PMS2-associated Lynch syndrome: Past, present and future.

Carriers of any pathogenic variant in one of the MMR genes (path_MMR carriers) were traditionally thought to be at comparable risk of developing a range of different malignancies, foremost colorectal cancer (CRC) and endometrial cancer. However, it is now widely accepted that their cancer risk and cancer spectrum range notably depending on which MMR gene is affected. Moreover, there is increasing evidence that the MMR gene affected also influences the molecular pathogenesis of Lynch syndrome CRC. Although substantial progress has been made over the past decade in understanding these differences, many questions remain unanswered, especially pertaining to path_PMS2 carriers. Recent findings show that, while the cancer risk is relatively low, PMS2-deficient CRCs tend to show more aggressive behaviour and have a worse prognosis than other MMR-deficient CRCs. This, together with lower intratumoral immune infiltration, suggests that PMS2-deficient CRCs might have more in common biologically with sporadic MMR-proficient CRCs than with other MMR-deficient CRCs. These findings could have important consequences for surveillance, chemoprevention and therapeutic strategies (e.g. vaccines). In this review we discuss the current knowledge, current (clinical) challenges and knowledge gaps that should be targeted by future studies.

Prospective evaluation of the motorized spiral enteroscope for previous incomplete colonoscopy.

Background and study aims A significant percentage of colonoscopies remain incomplete because of failure to intubate the cecum. The motorized spiral enteroscope (MSE) technique, originally developed for deep small bowel enteroscopy, may be an effective alternative technique in cases of incomplete examination of abnormally long colons (dolichocolon). We prospectively evaluated the success rate of cecal intubation, safety and the therapeutic consequences of using MSE after incomplete conventional colonoscopy. Patients and methods A total of 36 consecutive patients with an indication for diagnostic and/or therapeutic colonoscopy were prospectively enrolled in this multicenter trial. All patients had undergone at least one incomplete colonoscopy attributed to abnormally long colons. Patients with incomplete colonoscopy due to stenosis were excluded. Results Twenty-two men and 14 women (median age 66 years, range 35-82) were enrolled. Median procedure time was 30 minutes (range 16-50). Cecal intubation rate was 100 % and median cecal intubation time was 10 minutes (range 4-30). Abnormalities, mostly neoplastic lesions, were detected in 23 of 36 patients, corresponding to a diagnostic yield of 64 %. All these findings were in the right side of the colon and had not been described by the antecedent incomplete coloscopy. No adverse events occurred. Conclusions In case of a difficult and long colon, MSE is safe and effective for diagnostic and therapeutic colonoscopy. It may provide an attractive solution to accomplish completeness of previous incomplete colonoscopies in these patients.

The performance and safety of motorized spiral enteroscopy, including in patients with surgically altered gastrointestinal anatomy: a multicenter prospective study.

BACKGROUND: Data are scarce on the efficacy and safety of motorized spiral enteroscopy (MSE). No data are available on the utility of this technique in patients with surgically altered gastrointestinal (GI) anatomy. We aimed to evaluate the safety and efficacy of MSE in patients with suspected small-bowel disease, including those with surgically altered GI anatomy. METHODS: A multicenter prospective observational, uncontrolled study evaluated MSE in consecutive patients with suspected small-bowel pathology and an indication for diagnostic and/or therapeutic intervention. RESULTS: A total of 170 patients (102 men; median age 64 years, range 18-89) were included. The overall diagnostic yield was 64.1 %. Endotherapy was performed in 53.5 % of procedures. The median total procedure times for the antegrade and retrograde approaches were 45 minutes (interquartile range [IQR] 30-80) and 40 minutes (IQR 30-70), respectively. When total (pan)enteroscopy was intended, this was achieved at rate of 70.3 % (28.1 % by antegrade approach and 42.2 % by a bidirectional approach). Surgically altered GI anatomy was present in 34 /170 of all procedures (20.0 %) and in 11 /45 of the successful total enteroscopy procedures (24.4 %). Propofol sedation or general anesthesia were used in 92.9 % and 7.1 % of the procedures, respectively. Minor adverse events were observed in 15.9 % of patients, but there were no major adverse events. CONCLUSION: MSE seems to be an effective and safe endoscopic procedure. Total (pan)enteroscopy can be achieved, in one or two sessions, even in the presence of surgically altered GI anatomy. The total procedure time is relatively short. For both antegrade and retrograde MSE procedures, propofol sedation seems sufficient and safe.

Is a colorectal neoplasm diagnosis a trigger to change dietary and other lifestyle habits for persons with Lynch syndrome? A prospective cohort study.

A cancer diagnosis is suggested to be associated with changes in dietary and lifestyle habits. Whether this applies to persons with familial cancer, such as Lynch syndrome (LS) is unknown. We investigated whether a colorectal neoplasm (CRN) diagnosis in persons with LS is associated with changes in dietary and lifestyle habits over time. We used data of confirmed LS mutation carriers from the GEOLynch study, a prospective cohort study. Information on dietary intake and lifestyle habits was collected with a validated semi-quantitative food frequency questionnaire and a general questionnaire administered at baseline (2006-2008) and follow-up (2012-2017). Participants' medical records were used to identify CRN diagnoses. Changes in dietary and lifestyle habits in the CRN and the no-CRN group were compared using multivariable linear regression models for continuous variables and cross-tables with percentage change at follow-up compared with baseline for categorical variables. Of the 324 included participants, 146 developed a CRN (CRN group) between baseline and follow-up, while 178 did not (no-CRN group). Smoking cessation was more often reported in the CRN than in the no-CRN group (41.4% vs. 35.0%). There were no differences in changes of energy intake, alcohol, red meat, processed meat, dairy, fruit, vegetables and dietary fiber consumption, BMI, physical activity and NSAID use. Apart from a potentially higher likelihood of smoking cessation, we found little evidence that a CRN diagnosis is associated with changes in lifestyle habits in persons with LS.

Substantial and sustained improvement of serrated polyp detection after a simple educational intervention: results from a prospective controlled trial.

OBJECTIVE: Serrated polyps (SPs) are an important cause of postcolonoscopy colorectal cancers (PCCRCs), which is likely the result of suboptimal SP detection during colonoscopy. We assessed the long-term effect of a simple educational intervention focusing on optimising SP detection. DESIGN: An educational intervention, consisting of two 45 min training sessions (held 3 years apart) on serrated polyp detection, was given to endoscopists from 9 Dutch hospitals. Hundred randomly selected and untrained endoscopists from other hospitals were selected as control group. Our primary outcome measure was the proximal SP detection rate (PSPDR) in trained versus untrained endoscopists who participated in our faecal immunochemical test (FIT)-based population screening programme. RESULTS: Seventeen trained and 100 untrained endoscopists were included, who performed 11 305 and 51 039 colonoscopies, respectively. At baseline, PSPDR was equal between the groups (9.3% vs 9.3%). After training, the PSPDR of trained endoscopists gradually increased to 15.6% in 2018. This was significantly higher than the PSPDR of untrained endoscopists, which remained stable around 10% (p=0.018). All below-average (ie, PSPDR ≤6%) endoscopists at baseline improved their PSPDR after training session 1, as did 57% of endoscopists with average PSPDR (6%-12%) at baseline. The second training session further improved the PSPDR in 44% of endoscopists with average PSPDR after the first training. CONCLUSION: A simple educational intervention was associated with substantial long-term improvement of PSPDR in a prospective controlled trial within FIT-based population screening. Widespread implementation of such interventions might be an easy way to improve SP detection, which may ultimately result in fewer PCCRCs. TRIAL REGISTRATION NUMBER: NCT03902899.

Personalised surveillance for serrated polyposis syndrome: results from a prospective 5-year international cohort study.

BACKGROUND AND AIMS: Serrated polyposis syndrome (SPS) is associated with an increased risk of colorectal cancer (CRC). International guidelines recommend surveillance intervals of 1-2 years. However, yearly surveillance likely leads to overtreatment for many. We prospectively assessed a surveillance protocol aiming to safely reduce the burden of colonoscopies. METHODS: Between 2013 and 2018, we enrolled SPS patients from nine Dutch and Spanish hospitals. Patients were surveilled using a protocol appointing either a 1-year or 2-year interval after each surveillance colonoscopy, based on polyp burden. Primary endpoint was the 5-year cumulative incidence of CRC and advanced neoplasia (AN) during surveillance. RESULTS: We followed 271 SPS patients for a median of 3.6 years. During surveillance, two patients developed CRC (cumulative 5-year incidence 1.3%[95% CI 0% to 3.2%]). The 5-year AN incidence was 44% (95% CI 37% to 52%), and was lower for patients with SPS type III (26%) than for patients diagnosed with type I (53%) or type I and III (59%, p<0.001). Most patients were recommended a 2-year interval, and those recommended a 2-year interval were not at increased risk of AN: AN incidence after a 2-year recommendation was 15.6% compared with 24.4% after a 1-year recommendation (OR 0.57, p=0.08). CONCLUSION: Risk stratification substantially reduced colonoscopy burden while achieving CRC incidence similar to previous studies. AN incidence is considerable in SPS patients, but extension of surveillance intervals was not associated with increased AN in those identified as low-risk by the protocol. We identified SPS type III patients as low-risk group that might benefit from even less frequent surveillance. TRIAL REGISTRATION NUMBER: The study was registered on http://www.trialregister.nl; trial-ID NTR4609.

The (ir)relevance of the abandoned criterion II for the diagnosis of serrated polyposis syndrome: a retrospective cohort study.

The World Health Organization (WHO) recently updated the diagnostic criteria for serrated polyposis syndrome (SPS). One of the three previous diagnostic criteria (criterion II2010) is now abandoned: ≥ 1 serrated polyp (SP) proximal to the sigmoid in a first-degree relative (FDR) of a patient with SPS. Individuals fulfilling this abandoned criterion now receive the same surveillance recommendations as all FDRs of patients with SPS. We aimed to compare the incidence of advanced neoplasia (AN) in FDRs with vs. without fulfillment of the abandoned criterion II2010. We retrospectively recruited FDRs of patients with SPS who underwent a colonoscopy, and stratified them according to fulfilment of criterion II2010 at baseline. Our primary and secondary outcomes were AN incidence during surveillance and at baseline, respectively. We included 224 FDRs of patients with SPS, of whom 36 (16%) fulfilled criterion II2010 at baseline. One hundred and five underwent surveillance after baseline. Criterion II2010-positive FDRs were at increased risk of AN, both during surveillance (hazard ratio 8.94, 95% CI 2.15-37.1, p = .003) as well as at baseline (adjusted odds-ratio 9.30, 95% CI 3.7-23.3, p < .001). FDRs of patients with SPS that underwent colonoscopy and fulfilled the abandoned criterion II2010 for SPS diagnosis were at increased risk of AN at baseline and during surveillance in this small, retrospective cohort study. Our results should be interpreted with caution but suggest that adherence to surveillance recommendations for all FDRs of patients with SPS is important, especially for those that would have fulfilled the now abandoned criterion II2010.

Limited diagnostic accuracy and clinical impact of single-operator peroral cholangioscopy for indeterminate biliary strictures.

BACKGROUND: Single-operator peroral cholangioscopy (sPOCS) is considered a valuable diagnostic modality for indeterminate biliary strictures. Nevertheless, studies show large variation in its characteristics and measures of diagnostic accuracy. Our aim was to estimate the diagnostic accuracy of sPOCS visual assessment and targeted biopsies for indeterminate biliary strictures. Additional aims were: estimation of the clinical impact of sPOCS and comparison of diagnostic accuracy with brush cytology. METHODS: A retrospective single-center study of adult patients who underwent sPOCS for indeterminate biliary strictures was performed. Diagnostic accuracy was defined as sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV). The clinical impact of sPOCS was assessed by review of medical records, and classified according to its influence on patient management. RESULTS: 80 patients were included, with 40 % having primary sclerosing cholangitis (PSC). Prior ERCP was performed in 88 %, with removal of a biliary stent prior to sPOCS in 55 %. The sensitivity, specificity, PPV, and NPV for sPOCS visual impression and targeted biopsies were 64 %, 62 %, 41 %, and 84 %, and 15 %, 65 %, 75 %, and 69 %, respectively. The clinical impact of sPOCS was limited; outcome changed management in 17 % of patients. Sequential brush cytology sensitivity, specificity, PPV, and NPV were 47 %, 95 %, 80 %, and 83 %. CONCLUSIONS: The diagnostic accuracy of sPOCS for indeterminate biliary strictures was found to be inferior to brush cytology, with a low impact on patient management. These findings are obtained from a select patient population with a high prevalence of PSC and plastic stents in situ prior to sPOCS.

Molecular Fluorescence Endoscopy Targeting Vascular Endothelial Growth Factor A for Improved Colorectal Polyp Detection.

UNLABELLED: Small and flat adenomas are known to carry a high miss-rate during standard white-light endoscopy. Increased detection rate may be achieved by molecular fluorescence endoscopy with targeted near-infrared (NIR) fluorescent tracers. The aim of this study was to validate vascular endothelial growth factor A (VEGF-A) and epidermal growth factor receptor (EGFR)-targeted fluorescent tracers during ex vivo colonoscopy with an NIR endoscopy platform. METHODS: VEGF-A and EGFR expression was determined by immunohistochemistry on a large subset of human colorectal tissue samples--48 sessile serrated adenomas/polyps, 70 sporadic high-grade dysplastic adenomas, and 19 hyperplastic polyps--and tissue derived from patients with Lynch syndrome--78 low-grade dysplastic adenomas, 57 high-grade dysplastic adenomas, and 31 colon cancer samples. To perform an ex vivo colonoscopy procedure, 14 mice with small intraperitoneal EGFR-positive HCT116(luc) tumors received intravenous bevacizumab-800CW (anti-VEGF-A), cetuximab-800CW (anti-EGFR), control tracer IgG-800CW, or sodium chloride. Three days later, 8 resected HCT116(luc) tumors (2-5 mm) were stitched into 1 freshly resected human colon specimen and followed by an ex vivo molecular fluorescence colonoscopy procedure. RESULTS: Immunohistochemistry showed high VEGF-A expression in 79%-96% and high EGFR expression in 51%-69% of the colorectal lesions. Both targets were significantly overexpressed in the colorectal lesions, compared with the adjacent normal colon crypts. During ex vivo molecular fluorescence endoscopy, all tumors could clearly be delineated for both bevacizumab-800CW and cetuximab-800CW tracers. Specific tumor uptake was confirmed with fluorescent microscopy showing, respectively, stromal and cell membrane fluorescence. CONCLUSION: VEGF-A is a promising target for molecular fluorescence endoscopy because it showed a high protein expression, especially in sessile serrated adenomas/polyps and Lynch syndrome. We demonstrated the feasibility to visualize small tumors in real time during colonoscopy using a NIR fluorescence endoscopy platform, providing the endoscopist a wide-field red-flag technique for adenoma detection. Clinical studies are currently being performed in order to provide in-human evaluation of our approach.

Narrow-band imaging for the detection of polyps in patients with serrated polyposis syndrome: a multicenter, randomized, back-to-back trial.

BACKGROUND: Serrated polyposis syndrome (SPS) is characterized by the presence of multiple serrated polyps spread throughout the colon. Patients with SPS are considered to be at risk of colorectal cancer and are advised to undergo endoscopic surveillance. Narrow-band imaging (NBI) may improve the detection of polyps during these surveillance colonoscopies. OBJECTIVE: To compare polyp miss rates between NBI and high-resolution white-light endoscopy (HR-WLE). DESIGN: Multicenter, randomized, crossover study. SETTING: Four tertiary referral institutions. PATIENTS: A total of 52 patients with SPS undergoing surveillance colonoscopy. INTERVENTION: All patients underwent back-to-back colonoscopies with HR-WLE and NBI in a randomized order. MAIN OUTCOME MEASUREMENTS: Polyp miss rates of HR-WLE and NBI. RESULTS: In the HR-WLE group, 116 polyps were detected during the first inspection. A second inspection with NBI added 47 polyps, resulting in an overall polyp miss rate of 29% with HR-WLE (95% confidence interval, 22-36). In the NBI group, a total of 128 polyps were detected during the first inspection. Subsequent inspection with HR-WLE added 32 polyps, resulting in an overall polyp miss rate of NBI of 20% (95% confidence interval, 15-27). Comparison of the overall polyp miss rates of HR-WLE and NBI showed no significant difference (P = .065). LIMITATIONS: Small sample size; second inspection was performed by the same endoscopist. CONCLUSIONS: The results of our study suggest that NBI does not reduce polyp miss rates in patients with SPS compared with HR-WLE. Further multinational studies with larger numbers of patients are warranted to verify these results. ( CLINICAL TRIAL REGISTRATION NUMBER: NTR2497.).

Yield of screening colonoscopy in first-degree relatives of patients with serrated polyposis syndrome.

GOALS: We aimed to evaluate the diagnostic yield of screening colonoscopies in first-degree relatives (FDRs) of patients with serrated polyposis syndrome (SPS). BACKGROUND: Patients with SPS are at an increased risk for colorectal cancer. Although inheritance patterns are unknown, FDRs of these patients have an increased risk for both colorectal cancer and SPS. Prospective studies evaluating the yield of screening colonoscopies in this group are however scarce. This information would be useful to evaluate a possible mode of inheritance and to investigate whether screening colonoscopies are justified in this group. STUDY: FDR of patients with SPS were invited to undergo colonoscopy. The diagnostic yield was expressed by the number of FDRs with at least 1 significant polyp relative to the total number of included FDRs. Significant polyps were defined adenomas, traditional serrated adenomas, sessile serrated adenoma/polyp, or proximal hyperplastic polyp. Tissue specimens were reviewed by one expert pathologist. RESULTS: Seventy-seven FDRs underwent colonoscopy (median age 52 y; interquartile range, 41 to 60). Colorectal cancer was not diagnosed. One or more significant polyps were detected in 43% of FDRs. No differences based on age, gender, or familial relationship were observed in the detection of polyps. Seven first-degree (9%) relatives had multiple polyps (≥5). Eleven (14%) FDRs fulfilled SPS WHO-criterion 2, of whom 1 sibling also met SPS WHO-criterion 3. CONCLUSIONS: The yield of a single screening colonoscopy in FDRs of patients with serrated polyposis is substantial, warranting a colonoscopy screening program for these individuals.

Extracolonic cancer risk in patients with serrated polyposis syndrome and their first-degree relatives.

Serrated polyposis syndrome is associated with an increased colorectal cancer risk. Although the underlying genetic cause of the condition is unknown, first-degree relatives of patients with serrated polyposis have an increased risk for colorectal cancer compared with the general population. This suggests an inheritable component. Since other hereditary polyposis syndromes are often associated with an expanded extracolonic tumour spectrum, our aim was to determine the extra colonic cancer risks for patients with serrated polyposis and their first-degree relatives and compare these risks with the general population. Serrated polyposis index patients from 5 medical centres were included. Demographic data concerning age, sex and reported malignancies were ascertained by reviewing medical charts and histopathology reports. Family history was obtained by examining pedigree records from the department of Clinical Genetics. Incidence rates of extracolonic malignancies were compared with the general population through a person-year analysis, adjusted for age and sex. Population-based incidence data were derived from the Eindhoven Cancer Registry. A total of 105 patients with serrated polyposis and 341 first-degree relatives were included. Among the patients with serrated polyposis, 9 extracolonic cancers were observed, compared to 13 expected malignancies in the general population (RR 0.69 95% CI 0.36-1.33; p = 0.27). Among the first-degree relatives, 44 extracolonic malignancies were observed, compared to 48 expected malignancies (RR 0.92 95% CI 0.69-1.24; p = 0.60). In this study, the overall incidence of extracolonic malignancies in patients with serrated polyposis and their first-degree relatives was not increased. Large international studies are required to confirm these results.

Small bowel endoscopy in familial adenomatous polyposis and Lynch syndrome.

Patients with familial adenomatous polyposis (FAP) and patients with Lynch syndrome have an increased risk of developing small intestinal neoplasia. In both conditions, the lifetime risk to develop small bowel cancer is estimated to be around 5%. In FAP, this risk is associated with the degree of duodenal polyposis, classically assessed by the Spigelman classification. For this reason, gastroduodenal surveillance with forward-viewing and side-viewing endoscopy is generally recommended. Studies using video capsule endoscopy and balloon-assisted enteroscopy in FAP patients have revealed that jejunal and ileal polyps occur frequently in FAP, especially in those with extensive duodenal polyposis. Nevertheless, the clinical relevance of small bowel polyps beyond the duodenum appears to be limited. Compared to FAP, little is known about the prevalence and natural history of small bowel neoplasia in Lynch syndrome. Surveillance of the small bowel is not recommended in Lynch syndrome, although recent data using capsule endoscopy provided promising results.

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.

Listening to music does not reduce pain during sigmoidoscopy.

OBJECTIVE: Up to 40% of the sigmoidoscopies are considered painful by patients. Nonpharmacological intervention would be attractive, as sedation and analgesia carry the risk of side-effects and increase procedure-related costs. Music might have the potential of pain reduction, but its effect during sigmoidoscopy has not been established yet. To study whether listening to music reduces experienced pain during sigmoidoscopy. METHODS: Consecutive patients, above 18 years of age, undergoing sigmoidoscopy without sedation or analgesia and who gave their informed consent were included in this study. Patients in the music group listened to their preferred music (classical, jazz, English or Dutch Popular) during the sigmoidoscopy. The control group received care as usual. The outcome measures were pain intensity during sigmoidoscopy (measured with a 100-mm-long visual analogue scale) and the proportion of patients with at least moderate pain during sigmoidoscopy (pain intensity score of 50 mm or higher). RESULTS: The music groups consisted of 153 patients, the control group of 154 patients. The mean pain intensity + or - standard deviation was 36 + or - 27 mm in the music group and 40 + or - 29 in the control group (P=0.27) during sigmoidoscopy. The proportion of patients with at least moderate pain during sigmoidoscopy was 29 and 37% in the respective groups (P=0.12). CONCLUSION: Listening to music by patients did not reduce pain intensity during sigmoidoscopy. As a consequence, music during sigmoidoscopy is not recommended for this purpose.

JC virus infection in colorectal neoplasia that develops after liver transplantation.

PURPOSE: Liver transplant recepients (LTRs) have an increased risk of colorectal neoplasia. The mechanism responsible for this is unknown. JCV encodes for TAg and has been implicated in colorectal carcinogenesis. We hypothesized that the use of immunosuppression in LTRs facilitates activation of JCV and is responsible for the increased risk of neoplasia. EXPERIMENTAL DESIGN: JCV TAg DNA and protein expression were determined in normal colonic epithelium (n = 15) and adenomatous polyps (n = 26) from LTRs and compared with tissue samples from control patients (normal colon, n = 21; adenomas, n = 40). Apoptosis and proliferation were determined by M30 and Ki-67 immunoreactivity, respectively. RESULTS: JCV TAg DNA was found in 10 of 15 (67%) of normal colonic mucosa from LTRs compared with 5 of 21 (24%) of control normal mucosa (P = 0.025). JCV TAg DNA was detected in 16 of 26 (62%) of the adenomas from LTRs and in 20 of 40 (50%) of control adenomas. JCV TAg protein was expressed in 13 of 26 (50%) adenomas from LTRs versus 2 of 40 (5%) of adenomas from controls (P < 0.001). In adenomas from LTRs, the mean proliferative activity was higher compared with controls (60.3 +/- 3.2% versus 42.7 +/- 2.8%, P < 0.001), whereas mean apoptotic indices were lower in LTRs (0.29 +/- 0.08% versus 0.39 +/- 0.06%, P = 0.05). CONCLUSIONS: The presence of JCV in the colorectal mucosa and adenomas from LTRs, in concert with the use of immunosuppressive agents, suggests that JCV may undergo reactivation, and the subsequent TAg protein expression might explain the increased risk of colorectal neoplasia in LTRs.

Early carcinogenic events in HNPCC adenomas: differences with sporadic adenomas.

BACKGROUND: Tumorigenesis in hereditary nonpolyposis colorectal cancer (HNPCC) differs from that in sporadic colorectal cancer during the early stage. We examined the expression of proliferation- and apoptosis-regulating proteins in relation to proliferation and apoptosis in HNPCC and sporadic adenomas. METHODS: Proliferation and apoptosis were quantified, and the expression of cyclin B1, D3 and E, p21, p27, bcl-2, bax, p53 and cox-2 was determined by immunohistochemistry in 100 patients (42 with HNPCC and 48 with sporadic adenomas). RESULTS: No differences between the two groups of patients in terms of proliferation and apoptosis were detected. Low-grade dysplastic HNPCC adenomas differed from sporadic ones by expressing bcl-2 more often (69 vs. 42%) and bax less often (50 vs. 73%). In comparison to sporadic adenomas, fewer high-grade dysplastic HNPCC expressed cyclin B1 and E (50 and 38% vs. 87 and 87%, respectively), p21 (6% vs. 53%) and bax (31% vs. 80%). In addition, HNPCC adenomas had a lower overexpression of p53 (5 vs. 19%). CONCLUSION: The expression of cell cycle- and apoptosis-related proteins differs between HNPCC and sporadic adenomas from early through to advanced stages although proliferation and apoptosis are not different. These differences may contribute to the different clinical behavior of HNPCC and sporadic adenomas.