Hubert Allgayer

Chemoprevention of colorectal neoplasia in ulcerative colitis: the effect of 6-mercaptopurine.

BACKGROUND & AIMS Evidence suggests that mesalamine-based anti-inflammatory medicines may prevent colorectal cancer (CRC) in ulcerative colitis (UC). If mesalamine exerts its chemopreventive effect by its anti-inflammatory activity, then other medications that reduce colitis activity also should possess chemopreventive properties. Our aim was to determine the effect of the immunomodulators 6-mercaptopurine (6MP) and azathioprine (AZA) in preventing the development of dysplasia or CRC in UC. METHODS Patients with UC who underwent a surveillance colonoscopy in 1996-1997 were identified from a gastrointestinal pathology database. A proportional hazards analysis assessing 6MP/AZA use as a time-changing covariate was performed to evaluate the effect of 6MP/AZA on: (1) progression to any neoplasia (low-grade dysplasia, high-grade dysplasia, or CRC), and (2) progression to advanced neoplasia (high-grade dysplasia or CRC). RESULTS A total of 315 subjects met inclusion criteria and were followed for an average of 8 years from their first surveillance examination. There were no significant differences in rates of progression to advanced neoplasia or to any neoplasia between 6MP/AZA users and never-users by log-rank testing. The proportional hazards analysis resulted in hazard ratios of 1.06 (95% confidence interval, .59-1.93) and 1.30 (95% confidence interval, .45-3.75) when considering the effect of exposure to 6MP/AZA on progression to any or to advanced neoplasia, respectively. The results were unaffected by known potential confounders. CONCLUSIONS In UC patients with no initial history of dysplasia, 6MP/AZA use appears to have little or no effect on the rate of neoplastic transformation in the colon. Importantly, the use of 6MP/AZA did not increase malignant transformation in UC.

Short-term moderate exercise programs reduce oxidative DNA damage as determined by high-performance liquid chromatography-electrospray ionization-mass spectrometry in patients with colorectal carcinoma following primary treatment.

Objective. Oxidative DNA damage is believed to be involved in tumor formation and may be an important biomarker for malignant transition or relapse. A decrease of such damage has been observed in human and animal studies following dietary intervention and/or changes in lifestyle such as physical exercise at different levels of intensity. The purpose of this study was to carry out a clinical trial comparing the effects of a short-term (2 weeks) exercise program of moderate intensity (0.3–0.4× maximal exercise capacity) (MI) versus high intensity (0.5–0.6×maximal exercise capacity) (HI) on individual urinary excretion of 8-oxo-dG before and after completion of the exercise programs. Material and methods. In this short-term, prospective and randomized trial, 19 patients with colorectal cancer were allocated to the MI group following primary therapy and 29 to the HI group. Urinary 8-oxo-dG excretion concentration was determined by a highly sensitive detection method using high-performance liquid chromatography coupled to electrospray ionization mass spectrometry (HPLC-ESI-MS). Concentrations were determined immediately before and after completion of the exercise programs. Results. Using HPLC-ESI-MS, it was shown that MI exercise significantly reduced urinary 8-oxo-dG excretion levels from 8.47±1.99 to 5.81±1.45 (ng/mg creatinine, mean±SE, p=0.02), whereas HI exercise resulted in a non-significant increase from 5.00±1.31 to 7.11±1.63 (ng/mg creatinine, p=0.18). Clinical characteristics (gender, age, body mass index (BMI), diet, chemotherapy/irradiation) were not associated/correlated with urinary 8-oxo-dG levels. Conclusions. By using HPLC-ESI-MS it was shown that short-term MI exercise after primary therapy in patients with colorectal cancer was associated with lower levels of urinary 8-oxo-dG, suggesting decreased oxidative DNA damage. In contrast, HI exercise tended to increase DNA damage. A prospective trial is now warranted to prove that reduced oxidative DNA damage lowers the risk of relapse of colorectal cancer in treated patients.

Prospective comparison of short- and long-term effects of pelvic floor exercise/biofeedback training in patients with fecal incontinence after surgery plus irradiation versus surgery alone for colorectal cancer: Clinical, functional and endoscopic/endosonographic findings

Objective. The influence of irradiation on the clinical severity of incontinence, sphincter function, morphologic features and short/long-term treatment effects of sphincter training therapy is still insufficiently understood in irradiated patients with fecal incontinence after surgery for colorectal cancer. These parameters were compared in irradiated and non-irradiated patients and followed prospectively with regard to short- and long-term training effects. Material and methods. Forty-one patients having been irradiated after surgery (50.0±5.0 Gy) and 54 non-irradiated patients with fecal incontinence participated in this prospective, non-randomized trial. Baseline evaluation included a semiquantitative severity assessment score of fecal incontinence (modified Cleveland Incontinence Score (MCIS)), rectal manometry and endoscopy. After 3 weeks (short term) of intensive in-hospital pelvic floor exercise combined with biofeedback training, a second evaluation was made. In addition, anal endosonography (EUS) was performed in cases of treatment failure. After one year (long term) a third evaluation was made clinically (MCIS score). Results. Irradiated patients presented with a significantly higher degree of fecal incontinence (lower MCIS) compared to non-irradiated patients: 7.4±2.2 versus 8.7±2.7 points (p<0.001). Rectosigmoidal inflammation was more frequent in irradiated than non-irradiated patients (26.9% versus 9.3%) (p<0.03). Sphincter pressure, sensation/pain threshold and the rectoanal inhibitory reflex were similar in both groups. A significant short-term training effect was observed in both groups following sphincter training therapy in terms of an increase in MCIS from 7.4±2.2 to 9.4±2.7 points in the irradiated group and from 8.7±2.7 to 11.4±2.5 points in the non-irradiated group (p<0.0001). After one year the scores were 8.2±3.8 and 10.7±4.4 points, respectively (p<0.0001). There was a significant correlation (p<0.001) between baseline MCIS and the short- and long-term MCIS. In patients with short-term treatment failure (16.6%) anal EUS revealed structural defects of the external sphincter in four patients. There was no association of sphincter diameter with sphincter pressure, sensation/pain threshold and short/long-term MCIS. Conclusions. The main result of this study is that irradiated patients show short- and long-term training effects comparable with those of non-irradiated patients despite the higher degree of incontinence at baseline. The correlation between the initial MCIS and short- and long-term treatment effects may be regarded as an important clinical predictor for treatment outcome. Functional and morphologic features are less suitable for this purpose.

Modulation of Base Hydroxylation by Bile Acids and Salicylates in a Model of Human Colonic Mucosal DNA (Putative Implications in Colonic Cancer)

Bile acids are believed to be involved in theformation of colonic cancer, and 5-aminosalicylic acidand other salicylates may have a protective role. Theprecise mechanisms of both actions are not known, but modifications (stimulation or inhibition)of basal or oxygen-radical induced DNA basehydroxylation as potential early events in tumorformation by these compounds may be involved in suchactions. We, therefore, investigated whether: (1) bile acidsin concentrations as they occur systemically orintraluminally are able to enhance basal orOH-radical-stimulated base hydroxylation in DNA fromcalf thymus; (2) 5-aminosalicylic acid, its main intestinalmetabolite N -acetyl-aminosalicylic acid and salicylate,the main aspirin metabolite, are able to inhibit thishydroxylation; and (3) DNA from calf thymus can be used as a model by comparing its basecomposition and hydroxylation with DNA from normal humancolonic mucosa. We found an enhancement of theOH-radical-induced DNA hydroxylation especially 8-OH adenine with 214.0%. On the other hand 5-ASA,N -acetylASA, and salicylate showed aconcentration-dependent inhibition of OH-stimulatedhydroxylation with IC50 between 0.04 ±0.01 mM (X ± SD) and 1.3 ± 0.1 mM. No effects were observed onbasal hydroxylation. Electron spin resonancespectroscopy studies showed reduction of thecorresponding base signals pointing to a scavengermechanism. In DNA isolated from normal human colonic mucosa (N =7) a similar base distribution was found as in calfthymus; hydroxylation was 1.0% in both systems. From ourresults we conclude that DNA from calf thymus may serve as a model for human colonic mucosalDNA and that one of the carcinogenic actions of bileacids may be enhancement of oxygen-radical-induced DNAbase hydroxylation, especially 8-OH adenine. The absence of effects under unstimulatedconditions supports their role as cocarcinogens. Theconcentration-dependent inhibition of OH-stimulated DNAhydroxylation by 5-ASA, salicylate, and N-acetyl-ASA may be a possible mechanism ofchemoprevention.

Effects of bile acids on base hydroxylation in a model of human colonic mucosal DNA.

BACKGROUND AND AIMS Increased intestinal bile acids as a possible consequence of a high fat/meat, low fiber diet are believed to play an important role in the formation of colon cancer. Interactions of bile salts particularly secondary bile acids with different cell components including DNA may contribute to carcinogenesis. To further investigate DNA damage by bile salts, we assessed the effects of a bile salt mixture containing deoxycholate and chenodeoxycholate on base hydroxylation in Chelex-treated DNA from calf thymus as a model of human colonic mucosal DNA in the presence and absence of reactive oxygen metabolites (ROM). METHODS Chelex-treated DNA from calf thymus (to remove residual iron impurities) was incubated with different bile salt concentrations (4 microM, 4.0 mM) (20.0% deoxycholate, 21.0% chenodeoxycholate) in the presence and absence of an OH generating system (25 microM FeCl3, 50 microM H2O2, 100 microM nitrilotriacetic acid) for 18 h (37 degrees C). After hydrolyzation, lyophilization and derivatization hydroxylated DNA bases were characterised and quantitated with gas chromatography-mass spectrometry (GS-MS) and SIM analysis. Two concentration ranges of bile salts were used, micromolar concentrations being present in plasma, millimolar in the gut lumen. RESULTS In the absence of ROM Chelex-treated DNA preparations contain only small amounts of hydroxylated base products. Bile salts at 4.0 mM significantly increased the amounts of 5-OH uracil and cis-thymine glycol. In the presence of ROM bile salts at 4.0 microM increased the production of 8-OH adenine and 8-OH guanine whereas bile salts at 4.0 mM inhibited ROM-induced base hydroxylation. DISCUSSION In the absence of ROM millimolar concentrations of a bile salt mixture with deoxycholate and chenodeoxycholate increase basal (spontaneous) DNA hydroxylation, whereas, they are without effects at micromolar concentrations. In the presence of ROM micromolar concentrations enhance oxidative DNA damage and millimolar concentrations were inhibitory. These results support the view that bile acids may cause oxidative DNA damage depending on their concentrations and the surrounding conditions both directly (enhancement of basal hydroxylation) and indirectly (enhancement of ROM-induced hydroxylation).

Einheimische Sprue und Malignomrisiko

Although the absolute risk of enteropathy-associated malignancies in celiac disease is generally very small due to low prevalence/incidence rates, the relative risk may be considerable so that prevention strategies based on appropriate data seem clinically desirable. The great majority of the case-control and cohort studies which have been published in the last years point to a significantly elevated risk for tumors in the gastrointestinal (GI) tract in terms of hazard/odds ratios, observed/expected ratios, and/or standardized incidence/morbidity ratios in the magnitude>5.0, whereas the risk for tumor outside the GI tract seems to be much lower (PubMed December 2007). Chronic inflammation with persistent symptoms/complaints and especially chronic refractory disease type II are considered to be particular individual risk factors. In addition, genetic factors and/or certain gene combinations may unfavorably influence the course of the disease. In the absence of controlled and prospective trials and corresponding evidence-based guidelines as they have been published for colon cancer, the strategies of prevention in patients with celiac disease differ from center to center according to their own experience/ expertise. Besides regular clinical, serologic/immunologic and endoscopic/histologic assessment a careful history taking with special regard to the disease course and a detailed ultrasound examination of the entire abdomen in patients at risk may play an important role in the long-term follow-up.

Einheimische Sprue und Malignomrisiko@@@Celiac Sprue and Malignancies: Analysis of Risks and Prevention Strategies

Although the absolute risk of enteropathy-associated malignancies in celiac disease is generally very small due to low prevalence/incidence rates, the relative risk may be considerable so that prevention strategies based on appropriate data seem clinically desirable. The great majority of the case-control and cohort studies which have been published in the last years point to a significantly elevated risk for tumors in the gastrointestinal (GI) tract in terms of hazard/odds ratios, observed/expected ratios, and/or standardized incidence/morbidity ratios in the magnitude>5.0, whereas the risk for tumor outside the GI tract seems to be much lower (PubMed December 2007). Chronic inflammation with persistent symptoms/complaints and especially chronic refractory disease type II are considered to be particular individual risk factors. In addition, genetic factors and/or certain gene combinations may unfavorably influence the course of the disease. In the absence of controlled and prospective trials and corresponding evidence-based guidelines as they have been published for colon cancer, the strategies of prevention in patients with celiac disease differ from center to center according to their own experience/ expertise. Besides regular clinical, serologic/immunologic and endoscopic/histologic assessment a careful history taking with special regard to the disease course and a detailed ultrasound examination of the entire abdomen in patients at risk may play an important role in the long-term follow-up.

Morbus Crohn und Malignomrisiko

ZusammenfassungWährend für die Colitis ulcerosa gut gesicherte epidemiologische Daten bezüglich des Kolonkarzinomrisikos auf der Basis großer Kohortenstudien verfügbar sind und Leitlinien für eine Tumorprävention durch die Deutsche Gesellschaft für Verdauungs- und Stoffwechselerkrankungen (DGVS) im Jahre 2004 veröffentlicht wurden, sind die Risikokonstellationen bei Morbus Crohn weniger klar, allgemein verbindliche Präventionsempfehlungen/-leitlinien stehen nicht zur Verfügung. In dieser Übersichtsarbeit werden anhand einer aktuellen Literaturrecherche (PubMed März 2007) die veröffentlichten Daten zur Risikoabschätzung bezüglich eines kolorektalen Karzinoms/Dünndarmkarzinoms bei Patienten mit Morbus Crohn (relatives Risiko bzw. sog. standardisierte Inzidenz-/Morbiditätsraten) kritisch bewertet und anhand der Erfahrungen aus dem eigenen Krankengut Empfehlungen für eine an individuellen Risikokonstellationen orientierte Karzinomprävention gegeben.AbstractEpidemiologic data concerning the risk for colorectal cancer in ulcerative colitis are based on a variety of large and well-conducted cohort studies. Guidelines for tumor prevention have been published by the German Gastroenterology Society (DGVS) in 2004. By contrast, the risk constellations in Crohns disease are less clear and guidelines are lacking. Based on a recent literature search (PubMed March 2007), the published data predominantly expressed as relative risk and/or standardized incidence/mortality ratio are critically reviewed with recommendations for tumor prevention strategies based on individual risk constellations.

Morbus Crohn und Malignomrisiko@@@Crohn's Disease and Cancer Risk. Incidence/Prevalence, Clinical Characteristics, and Potential Prevention Strategies: Häufigkeit, klinische Charakteristika und mögliche Präventionsstrategien

ZusammenfassungWährend für die Colitis ulcerosa gut gesicherte epidemiologische Daten bezüglich des Kolonkarzinomrisikos auf der Basis großer Kohortenstudien verfügbar sind und Leitlinien für eine Tumorprävention durch die Deutsche Gesellschaft für Verdauungs- und Stoffwechselerkrankungen (DGVS) im Jahre 2004 veröffentlicht wurden, sind die Risikokonstellationen bei Morbus Crohn weniger klar, allgemein verbindliche Präventionsempfehlungen/-leitlinien stehen nicht zur Verfügung. In dieser Übersichtsarbeit werden anhand einer aktuellen Literaturrecherche (PubMed März 2007) die veröffentlichten Daten zur Risikoabschätzung bezüglich eines kolorektalen Karzinoms/Dünndarmkarzinoms bei Patienten mit Morbus Crohn (relatives Risiko bzw. sog. standardisierte Inzidenz-/Morbiditätsraten) kritisch bewertet und anhand der Erfahrungen aus dem eigenen Krankengut Empfehlungen für eine an individuellen Risikokonstellationen orientierte Karzinomprävention gegeben.AbstractEpidemiologic data concerning the risk for colorectal cancer in ulcerative colitis are based on a variety of large and well-conducted cohort studies. Guidelines for tumor prevention have been published by the German Gastroenterology Society (DGVS) in 2004. By contrast, the risk constellations in Crohns disease are less clear and guidelines are lacking. Based on a recent literature search (PubMed March 2007), the published data predominantly expressed as relative risk and/or standardized incidence/mortality ratio are critically reviewed with recommendations for tumor prevention strategies based on individual risk constellations.

[Crohn's disease and cancer risk. Incidence/prevalence, clinical characteristics, and potential prevention strategies].

ZusammenfassungWährend für die Colitis ulcerosa gut gesicherte epidemiologische Daten bezüglich des Kolonkarzinomrisikos auf der Basis großer Kohortenstudien verfügbar sind und Leitlinien für eine Tumorprävention durch die Deutsche Gesellschaft für Verdauungs- und Stoffwechselerkrankungen (DGVS) im Jahre 2004 veröffentlicht wurden, sind die Risikokonstellationen bei Morbus Crohn weniger klar, allgemein verbindliche Präventionsempfehlungen/-leitlinien stehen nicht zur Verfügung. In dieser Übersichtsarbeit werden anhand einer aktuellen Literaturrecherche (PubMed März 2007) die veröffentlichten Daten zur Risikoabschätzung bezüglich eines kolorektalen Karzinoms/Dünndarmkarzinoms bei Patienten mit Morbus Crohn (relatives Risiko bzw. sog. standardisierte Inzidenz-/Morbiditätsraten) kritisch bewertet und anhand der Erfahrungen aus dem eigenen Krankengut Empfehlungen für eine an individuellen Risikokonstellationen orientierte Karzinomprävention gegeben.AbstractEpidemiologic data concerning the risk for colorectal cancer in ulcerative colitis are based on a variety of large and well-conducted cohort studies. Guidelines for tumor prevention have been published by the German Gastroenterology Society (DGVS) in 2004. By contrast, the risk constellations in Crohns disease are less clear and guidelines are lacking. Based on a recent literature search (PubMed March 2007), the published data predominantly expressed as relative risk and/or standardized incidence/mortality ratio are critically reviewed with recommendations for tumor prevention strategies based on individual risk constellations.