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Microsatellite instability in non neoplastic colonic mucosa of patients with inflammatory bowel disease
101
103
BOWEL WALL THICKNESS AT ABDOMINAL ULTRASOUND AND THE 1 YEAR-RISK OF SURGERY IN PATIENTS WITH CROHN’S DISEASE. Castinlione F, De Sio I, Del Vecchio Blanc0 G,
MICROSATELLITE COLONIC MUCOSA BOWEL DISEASE
Rispc A, Cozzolino A, Di Girolamo E, Caste&no Divisions of Gastroenterology, University of Naples Second University, Naples, Italy.
V. Rovella, A. Armuzzi, M Genuardi, A. Pastor&i, M. Paolucci, FM Vecchio, G. Neri G. Gasbarrini, M. Anti.
L, Mazzacca G. “Federico II” and
IN NON NEOPLASTlC WITH INFLAMMATORY
Cattedra di Medicina Interna II, Istituto di Genetica Medica, Istituto di Anatomia Patologica, Universitll Cattolica del Sacro Cuore, Roma.
Abdominal ultrasound (US) has been proposed as a reliable tool to assess disease extent and localization in patients with Crohn’s disease (CD). Correlation between US findings and clinical activity or laboratory signs of inflammation has not been clearly established. Increased bowel wall thickness (BWT) at US is the most common sign in patients with CD. Our aim was to correlate BWT, evaluated by US, with the risk of surgery in the short term (1 year) in patients with CD during follow-up. Methods: From 1996 to 1999 we performed US (Aloka SSD-1700; convex probe 5 MHz) in 117 consecutive CD patients (68 male; 49 female; mean age 37 yrs). A BWT up to 4 mm was considered as normal. Patients were divided in two groups according to their BWT (< 8 mm or 2 8 mm) and the occurrence of surgical operations was recorded over a I year follow up. RemIts: Seven patients were excluded because of negative US findings. The remaining 110 patients were analysed. Fifty-one patients (28 ileal, 5 colonic, and 18 ileo-colonic disease) had a BWT < 8 mm. In this group (mean duration of CD 5.5 yr.; 23% with CDAI>lSO) 3 patients (5.8 %) underwent intestinal resection during the l-year follow up. Among the 59 patients (30 ileal, 3 colonic, 26 ileo-colonic) with a BWI 2 8 mm (mean duration of CD 4.5 yr.; 57% with CDAI>I50), 29 patients (49 %) underwent intestinal resection during the same period. The risk of surgery at 1 year in the two groups of patients was significantly different (p < 0.001). Only in 11 out of 32 operated patients (34%) was the increased BWT associated to bowel dilatation at US. Conclusion: Our data suggest that BWT 2 8 mm at US is a significant risk factor for intestinal resection over a short period of time in patients with Crohn’s disease.
Background:
102
INSTABILITY OF PATIENTS
BACKGROUND., Patients with Inflammatory Bowel Disease (IBD) have a well-establiihed risk for the development of colorectal cancer. Dysplasia is the morphological change identified as the premalignant precursor that precedes cancjer development. However the molecular bases o; carcinogenesis in IBD are not clearly defmed. Microsatellite instability (MSI) is a marker of genome-wide mutations and of DNA mismatch repair (MMR) deficiency. MS1 has been previously reported not only in malignant or premalignant tissues, but even in inflammatory non neopkstic conditions ofgastmintestinal tract. AIM. To investigate the frequency of MS1 in IBD in order to verify if MMFt deficiency may have a role in the carcinogenetic pathway of these diseases MATERIALS AND METHODS. Archivial bioptic or surgical colonic samples were selected t?om 46 IBD patients ( 37 Ulcerative Colitis, 7 Crobo’s disease, 2 “indefinite” IBD). In total 54 samples of non-neoplastic inflammatory / regenerative lesions, I6 of’ dysplasia, 5 of UC- associated cancer and CD- associated cancer were examined respectively. Afler extractiob DNA was amplified by PCR using 0.2 &I of ‘* P-lab&d dCTP incorporated into IO pl reaction mixture. PCR products were separated by elctrophoresis on denaturing 6% polyacrylamide gel and visualizated by autoradiography. The following markers were analysed: BAT-25, BAT-26, D2Sl23, TGFPRII, IGFIIR. MS1 was &Bned as the presence of at least one band shifl (novel allele) in the sample tissue that was not visible in the constitutional DNA (matching sample). RESULTS. No MS1 was found in dysplasia, UC- and CD- associated
cancers; only one case of non cancemus samples showed MS1 for BAT-26. CONCLUSIONS. MS1 is a rare event in the setting of IBD: IIowever the -~____
detection of mutation in microsatelliie sequences related to MSH2 gene
(BAT-26) in non-neoplastic tissues of UC indicates that a deficiency of MMR machinery may occasionally occur early in UC.
104 DISSOCIATION BETWEEN SERUM LEFTIN AND TNF- a LEVELS IN ENERGY METABOLISM REGULATION IN PATIENTS WITH INFLAMMATORY BOWEL DISEASE. E. Capristo, G. Addolorato, A. Scarfone, G. Valentini, G. Mingrone, M. Manco, C. Ancona, AV. Greco, G. Gasbarfini. Institute of Internal Medicine, Catholic University, Rome, Italy. Background and Aim: Patients with inflammatory bowel disease (IBD) are at high risk of malnutrition, as they have reduced fat mass, mcreased utilisation of lipids as energy substrate and difficulty in gaining weight. Adipose tissue is responsible for leptin and tumor necrosis factor (TF)a production, and these two cytokines were recently shown to be acttvely involved in energy balance in humans. The purpose of the present study was to evaluate the influence of serum leptin and TNF- o concentration on body composition and energy metabolism in patients affected by IBD. Maferial and Methods: Sixty-three patients, with either ileal or ileocolonic Crohn’s disease (CD) (n=39, 21MilSF) or ulcerative cqlitis (UC) (n=24, llM/13F9 were consecutively enrolled in the study. Pattents were not receiving steroids or nutritional support in the 2 weeks preceding the study. Disease activity was assessed by the simplified CD actlvtty index and the Tmelove and Witts criteria. Forty healthy subjects, comparable for age, height and gender were studied as controls. Fat (FM) and fatfree mass (FFM) were assessed by dual-energy X-ray abs?rpti!metry. Resting metabolic rate (RMR), carbohydrate and lipid oxldatlon were measured by open-circuit indirect calorimetry and 24-hr, yitrogen excretion. Serum leptin concentration was measured by radio-lmmuno assay and TNF- a was determined by an ELISA procedure. Results: Serum leptin level (@ml) was significantly lower in patients with CD (4.8~2.7) with respect to both UC (9.6~5.8; PcO.001) and control subjects (8.9+4.9; P
ANTITUMOR
NECROSIS
TBERAPY IN PATIENTS WITH FISTuLAs.
FACTOR ANTIBODY ACTIVEi CROBN’S
WITH
@NFL=)
DISEASE AND
Mattorana G, Oliva L, Orlando A, Ca& A and Cottone M. Divisione di Medicina e Pneumologia Clinica Medioa R Azienda Ospedaliera V. CerveIIo - PaIermo. Background and aim: Several studies have demonstrated the efficacy of infliximab, a monoclonal anti-tumor necrosis fkctor antibody in the treatment of patients (pts) with active Crohn’s disease (CD) compIicated or not with fitias, not responding to conventional therapies. The aim of this open-label study was to confirm the efficacy and the safety of infliximab in this subgroup of pts. Material8 and methods: 22 pts (8 males, 14 females) were included in the study, 10 with active treatment-resistaM CD, 6 with active treatmentresistant disease complicated with fistulas (perianal or abdominal) and 6 with fistulas only &&anal or abdominal). Pts without fitilaa received a single infusion of 5 mg of intliximab per kilogram of body weight, while pts with fistulas received three iafusions of 5 mg of intIiimab par kilogram of body weight at wee&s (wks) 0, 2 and 6. Clinical response or remission were defined as the reduction of more of 70 points or below 150 points of the CDAI score, respectively. For fistulas, response was defined as the reduction of 50 percent or more J?om baseline in the number of draining fistulas or of the quantity of drainage, remission as the closure of them. Results: at 2 wks ftom infusion all pts (16/16) treated for active disease obtained a clinical response and 10 out 16 (62.5%) the remission. A! 8 wks 9/16 (56.2%)
pts treated for active disease mantabed
the remission
and
6/16 (37.5%) a clinical response, while 6/12 (50%) pta asated for fiat&as manteincd the remission and the 5/12 (41.6%) the response while 202 (16.6%) didn’t have any response. Over 16 wks, 9112 (75%) pts treated for active disease and 13/16 (81.25%) treated for fist&a had a recurreoce in a median time of 18.3 wks (range, l-36 wks) after the tint infUsion. No serious adverse events were reported during infusions; two pts developed subocclusive bouts and one of them needed surgery. Conclusions: Clur data umftrtn that therapy with iniliximab has a role in the treatment of pts with active CD complicated or not with fist&s, with low incidence of adverse events but with an high rate of recurrences.
103
BOWEL WALL THICKNESS AT ABDOMINAL ULTRASOUND AND THE 1 YEAR-RISK OF SURGERY IN PATIENTS WITH CROHN’S DISEASE. Castinlione F, De Sio I, Del Vecchio Blanc0 G,
MICROSATELLITE COLONIC MUCOSA BOWEL DISEASE
Rispc A, Cozzolino A, Di Girolamo E, Caste&no Divisions of Gastroenterology, University of Naples Second University, Naples, Italy.
V. Rovella, A. Armuzzi, M Genuardi, A. Pastor&i, M. Paolucci, FM Vecchio, G. Neri G. Gasbarrini, M. Anti.
L, Mazzacca G. “Federico II” and
IN NON NEOPLASTlC WITH INFLAMMATORY
Cattedra di Medicina Interna II, Istituto di Genetica Medica, Istituto di Anatomia Patologica, Universitll Cattolica del Sacro Cuore, Roma.
Abdominal ultrasound (US) has been proposed as a reliable tool to assess disease extent and localization in patients with Crohn’s disease (CD). Correlation between US findings and clinical activity or laboratory signs of inflammation has not been clearly established. Increased bowel wall thickness (BWT) at US is the most common sign in patients with CD. Our aim was to correlate BWT, evaluated by US, with the risk of surgery in the short term (1 year) in patients with CD during follow-up. Methods: From 1996 to 1999 we performed US (Aloka SSD-1700; convex probe 5 MHz) in 117 consecutive CD patients (68 male; 49 female; mean age 37 yrs). A BWT up to 4 mm was considered as normal. Patients were divided in two groups according to their BWT (< 8 mm or 2 8 mm) and the occurrence of surgical operations was recorded over a I year follow up. RemIts: Seven patients were excluded because of negative US findings. The remaining 110 patients were analysed. Fifty-one patients (28 ileal, 5 colonic, and 18 ileo-colonic disease) had a BWT < 8 mm. In this group (mean duration of CD 5.5 yr.; 23% with CDAI>lSO) 3 patients (5.8 %) underwent intestinal resection during the l-year follow up. Among the 59 patients (30 ileal, 3 colonic, 26 ileo-colonic) with a BWI 2 8 mm (mean duration of CD 4.5 yr.; 57% with CDAI>I50), 29 patients (49 %) underwent intestinal resection during the same period. The risk of surgery at 1 year in the two groups of patients was significantly different (p < 0.001). Only in 11 out of 32 operated patients (34%) was the increased BWT associated to bowel dilatation at US. Conclusion: Our data suggest that BWT 2 8 mm at US is a significant risk factor for intestinal resection over a short period of time in patients with Crohn’s disease.
Background:
102
INSTABILITY OF PATIENTS
BACKGROUND., Patients with Inflammatory Bowel Disease (IBD) have a well-establiihed risk for the development of colorectal cancer. Dysplasia is the morphological change identified as the premalignant precursor that precedes cancjer development. However the molecular bases o; carcinogenesis in IBD are not clearly defmed. Microsatellite instability (MSI) is a marker of genome-wide mutations and of DNA mismatch repair (MMR) deficiency. MS1 has been previously reported not only in malignant or premalignant tissues, but even in inflammatory non neopkstic conditions ofgastmintestinal tract. AIM. To investigate the frequency of MS1 in IBD in order to verify if MMFt deficiency may have a role in the carcinogenetic pathway of these diseases MATERIALS AND METHODS. Archivial bioptic or surgical colonic samples were selected t?om 46 IBD patients ( 37 Ulcerative Colitis, 7 Crobo’s disease, 2 “indefinite” IBD). In total 54 samples of non-neoplastic inflammatory / regenerative lesions, I6 of’ dysplasia, 5 of UC- associated cancer and CD- associated cancer were examined respectively. Afler extractiob DNA was amplified by PCR using 0.2 &I of ‘* P-lab&d dCTP incorporated into IO pl reaction mixture. PCR products were separated by elctrophoresis on denaturing 6% polyacrylamide gel and visualizated by autoradiography. The following markers were analysed: BAT-25, BAT-26, D2Sl23, TGFPRII, IGFIIR. MS1 was &Bned as the presence of at least one band shifl (novel allele) in the sample tissue that was not visible in the constitutional DNA (matching sample). RESULTS. No MS1 was found in dysplasia, UC- and CD- associated
cancers; only one case of non cancemus samples showed MS1 for BAT-26. CONCLUSIONS. MS1 is a rare event in the setting of IBD: IIowever the -~____
detection of mutation in microsatelliie sequences related to MSH2 gene
(BAT-26) in non-neoplastic tissues of UC indicates that a deficiency of MMR machinery may occasionally occur early in UC.
104 DISSOCIATION BETWEEN SERUM LEFTIN AND TNF- a LEVELS IN ENERGY METABOLISM REGULATION IN PATIENTS WITH INFLAMMATORY BOWEL DISEASE. E. Capristo, G. Addolorato, A. Scarfone, G. Valentini, G. Mingrone, M. Manco, C. Ancona, AV. Greco, G. Gasbarfini. Institute of Internal Medicine, Catholic University, Rome, Italy. Background and Aim: Patients with inflammatory bowel disease (IBD) are at high risk of malnutrition, as they have reduced fat mass, mcreased utilisation of lipids as energy substrate and difficulty in gaining weight. Adipose tissue is responsible for leptin and tumor necrosis factor (TF)a production, and these two cytokines were recently shown to be acttvely involved in energy balance in humans. The purpose of the present study was to evaluate the influence of serum leptin and TNF- o concentration on body composition and energy metabolism in patients affected by IBD. Maferial and Methods: Sixty-three patients, with either ileal or ileocolonic Crohn’s disease (CD) (n=39, 21MilSF) or ulcerative cqlitis (UC) (n=24, llM/13F9 were consecutively enrolled in the study. Pattents were not receiving steroids or nutritional support in the 2 weeks preceding the study. Disease activity was assessed by the simplified CD actlvtty index and the Tmelove and Witts criteria. Forty healthy subjects, comparable for age, height and gender were studied as controls. Fat (FM) and fatfree mass (FFM) were assessed by dual-energy X-ray abs?rpti!metry. Resting metabolic rate (RMR), carbohydrate and lipid oxldatlon were measured by open-circuit indirect calorimetry and 24-hr, yitrogen excretion. Serum leptin concentration was measured by radio-lmmuno assay and TNF- a was determined by an ELISA procedure. Results: Serum leptin level (@ml) was significantly lower in patients with CD (4.8~2.7) with respect to both UC (9.6~5.8; PcO.001) and control subjects (8.9+4.9; P
ANTITUMOR
NECROSIS
TBERAPY IN PATIENTS WITH FISTuLAs.
FACTOR ANTIBODY ACTIVEi CROBN’S
WITH
@NFL=)
DISEASE AND
Mattorana G, Oliva L, Orlando A, Ca& A and Cottone M. Divisione di Medicina e Pneumologia Clinica Medioa R Azienda Ospedaliera V. CerveIIo - PaIermo. Background and aim: Several studies have demonstrated the efficacy of infliximab, a monoclonal anti-tumor necrosis fkctor antibody in the treatment of patients (pts) with active Crohn’s disease (CD) compIicated or not with fitias, not responding to conventional therapies. The aim of this open-label study was to confirm the efficacy and the safety of infliximab in this subgroup of pts. Material8 and methods: 22 pts (8 males, 14 females) were included in the study, 10 with active treatment-resistaM CD, 6 with active treatmentresistant disease complicated with fistulas (perianal or abdominal) and 6 with fistulas only &&anal or abdominal). Pts without fitilaa received a single infusion of 5 mg of intliximab per kilogram of body weight, while pts with fistulas received three iafusions of 5 mg of intIiimab par kilogram of body weight at wee&s (wks) 0, 2 and 6. Clinical response or remission were defined as the reduction of more of 70 points or below 150 points of the CDAI score, respectively. For fistulas, response was defined as the reduction of 50 percent or more J?om baseline in the number of draining fistulas or of the quantity of drainage, remission as the closure of them. Results: at 2 wks ftom infusion all pts (16/16) treated for active disease obtained a clinical response and 10 out 16 (62.5%) the remission. A! 8 wks 9/16 (56.2%)
pts treated for active disease mantabed
the remission
and
6/16 (37.5%) a clinical response, while 6/12 (50%) pta asated for fiat&as manteincd the remission and the 5/12 (41.6%) the response while 202 (16.6%) didn’t have any response. Over 16 wks, 9112 (75%) pts treated for active disease and 13/16 (81.25%) treated for fist&a had a recurreoce in a median time of 18.3 wks (range, l-36 wks) after the tint infUsion. No serious adverse events were reported during infusions; two pts developed subocclusive bouts and one of them needed surgery. Conclusions: Clur data umftrtn that therapy with iniliximab has a role in the treatment of pts with active CD complicated or not with fist&s, with low incidence of adverse events but with an high rate of recurrences.