adjustment for demographic characteristics. Population-based incidence data from the Eindhoven Cancer Registry during the period 1970–2006 were used to compare observed numbers of CRC cases in FDRs with expected numbers based on the incidence in the general population. Results A total of 347 FDRs (41% male) from 57 pedigrees were included, contributing 11 053 person-years of follow-up. During the study period, a total of 27 CRC cases occurred among FDRs compared to five expected CRC cases (p<0.001). The RR of CRC in FDRs compared to the general population was 5.4 (95% CI 3.7 to 7.8). Four FDRs satisfied the criteria for HPS. Based on the estimated HPS prevalence of 1:3000 in the general population the projected RR of HPS in FDRs was 39 (95% CI 13 to 121). Conclusions FDRs of HPS patients have an increased risk for both CRC and HPS compared to the general population. Hence, as long as no genetic substrate has been identified, screening colonoscopies for FDRs seem justified but this needs to be prospectively evaluated.

Changes in apoptosis during the development of colorectal cancer: a systematic review of the literature

The development of colorectal cancer is characterised by an accumulation of molecular genetic alterations causing disorders in cell growth, differentiation and apoptosis. Although changes in apoptosis with colorectal cancer development have been studied extensively, a clear consensus of opinion has not yet emerged. In this review, the literature about changes in the frequency and distribution of apoptosis in tissue sections of normal and neoplastic colorectal tissues was reviewed systematically. Using a PUBMED search, 53 relevant articles were identified. Data from these studies are discussed with respect to the following aspects: methods used to detect apoptotic cell death; frequency and locoregional distribution of apoptosis in normal mucosa, adenomas and carcinomas; the correlation between levels of apoptosis and proliferation and the prognostic significance of the degree of apoptosis in colorectal cancer. Possible underlying mechanisms of dysregulation of apoptosis are discussed briefly. Finally, possible therapeutic implications of knowledge of the molecular regulation of apoptosis are discussed and potential options for further research are suggested.